bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–02–08
88 papers selected by
Cédric Chaveroux, CNRS
  1. Fibrillarin/Nop1 perturbs RNA folding and assembly independently of liquid-liquid phase separation.
  2. Epitranscriptomic control of stress adaptations in Escherichia coli.
  3. The 5' Cap Epitranscriptome and Beyond: Natural and Engineered 5' Cap Modifications for Optimizing mRNA Therapeutics and Functional Studies.
  4. RNA Structure Coordinates Translation Across the Meiotic Program.
  5. Decreased tRNA abundance contributes to decreased translation elongation rate in a prolonged mitosis.
  6. Molecular chaperones and proteostasis regulation during cytosolic translation.
  7. A non-canonical role for HIF-1α: redirecting DGCR8 to the RNA exosome for snoRNA degradation and translational modulation.
  8. Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.
  9. Intronic polyadenylation-derived long noncoding RNA modulates nucleolar integrity and function.
  10. eRNAs Modulate mRNA Stability and Translation Efficiency to Bridge Transcriptional and Post-transcriptional Gene Regulation.
  11. Cytoplasmic poly-adenosine binding proteins modulate susceptibility of mRNAs to Pumilio-mediated decay.
  12. RNA exoribonucleases in E. coli.
  13. RK-33 inhibits the OC43 Coronavirus and induces stress granules via DDX3X-independent mechanisms.
  14. Epitranscriptomics as a Candidate Universal Modulator of Dormancy Transitions.
  15. Functional characterisation of tumour suppressor PDCD4 reveals previously undisclosed role in the control of cell adhesion.
  16. PTBP1 controls miRNA loading on target RNAs: lessons from the CyCoNP lncRNA.
  17. Redox-sensitive N6-methyladenosine RNA epitranscriptomic mechanisms in environmental stress and hazard.
  18. Inosine misincorporation into mRNA triggers the integrated stress response and activates an innate immune gene expression signature.
  19. Protocol for Efficient Ribodepletion of Euglena gracilis RNA.
  20. Small RNA Profiling in Trypanosomes.
  21. The circular RNA landscape: Biogenesis, functions, identification pipelines, and biomedical applications.
  22. ENY2 transcription and export complex 2 subunit deficiency induces nucleolar stress to inhibit tumor progression through NPM1/MDM2/p53-dependent and -independent responses.
  23. Stress-responsive roles of the C. neoformans human-like eIF3 complex.
  24. Poly(A) Profiling for Euglenozoans Using Oxford Nanopore Direct RNA Sequencing, Illustrated by the Example of Euglena gracilis.
  25. Structure-Guided Synthetic Peptide Targeting Nucleolus and Neural Progenitor Protein Nuclear Import Impairs Ribosome Biogenesis and Cancer Cell Proliferation.
  26. Struct2SeQ: RNA inverse folding with Deep Q-Learning.
  27. Regulation of mRNA decay and translation during the mammalian cell cycle.
  28. RALY promotes Epithelial-mesenchymal transition in Hepatocellular carcinoma by regulating Snail.
  29. Ribosomal Protein bL27 Protects Translating Ribosomes from tmRNA-SmpB.
  30. m5c-modified LINC01094 participates in epithelial-mesenchymal transition and metastasis of cervical cancer cells via the ZNF582-SIRT1/p53 axis.
  31. TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.
  32. Starvation-independent alarmone production inhibits translation through GTP depletion.
  33. Ribosome-associated quality control of aberrant protein production during amino acid limitation.
  34. Phosphorylation-dependent regulation of serine/arginine-rich proteins and U2AF1 interactions in early spliceosome assembly.
  35. Significance of MALAT1 long non-coding RNA and miR-20a-5p in regulating epithelial mesenchymal transition in luminal breast cancer patients.
  36. Distribution and structural diversity of Type IV internal ribosome entry sites.
  37. Maize ZmBCCIP facilitates cleavage at the A3 site in pre-rRNA processing and is crucial to seed development and vegetative growth.
  38. AHCY: A Metabolic Gatekeeper at the Interface of Methylation, Redox Balance, and Cellular Stress Response.
  39. Nuclear speckles are regulatory hubs for viral and host mRNA expression during HSV-1 infection.
  40. Human CCR4-NOT suppresses pervasive transcription and retrotransposable elements.
  41. Critical roles of m6A demethylase FTO in ovarian aging.
  42. Exosomal CeRNAs from the tumor microenvironment: hidden drivers of colorectal cancer progression.
  43. Programmed Double-stranded RNA Formation Enables Meiotic Stage Transitions.
  44. Transcriptional and metabolic stasis define desiccation-induced dormancy in the soil bacterium Arthrobacter sp. AZCC_0090 until water vapor initiates resuscitation.
  45. Characterization of the Citrus Leaf Blotch Virus AlkB Domain and Its Involvement in Viral Accumulation.
  46. The repertoire of binding specificities for two repeats in the RNA-binding domain of Drosophila Pumilio.
  47. Molecular messengers of the brain: tRNA-derived small RNAs at the crossroads of brain development and neurodevelopmental disorders.
  48. Neural microexons contain lengthened sequence and extended RNA structure between the branchpoint and splice site motif.
  49. Mapping SBiP1 protein-protein interactions in Symbiodinium microadriaticum CassKB8 using the Yeast Two-Hybrid assay and structural prediction.
  50. Structure under stress: conserved RNA structure in plant interaction with the environment.
  51. PCLIPtools: a robust framework for identifying RNA-protein interaction sites from PAR-CLIP experiments.
  52. Regulation of tension-dependent localization of LATS1 and LATS2 to adherens junctions.
  53. Cleavage of mRNAs by a minority of pachytene piRNAs improves sperm fitness.
  54. The eIF5-Mimic Protein 5MP1: A Regulator of Translation Stringency and a Multifaceted Oncogene.
  55. K92 Lactylation of YBX1 orchestrates m5C RNA recognition to facilitate colorectal Cancer progression.
  56. Circular RNAs in intervertebral disc degeneration: Current insights into mechanisms and therapeutic potentials (Review).
  57. Chemical Biology Tools for Decoding the Cell Surface GlycoRNA.
  58. Genome-wide analysis of long non-coding RNAs and mRNAs in lung adenocarcinoma with pulmonary thromboembolism.
  59. Live-cell single-molecule dynamics of eukaryotic RNA polymerase machineries.
  60. LncRNA TMPO-AS1 aggravates the cisplatin resistance in cervical cancer via miR-140-5p/DNMT1 axis-mediated DNA methylation of KLK10.
  61. Small RNA sequencing of human sural nerves identifies widespread microRNA dysregulation and Schwann cell-localized miR-21-5p in diabetic peripheral neuropathy.
  62. A Bifunctional Small Molecule Degrader of the Long Noncoding RNA MALAT1 Triplex.
  63. NEAT1/miR-181a-5p/HMGB1 Axis Regulates Macrophage Polarization and Inflammation in Sepsis Models.
  64. Super-resolved, three-dimensional spatial transcriptomics reveals cell-type and brain-region-specific modulation of key epitranscriptomic switches following adolescent alcohol exposure.
  65. Systematic fusion transcript discovery in mantle cell lymphoma using long-read sequencing.
  66. circIRES-DAF: A dual-attenuation fusion framework for identification of internal ribosome entry sites in circular RNAs.
  67. Epimutations driven by RNAi or heterochromatin evoke transient antimicrobial drug resistance in pathogenic Mucor fungi.
  68. LNC01089-LINC00963/miR-1244-5p/IGF1 ceRNA Axis Regulate FOXO Signaling Pathway in Breast Cancer Patients: A Biomarker Discovery Investigation.
  69. Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.
  70. Noncoding RNAs are indispensable architects and regulators of biomolecular condensates.
  71. The METTL3-IGF2BP3 axis drives osteosarcoma progression by enhancing ID1 mRNA stability.
  72. mRNA translation and proteasomal degradation in health and neurological disease.
  73. Genome-wide profiling of RNA 2'-O-methylation in neurons and identification of orphan snoRNA targets.
  74. Cullin-3 adaptor SHKBP1 inhibits SQSTM1/p62 oligomerization and Keap1 sequestration.
  75. The role of Alanyl-tRNA synthetase 1 lactylation in tumors and other diseases.
  76. Re‑thinking translation quality control in bacteria: from trans‑translation to collided‑disome surveillance.
  77. Pseudogene-derived long non-coding RNAs GSM3P1/Gstm2-ps1 exacerbate sepsis-associated acute kidney injury by suppressing their parent gene translation.
  78. AquIRE reveals the mechanisms of clinically induced RNA damage and the conservation and dynamics of glycoRNAs.
  79. Integrative analysis for identification of key miRNA-mRNA regulatory axes in esophageal cancer and preliminary validation of the regulatory role of miR-15b-5p/BTG2 therein.
  80. The role of non-coding RNAs in Staphylococcus aureus infections: mechanisms, biomarkers, and therapeutic implications.
  81. Nucleolar Protein Nop2 Promotes Neural Differentiation by Regulating Ribosome Biogenesis-Related Processes.
  82. Exosome-Derived Circular RNAs in Colorectal Cancer: Emerging Roles in Tumorigenesis, Diagnosis, and Therapy.
  83. Nuclear DNA of plastid origin (NUPTs), neglected driver of genome variation and evolutionary innovation.
  84. Tomato RING Type E3 Ligases, SlRGLGs, Positively Regulate the Dehydration Stress Response.
  85. POM121 Drives Gastric Cancer Progression via the mTOR/p70S6K Signaling Axis.
  86. Single-nucleus transcriptomics reveal stress-related prefrontal activation in Tourette disorder.
  87. A combined computational and functional approach identifies FBLN5 as an amino acid metabolism-related gene and suppressing colorectal cancer progression.
  88. Exploring the regulatory potential of RNA structures in 202 cyanobacterial genomes.
  1. Nucleic Acids Res. 2026 Jan 22. pii: gkag065. [Epub ahead of print]54(3):
    Fibrillarin/Nop1 perturbs RNA folding and assembly independently of liquid-liquid phase separation.
    Yunsheng Sun, Sarah A Woodson.
      The liquid-liquid phase-separated environment of the eukaryotic nucleolus is proposed to benefit ribosome assembly by chaperoning rRNA folding and spatially sorting ribosome assembly factors. Yet, how microscopic interactions within the condensed nucleolus affect rRNA folding and assembly is largely unknown. We used single-molecule fluorescence microscopy to monitor folding of the Tetrahymena ribozyme and an rRNA domain inside and outside droplets of Nop1/fibrillarin, a major constituent of the nucleolus. We found that Nop1 destabilizes tertiary docking of the ribozyme substrate helix equally in dilute and condensed phases, depending only on transient molecular interactions between Nop1 and the ribozyme. Nop1 binding also inhibits rRNA unwinding by a DEAD-box helicase and nonspecific binding of a ribosomal protein. Over time, nonspecific interactions with Nop1 are outcompeted by specific RNA-protein assembly. Our results illustrate how RNA-binding proteins residing in the nucleolus tune RNA folding stability while permitting assembly of native ribosomal complexes.
    DOI:  https://doi.org/10.1093/nar/gkag065
  2. Nucleic Acids Res. 2026 Jan 22. pii: gkag042. [Epub ahead of print]54(3):
    Epitranscriptomic control of stress adaptations in Escherichia coli.
    Sebastián Riquelme-Barrios, Siobhan A Cusack, Luis Rivera-Montero, Leonardo Vásquez-Camus, Korinna Burdack, Sophie Brameyer, Maximilian Berg, G Nur Yeşiltaç-Tosun, Stefanie Kaiser, Pascal Giehr, Kirsten Jung.
      The impacts of various stressors on bacterial systems have been studied at the phenotypic, transcriptional, and translational levels during the early stress response. However, the contributions of RNA modifications during stress adaptation remain largely unexplored. Here, we map the epitranscriptomic changes of Escherichia coli after exposure to oxidative and acid stress using direct RNA sequencing of mRNA, rRNA, pre-tRNA, and tRNA, combined with mass spectrometry, deletion mutant phenotyping, and single-nucleotide PCR. We identified widespread, dynamic mRNA modifications that include central metabolism transcripts and increased levels of rRNA methylations (m4Cm and m5C) under both stresses, with potential consequences for translation. In uncharged pre-tRNAs, stress-specific modifications via the Mnm and Q pathways accumulated at the wobble position; these modifications proved crucial for survival. Together, these findings reveal a multifaceted layer of post-transcriptional regulation, establishing the first comprehensive view of the bacterial epitranscriptome during the early stress response.
    DOI:  https://doi.org/10.1093/nar/gkag042
  3. ChemMedChem. 2026 Jan;21(2): e202500826
    The 5' Cap Epitranscriptome and Beyond: Natural and Engineered 5' Cap Modifications for Optimizing mRNA Therapeutics and Functional Studies.
    Greta Charlotte Dahm, Melissa Pieper, Helena Schepers, Andrea Rentmeister.
      Eukaryotic mRNAs made by in vitro transcription have emerged as medical modalities for vaccination and protein replacement therapy. The 5' cap is an essential feature of eukaryotic mRNAs providing stability, reducing immunogenicity, and serving as starting point for translation initiation. The "cap epitranscriptome" comprises several natural 5' cap modifications that can impact mRNA interactions and fate. Manipulating this privileged structure provides a powerful handle to optimize mRNA properties and to build a toolbox for investigating and controlling mRNA-related processes. In this article, the impact of natural 5' cap modifications on mRNA translation, immunogenicity, and stability is highlighted. Then, it is shown how non-natural 5' cap modifications have been used to manipulate and optimize various mRNA properties. Finally, non-natural modifications can equip mRNA with reactive handles, which provide a toolbox for studying interactions and controlling the function of mRNAs.
    Keywords:  5′ cap; AdoMet; RNA modifications; mRNA; methylation
    DOI:  https://doi.org/10.1002/cmdc.202500826
  4. bioRxiv. 2026 Jan 22. pii: 2026.01.15.699792. [Epub ahead of print]
    RNA Structure Coordinates Translation Across the Meiotic Program.
    Hao Wu, Caini Zhou, Shoucheng Du, Simon Felder, Yihan Xiong, Kevin M Weeks, Yun Bai.
      mRNA structure is a key determinant of translation efficiency for individual transcripts, yet its role in coordinating complex physiological processes remains elusive. We profiled mRNA structures during yeast meiosis, deriving a high-resolution structurome covering ∼70% of annotated mRNAs, with multi-time-point measurements for 2,084 mRNAs. Transcripts upregulated during meiosis generally have flexible structures that enhance translation. In contrast, complex structures impede translation during meiosis by reducing ribosome flux in coding regions and promoting alternative initiation, including in the highly abundant transcript CCW22 . We uncovered a high-low-high oscillation in cytoplasmic RNA helicase levels, which dynamically reprograms cell-wide translational preferences for RNA structure, shaping the temporal translation of hundreds of mRNAs. Disrupting RNA structure in CCW22 or altering Ded1p helicase levels interfered with meiotic proteostasis, hindering meiosis progression. Our study reveals that the concerted action of RNA structure and RNA helicases coordinates cell-wide translation dynamics, highlighting a potent post-transcriptional regulatory layer during meiosis when transcription is limited by chromosome condensation.
    DOI:  https://doi.org/10.64898/2026.01.15.699792
  5. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699274. [Epub ahead of print]
    Decreased tRNA abundance contributes to decreased translation elongation rate in a prolonged mitosis.
    Emily Sparago, Ryan Johnston, Shawn M Lyons, Michael D Blower.
      Cells undergo dramatic structural rearrangements upon entering mitosis. In addition, the biochemistry of mitotic cells is dramatically altered, including a significant decrease in protein synthesis. The majority of studies of mitotic translation have used cells synchronized by cell cycle altering drugs in transformed cells and much less is known about mitotic translation in primary cells under native conditions. Previous work has found that mitosis activates the integrated stress response (ISR) to trigger eIF2α phosphorylation, but little is known about the input for this response. In this study, we focus on mitotic translational regulation in an immortalized, non-transformed cell line. We confirm decreased mitotic protein synthesis in primary cells and under native conditions. Additionally, we confirm activation of the ISR by phosphorylation of eIF2α during both normal and prolonged mitosis. Interestingly, we also find that decreased translational elongation during mitosis, as evidenced by increased eEF2 phosphorylation and a slower elongation rate. Analysis of mitotic ribosome profiling data revealed an increase in pausing at Alanine-GCG codons during mitosis and a decreased abundance of its cognate tRNA-Ala CGC by northern blotting. Decreased tRNA-Ala CGC is likely sustained by the inability to synthesize additional tRNA due to RNAPol III inhibition in mitosis, yielding an stronger effect with an increased time in mitosis. These results suggest that decreased translation elongation in mitosis triggers inhibition of initiation to decrease global protein synthesis.
    DOI:  https://doi.org/10.64898/2026.01.13.699274
  6. FEBS J. 2026 Jan 30.
    Molecular chaperones and proteostasis regulation during cytosolic translation.
    Ulrike Topf.
      Molecular chaperones ensure that proteins attain their mature state by assisting in proper folding, preventing aggregation, refolding misfolded proteins, and targeting irreparably misfolded proteins for degradation. This comprehensive role is vital for maintaining cellular homeostasis and responding to stress conditions. In this review, I focus on the multifaceted roles of chaperones in regulating protein production, spanning from ribosome biogenesis to controlling translation rate and translation fidelity through the folding of essential translation factors in eukaryotes. I discuss the function of ribosome- and nascent chain-bound molecular chaperones for the translation machinery and protein synthesis. Finally, I highlight findings on the interdependence of the two pillars of protein homeostasis when cells experience cellular stress and organisms face pathophysiological conditions.
    Keywords:  chaperones; folding; proteostasis; ribosome biogenesis; translation
    DOI:  https://doi.org/10.1111/febs.70419
  7. Nucleic Acids Res. 2026 Jan 22. pii: gkag070. [Epub ahead of print]54(3):
    A non-canonical role for HIF-1α: redirecting DGCR8 to the RNA exosome for snoRNA degradation and translational modulation.
    Jie-Ning Li, Ming-Yang Wang, Chiao Lo, Laising Yen, Chien-Hung Yu, Yu-Jhen Lyu, Pai-Sheng Chen.
      The RNA exosome complex (EC) is a multi-protein complex responsible for RNA surveillance. Guided by specific adaptor factors, the EC recognizes RNA species as substrates for processing or degradation. Although its basic structure and components are documented, the regulatory mechanisms that enable this fundamental machinery to respond to biological signals remain unclear. Here, we demonstrate that hypoxia-inducible factor 1-alpha (HIF-1α) brings DGCR8 to associate with the EC in an RNA-independent manner and shifts DGCR8's RNA-binding preference toward small nucleolar RNAs (snoRNAs). This circuit triggers the snoRNA degradation without affecting their transcription or processing, ultimately impairing ribosomal RNA (rRNA) modifications such as pseudouridylation and 2'-O-methylation, compromising rRNA processing, and reducing global translation efficiency. The HIF-1α-mediated reconfiguration of DGCR8 with EC involves the release of DGCR8 and RRP6 from the nucleoli to the nucleoplasm and is conserved across multiple species, including worms and flies. Under conditions where HIF-1α is induced, we found that the MC-to-EC switch dynamically responds to hypoxic conditions and growth factor signals. In conclusion, the discovery of MC-to-EC switch reveals a multifaceted function of HIF-1α in noncoding RNA regulation, also emphasizing its non-transcriptional impact on the DGCR8-EC-mediated snoRNA degradation pathway and its consequential effects on rRNA modifications and translation, providing new insights into RNA homeostasis regulation.
    DOI:  https://doi.org/10.1093/nar/gkag070
  8. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2526598123
    Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.
    Yixin Liu, Jagannath Misra, Debarshi Ryan Bhowmik, Brady O'Boyle, Kirk A Staschke, Natarajan Kannan, Ronald C Wek, Natalia Jura.
      The general control nonderepressible 2 (GCN2) is a conserved stress-responsive protein that plays a critical role in restoring cellular homeostasis in the integrated stress response (ISR). In response to amino acid starvation or ribosome stalling and collisions, GCN2 phosphorylates the translation initiation factor eIF2α, conferring translational control to alleviate stress. GCN2 is a multidomain protein, containing a tandem kinase domain (KD) and a catalytically inactive pseudokinase domain (ψKD). Stress-induced activation of the kinase domain requires allosteric regulation and dimerization mediated by its regulatory domains. While the pseudokinase domain is essential for GCN2 function in yeast, its mechanistic role remains unclear and underexplored in other organisms. Here, we present the first crystal structure of the human GCN2 ψKD, revealing its distinct structural features. The structure visualizes an insertion N-terminal to helix αC unique to the GCN2 ψKD that interacts with the pseudoactivation loop, stabilizing an inactive conformation. Further structural analysis shows that the ψKD forms a dimer in the crystal lattice via a network of hydrophobic and electrostatic interactions spanning both the N- and C-lobes. Mutations that disrupt the dimer interface reduced downstream ATF4 expression that is important for stress adaptation, underscoring the functional significance of the GCN2 ψKD dimer in regulating GCN2 activity. Complementary AI-guided structure predictions indicate that the dimeric GCN2 ψKD architecture is conserved across evolution. These results support the role of ψKD dimerization as a regulatory feature in GCN2-mediated ISR signaling.
    Keywords:  ATF4 translation; GCN2; dimerization; integrated stress response; pseudokinase
    DOI:  https://doi.org/10.1073/pnas.2526598123
  9. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2514521123
    Intronic polyadenylation-derived long noncoding RNA modulates nucleolar integrity and function.
    Sumana Mallick, Pranita Borkar, Jaspreet Thind, Daniel Chung, Taylor Hubbs, Irtisha Singh.
      RNAs transcribed from protein-coding gene loci are widely assumed to be translated into proteins. However, intronic polyadenylation (IPA) occurring near the transcription start site or within early introns can generate noncoding RNAs derived from protein-coding loci. Despite their abundance, the functional roles of such RNAs remain largely unexplored. In this study, we investigated one such noncoding RNA, CUL1-IPA, transcribed from the CUL1 gene locus. Our study revealed that CUL1-IPA is an RNA polymerase II-dependent IPA isoform that is polyadenylated, stable, and translocates to the nucleolus. Functional characterization demonstrated CUL1-IPA to play a critical role in maintaining nucleolar integrity. RNA-protein interaction assay identified GPATCH4 and NOP58, nucleolar proteins involved in ribosomal RNA (rRNA) processing, as binding partners of CUL1-IPA. Consistent with its localization and interactions, loss of CUL1-IPA led to the reduction in rRNA levels and consequent decrease in overall protein synthesis. This effect on rRNA levels could be reversed by reintroducing CUL1-IPA, confirming its functional importance. Furthermore, as nucleolar stress is known to affect cell cycle progression, we found that CUL1-IPA loss resulted in G2/M cell cycle phase arrest. Moreover, reduced CUL1-IPA expression was associated with improved survival outcomes in cancer patients. Together, our findings demonstrate that CUL1-IPA, an IPA-derived long noncoding RNA (lncRNA), forms an RNA-protein complex in the nucleolus to support nucleolar structure and function. This study provides an insight into the biological function of a lncRNA originating from a protein-coding gene and highlights the broader significance of IPA-derived noncoding RNAs as regulatory molecules.
    Keywords:  intronic polyadenylation; long noncoding RNA; nucleolus
    DOI:  https://doi.org/10.1073/pnas.2514521123
  10. RNA. 2026 Feb 03. pii: rna.080681.125. [Epub ahead of print]
    eRNAs Modulate mRNA Stability and Translation Efficiency to Bridge Transcriptional and Post-transcriptional Gene Regulation.
    Rene Kuklinkova, Natalia Benova, Chinedu Anthony Anene.
      Enhancer RNAs (eRNAs) are best known for their role in transcriptional regulation, where they facilitate enhancer-promoter communication and chromatin remodelling. Yet growing evidence suggests that their function may extend beyond the nucleus. Here, we systematically characterise the decay kinetics of eRNAs across human cell types using time-resolved transcriptomics and kinetic modelling. While most eRNAs undergo canonical exponential decay, a subset displays non-linear dynamics, suggesting context-dependent degradation mechanisms. Perturbation of core decay regulators, including components of the m⁶A and CCR4-NOT pathways, reveals that eRNA stability is modulated by a patchwork of pathways governing mRNA turnover. Integrating transcriptome-wide ribosome profiling, RNA-Seq, and half-life data, we identify eRNAs associated with changes in mRNA stability and translation efficiency of their target protein-coding transcripts. Functional validation of one such eRNA, en4528, shows it regulates CDKN2C mRNA independently of transcription and impacts cell migration. These findings redefine the regulatory scope of eRNAs, positioning them as active participants in post-transcriptional gene control and cellular behaviour. The resulting decay profiles and regulatory annotations have been incorporated into the eRNAkit database, available at https://github.com/AneneLab/eRNAkit, enhancing its capacity for integrative systems-level analysis of eRNA function.
    Keywords:  Enhancer RNA; Post-transcriptional regulation; RNA–RNA interaction; eRNAs; mRNA stability
    DOI:  https://doi.org/10.1261/rna.080681.125
  11. Nucleic Acids Res. 2026 Feb 05. pii: gkag075. [Epub ahead of print]54(4):
    Cytoplasmic poly-adenosine binding proteins modulate susceptibility of mRNAs to Pumilio-mediated decay.
    Katherine M McKenney, Carmen Hernandez-Perez, Elise B Dunshee, John M Pum, Anna J DesMarais, Robert P Connacher, Aaron C Goldstrohm.
      The cytoplasmic fate of messenger RNAs (mRNAs) is dictated by the balance of translation and mRNA degradation, governed in part by the 3' poly-adenosine tail and cytoplasmic poly(A)-binding proteins (PABPCs). Deadenylases remove poly(A) to initiate mRNA decay, while sequence-specific RNA-binding factors, including Pumilio proteins (PUM1 and PUM2), modulate these processes. We investigated how human PUM1&2 repress target mRNAs by accelerating their degradation. We found that the poly(A) tail plays a central role in PUM repression, dependent on the interplay of deadenylases and PABPCs. PUM-mediated repression requires the CCR4-NOT deadenylase but not the poly(A) nuclease. PUMs associate with and require PABPC1 and PABPC4 to repress. In the absence of PABPCs, both PUM targets and non-targets become unstable, bypassing PUM control. Increasing PABPC inhibits PUM activity in a concentration-dependent manner by stabilizing poly(A) mRNAs. The results support a Goldilocks principle, wherein PABPC abundance tunes the response of mRNAs to PUM-mediated repression through protection of poly(A) from deadenylation. We propose that this principle may apply to other poly(A) dependent regulatory factors. Variation of PABPC levels across tissues and development suggests physiological relevance for this mechanism.
    DOI:  https://doi.org/10.1093/nar/gkag075
  12. Arch Microbiol. 2026 Feb 02. 208(4): 161
    RNA exoribonucleases in E. coli.
    Ashaq Hussain, Malay Kumar Ray.
      Ribonucleases are associated with processing and degradation of diverse RNA substrates. These enzymes act on the substrate with high specificity, often in association with their interacting partners. Functionally redundant exoribonucleases are indispensable for maintaining the physiological homeostasis under normal and challenging conditions for growth. In this review article, we will report the comprehensive role of exoribonucleases in RNA metabolism especially the processing, maturation and degradation. Structural aspects of exonucleases, tendency to oligomerize, and their association with other cellular proteins that facilitate their interaction with RNA substrate and modulate their activity have also been highlighted. Transcription and post-transcriptional regulatory mechanisms of gene expression that are crucial for maintaining levels of exoribonuclease expression has been briefly discussed.
    Keywords:  Active site; Degradation; Exoribonuclease; Exosome; Maturation; Polarity; Polyadenylation; Processing; Processivity; RNA; Secondary structure
    DOI:  https://doi.org/10.1007/s00203-026-04718-8
  13. RNA. 2026 Jan 30. pii: rna.080931.125. [Epub ahead of print]
    RK-33 inhibits the OC43 Coronavirus and induces stress granules via DDX3X-independent mechanisms.
    Cody J S Hecht, Roy R Parker.
      DDX3X is a human DEAD-Box RNA helicase with multiple functions in RNA metabolism. Previous studies have suggested that DDX3X is an important pro-viral host factor for numerous RNA viruses, including HIV, HCV, and SARS-CoV-2, and may be targetable with inhibitors such as RK-33 for therapeutic benefit. In exploring the role of DDX3X and its homolog DDX3Y in coronavirus replication, we found that the DDX3X inhibitor RK-33 inhibits propagation of the OC43 coronavirus through a DDX3X/DDX3Y-independent mechanism. Knockdowns of DDX3X or DDX3X and DDX3Y had little effect on OC43 growth in multiple cell lines, yet RK-33 treatment potently reduced OC43 replication in the presence or absence of DDX3 proteins. We observed that RK-33 stimulates the integrated stress response independently of DDX3 proteins to cause stress granule formation, although this is not the primary mechanism by which RK-33 suppresses OC43. Together, our results show that DDX3 proteins are likely not a general pro-coronaviral host factor, and caution should be used in interpreting results with RK-33 given its off-target activity.
    Keywords:  DDX3X; Integrated stress response; OC43; RK-33; stress granules
    DOI:  https://doi.org/10.1261/rna.080931.125
  14. Ecol Evol. 2026 Feb;16(2): e73007
    Epitranscriptomics as a Candidate Universal Modulator of Dormancy Transitions.
    Ehsan Pashay Ahi.
      Dormancy has been widely recognized as an evolutionarily conserved strategy that enables cells and organisms to endure environmental stress, resource scarcity, or developmental arrest. While transcriptional regulation has been extensively studied in this context, increasing attention is being directed toward post-transcriptional mechanisms that allow rapid and energy-efficient control of gene expression. Among these, epitranscriptomic modifications, chemical marks added to RNA, have emerged as dynamic and reversible regulators of mRNA fate. In this perspective, it is proposed that RNA modifications can play a central role in establishing and maintaining dormancy across diverse biological systems. Evidence from plant seeds, microbial persisters, stem cells, and dormant cancer cells suggests that specific RNA marks, such as N6-methyladenosine (m6A), influence mRNA stability, translation, and localization in a context-dependent manner. It is argued that these modifications serve as a molecular interface between environmental signals and cellular responses, fine-tuning the transition between active and paused states. This article presents a unifying model, grounded in epitranscriptomics, in which RNA modifications modulate entry into, maintenance of, and exit from dormancy across taxa by tuning mRNA stability, translation, and localization-an underexplored regulatory layer in inactive states-and highlights key mechanistic insights, evolutionary parallels, and outstanding questions at the intersection of RNA regulation and cellular dormancy.
    Keywords:  N6‐methyladenosine (m6A); RNA chemical modifications; dormancy; eco‐evolutionary adaptation; epitranscriptomics
    DOI:  https://doi.org/10.1002/ece3.73007
  15. Nucleic Acids Res. 2026 Jan 22. pii: gkag071. [Epub ahead of print]54(3):
    Functional characterisation of tumour suppressor PDCD4 reveals previously undisclosed role in the control of cell adhesion.
    Veronica Dezi, Robert F Harvey, Tom Smith, Cameron H Cole, Mariavittoria Pizzinga, Mark Stoneley, Gavin D Garland, Emilie Horvilleur, Lajos Kalmar, Ritwick Sawarkar, Kathryn S Lilley, Anne E Willis.
      PDCD4 is a multifunctional RNA-binding protein that has tumour suppressor function. To more fully understand how dysregulation of this protein contributes to carcinogenesis, we have carried out a comprehensive analysis of the role of PDCD4 in RNA metabolism in untransformed epithelial cells. We show that PDCD4 predominantly localises in the nucleus, where it interacts with proteins involved in a range of different RNA metabolic processes. We find that PDCD4 knockdown is associated with significant changes in either the expression or splicing of a number of transcripts, although it appears to have an indirect role in splicing. We identified the RNA targets of PDCD4 using iCLIP and observed an enrichment in binding to transcripts encoding cell adhesion and structural proteins. Consistent with these data, we show that PDCD4 acts as a general regulator of cell adhesion, which in a tumour setting would increase the metastatic potential of cells, and demonstrate that the nuclear localisation of PDCD4 is crucial in this process. Overall, the information obtained in untransformed cells provides a new perspective for the role of PDCD4 as a tumour suppressor.
    DOI:  https://doi.org/10.1093/nar/gkag071
  16. RNA. 2026 Feb 03. pii: rna.080705.125. [Epub ahead of print]
    PTBP1 controls miRNA loading on target RNAs: lessons from the CyCoNP lncRNA.
    Alessandro Grazzi, Fabio Desideri, Irene Bozzoni.
      The concerted action of regulatory RNA and RNA binding proteins (RBPs) provide cells with highly versatile and transient tools to fine tune gene expression in a broad variety of cellular systems (Unfried and Ulitsky 2022, Hentze et al. 2018, Suzuki et al. 2018). In this work, we explore the function of a specific interaction between PTBP1 and the cytoplasmic long non-coding RNA (lncRNA) CyCoNP, highly expressed in neural progenitors (Desideri et al. 2024), in which the RBP regulates the abundance of the lncRNA by a miRNA-mediated mechanism. PTBP1 is a well-known splicing regulator, although limited and peculiar examples of its involvement in other cellular processes, such as IRES-dependent translation and miRNA recognition of target RNAs, have been described (Dorn et al. 2023, Kim et al. 2021). We have recently characterized CyCoNP lncRNA as a regulator of NCAM1, which acts through a mechanism that involves direct RNA-RNA interaction with NCAM1 mRNA, balancing the availability and the localization of miR-4492 in its vicinity (Desideri et al. 2024). Here we expand the repertoire of molecular players acting in this circuitry by describing a direct interaction between PTBP1 and CyCoNP lncRNA. Through endogenous RNA purification, protein immunoprecipitation and exploiting CyCoNP mutant constructs we found that PTBP1, when interacting with CyCoNP, hampers miR-4492 binding to the lncRNA and in turn impedes its regulation on NCAM1 mRNA. This work aims to expand the biochemical characterization of regulatory networks relying on RBPs and their cognate target RNAs, highlighting the relevance of the analysis of the subcellular environment for each case of study.
    Keywords:  Cytoplasmic PTBP1; NcRNA; LncRNA; RNA-Protein interactions; RNA-RNA interactions; miRNA loading
    DOI:  https://doi.org/10.1261/rna.080705.125
  17. Redox Biol. 2026 Jan 07. pii: S2213-2317(26)00015-7. [Epub ahead of print]90 104017
    Redox-sensitive N6-methyladenosine RNA epitranscriptomic mechanisms in environmental stress and hazard.
    Yán Wāng.
      Oxidative stress is a central driver of environmental stress responses and disease pathogenesis. Increasing evidence indicates that RNA epigenetic regulation, particularly N6-methyladenosine (m6A) modification, represents a critical interface linking redox imbalance to cellular dysfunction. Arsenic, a prototypical redox-active toxicant, provides a robust model for understanding how environmental oxidative stress disrupts m6A-mediated post-transcriptional control. Recent studies demonstrate that arsenic-induced redox perturbation reshapes the expression and activity of m6A writers (METTL3/METTL14), erasers (FTO/ALKBH5), and readers (YTHDF/YTHDC families), leading to widespread alterations in mRNA stability, translation, and metabolic reprogramming. Mechanistic findings from cellular and animal models implicate m6A-dependent pathways in modulating oxidative stress responses, mitochondrial function, inflammation, and senescence-biological processes fundamental to redox biology. These insights reveal that m6A is not merely a downstream marker of stress, but an active mediator of adaptive and maladaptive responses to redox disruption. Despite significant progress, population-level evidence and high-resolution mapping of RNA modifications under oxidative conditions remain limited. Future work integrating advanced epitranscriptomic profiling, multi-omics approaches, and exploration of additional RNA modifications (m7G, m1A, m5C) will be essential for defining how redox-sensitive RNA regulation shapes disease risk. Collectively, this review highlights m6A modification as a dynamic regulatory node connecting environmental redox stress to gene expression control, providing new mechanistic insight and potential targets for intervention in redox-related diseases.
    Keywords:  Environmental exposure; Epigenetic; Epitranscriptomics; RNA methylation; Reproduction; Transgenerational inheritance
    DOI:  https://doi.org/10.1016/j.redox.2026.104017
  18. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699979. [Epub ahead of print]
    Inosine misincorporation into mRNA triggers the integrated stress response and activates an innate immune gene expression signature.
    Jacob H Schroader, Naa N Adade, Emmanuel E Adade, Mark A Bratslavsky, Hannah K Shorrock, Bradley R Smith, Ting Zhou, Steven Lotz, Taylor Bertucci, Sally Temple, Alex M Valm, Cara T Pager, J Andrew Berglund, Mark T Handley, Gabriele Fuchs, Kaalak Reddy.
      The inosine triphosphate pyrophosphatase (ITPase) enzyme restricts levels of the non-canonical nucleotides (deoxy)inosine triphosphate (dITP/ITP) and prevents their aberrant misincorporation into nucleic acids. ITPase deficiency is associated with dilated cardiomyopathy and epileptic encephalopathy in humans and is usually fatal in infancy. It leads to pronounced inosine misincorporation into RNA but the cellular consequences of this misincorporation are not well understood and the pathogenic basis of ITPase deficiency remains unknown. Here we show that cellular transfection of mRNA with inosine misincorporation activates the integrated stress response (ISR) with an innate immune gene expression signature. This stress response triggers stress granule formation and is modulated by the double stranded RNA sensor protein Kinase R (PKR). Inosine nucleoside treatment of ITPase-deficient cells leads to endogenous inosine misincorporation into mRNA and activation of the ISR. Further, differentiation of human ITPase-deficient induced pluripotent stem cells into neurons results in a low-level stress response. Thus, our study establishes inosine misincorporation into mRNA as an unappreciated form of cellular stress. This is normally prevented by the ITPase enzyme, with implications for the pathogenesis of ITPase deficiency.
    DOI:  https://doi.org/10.64898/2026.01.16.699979
  19. Methods Mol Biol. 2026 ;3014 27-36
    Protocol for Efficient Ribodepletion of Euglena gracilis RNA.
    Natalia Gumińska, Paweł Hałakuc, Bożena Zakryś, Rafał Milanowski.
      Ribosomal RNA (rRNA) constitutes a large proportion of total RNA, often making it necessary to deplete rRNA to enrich other RNA species for downstream applications. Ribodepletion is particularly challenging in Euglena gracilis, as its large subunit (LSU) rRNA is inherently fragmented into 14 stable pieces, rendering standard depletion methods ineffective. To address this limitation, we developed a targeted depletion strategy employing sequence-specific oligonucleotides and streptavidin beads to selectively remove rRNA while preserving other RNA species. Furthermore, the modular design of our oligonucleotide probe system facilitates straightforward adaptation to other euglenids and euglenozoans, thereby advancing transcriptomic research in this evolutionarily significant protist group.
    Keywords:  Euglena gracilis; Euglenids; Ribodepletion; Ribosomal RNA; rRNA
    DOI:  https://doi.org/10.1007/978-1-0716-5146-9_2
  20. Methods Mol Biol. 2026 ;3013 235-244
    Small RNA Profiling in Trypanosomes.
    Florencia Díaz-Viraqué, Gonzalo Greif, María Rosa García-Silva, Carlos Robello.
      Trypanosomatids express a diverse repertoire of small non-coding RNAs despite lacking the canonical RNA interference machinery in most species. These small RNAs-including fragments derived from tRNAs, rRNAs, and other non-coding sources-are thought to play regulatory roles in parasite biology and host-parasite interactions. In this chapter, we provide a detailed protocol for the isolation, library preparation, sequencing, and computational analysis of small RNAs in trypanosomes. The method is optimized to preserve short RNA species while minimizing artifacts such as adaptor dimers and concatamerization. It includes quality control and size selection steps to ensure the reproducibility and high quality of the libraries, allowing the study of the transcriptome of small RNAs in these parasites.
    Keywords:  Next-generation sequencing; Non-coding RNAs; Protist parasites; Small RNAs; Trypanosomes
    DOI:  https://doi.org/10.1007/978-1-0716-5142-1_13
  21. Noncoding RNA Res. 2026 Jun;18 39-51
    The circular RNA landscape: Biogenesis, functions, identification pipelines, and biomedical applications.
    Chaimae Baiddou, Mehdi Knidiri, Bouchra Ghazi, Asmaa Abu Obaid, Salsabil Hamdi, Khaoula Errafii.
      Circular RNAs (circRNAs), a subtype of RNA molecules, possess distinctive characteristics, including their closed circular structure, stability, tissue specificity and long half-life compared to their linear counterparts. Initially presumed to be non-functional byproducts of splicing, advances in RNA-seq and bioinformatics have revealed the existence of these RNAs and begun to clarify their functions. Insight into their diverse functions revealed their roles, including regulating various cellular processes such as gene expression, transcription, translation into proteins (e.g., cap-independent translation), binding to microRNAs (miRNAs), and interacting with proteins. Moreover, mitochondria-encoded circular RNAs (mecciRNAs) have emerged as a novel subclass of circRNAs. Notably circRNAs have been associated with the development or progression of diseases (e.g., cancer, cardiometabolic and neurodegenerative disorders), highlighting diagnostic and therapeutic potential. In our review, we aim to summarize the current knowledge on circRNAs, covering their biogenesis, functions, identification tools, and potential biomedical applications.
    Keywords:  Back-splicing; Biomarker; Circular RNA; Liquid biopsy; RNA-Binding proteins; ceRNA; m6A
    DOI:  https://doi.org/10.1016/j.ncrna.2025.12.005
  22. Cell Oncol (Dordr). 2026 Feb 05. 49(1): 41
    ENY2 transcription and export complex 2 subunit deficiency induces nucleolar stress to inhibit tumor progression through NPM1/MDM2/p53-dependent and -independent responses.
    Shiqi Zuo, Siyuan He, Zhiqin Zhu, Yanjie Hou, Ziqing Wu, Yao Tang, Yujiao Zou.
       PURPOSE: The selective induction of nucleolar stress in cancer cells has become a potential anticancer therapy. However, precisely regulating the key molecules involved in nucleolar stress remains a challenging topic in current research. ENY2 transcription and export complex 2 subunit (ENY2) is a transcription-associated nuclear protein that is upregulated in several cancers. However, its specific function and mechanistic role in oncogenesis remain poorly characterized and require further exploration.
    METHODS: ENY2 was identified by screening ChIP-seq and public databases. Its role in tumor development was confirmed through in vivo and in vitro experiments. RNA sequencing, polysome profiling, agarose gel electrophoresis, and immunofluorescence suggested ENY2's involvement in ribosome biogenesis. Interacting proteins were identified by confocal microscopy, co-IP, and molecular docking, then validated by western blotting and ubiquitination assays. Finally, drug resistance experiments evaluated ENY2's clinical potential.
    RESULTS: We discovered that the overexpression of ENY2 significantly enhances tumor growth and cell cycle progression both in vitro and in vivo. Conversely, depletion of ENY2 facilitating the release of NPM1 into the nucleoplasm, thereby impeding ribosomal subunit export and inducing nucleolar stress. Additionally, the released NPM1 interacts with MDM2 within the nucleus to stabilize p53 protein levels, consequently inhibiting tumor growth. Notably, knockdown of ENY2 in p53-mutant cancer cell lines exhibits an augmented binding affinity and silencing efficacy of RISC towards target mRNA molecules, ultimately suppressing tumor proliferation through a p53-independent manner.
    CONCLUSIONS: This study elucidated a previously unrecognized role of ENY2 in tumor growth, clarified the NPM1/MDM2/ p53-dependent mechanism of ENY2-mediated tumor cell growth suppression. We also provided a novel p53-independent RISC-IL11 nucleolar stress response pathway, which may provide a new target for the treatment of breast cancer.
    Keywords:  ENY2 transcription and export complex 2 subunit; NPM1; Nucleolar stress; anti-IL11 therapy; p53-independent response pathway
    DOI:  https://doi.org/10.1007/s13402-025-01148-4
  23. bioRxiv. 2026 Jan 12. pii: 2026.01.12.698982. [Epub ahead of print]
    Stress-responsive roles of the C. neoformans human-like eIF3 complex.
    Maritza N Ventura, Prabhakar Singh, David Goich, John C Panepinto.
      Eukaryotic translation initiation factor 3 (eIF3) is a complex of proteins that plays a pleiotropic role in translation regulation across eukaryotes, but the composition of eIF3 complexes varies with retention and loss of subunit genes across evolution. The model yeast Saccharomyces cerevisiae encodes six eIF3 subunits whereas mammals encode thirteen subunits. The basidiomycete fungus and opportunistic fungal pathogen, Cryptococcus neoformans , encodes a mammalian complement of eIF3 subunits. In this report, we investigated the contribution of the non-essential eIF3 subunit genes to cryptococcal stress tolerance. We found that mutants in the four nonessential subunits, eIF3d, eIF3e, eIF3k and eIF3l all exhibit sensitivity to mitochondrial perturbation, and that mutants in eIF3d and eIF3e exhibit opposite susceptibilities to the antifungal drug fluconazole and the hypoxia mimetic cobalt chloride. Loss of eIF3d resulted in reduced eIF2α phosphorylation in response to stress, but the mutant was still able to repress translation to the same extent as the wild type and was defective in induction of integrated stress response regulon. Despite producing higher levels of urease and melanin, the eIF3d deletion mutant was avirulent in Galleria mellonella larvae. Together our data demonstrates the importance of C. neoformans eIF3 in stress adaptation and pathogenesis.
    Importance: Cryptococcus neoformans is an opportunistic fungal pathogen that causes cryptococcal meningoencephalitis in immunocompromised individuals leading to ∼120,000 deaths worldwide annually. When C. neoformans is exposed to host-relevant stressors, such as oxidative stress and thermal stress, it reprograms the translating pool of mRNAs to favor stress adaptation. Eukaryotic translation initiation factor 3 is a multi-subunit complex with roles in stress-responsive translation across eukaryotes yet is unexplored in C. neoformans. We found that C. neoformans encodes orthologues of all thirteen mammalian eIF3 subunits. Mutational analysis of non-essential subunits implicated eIF3 in responses to mitochondrial stress and antifungal susceptibility in C. neoformans, and demonstrates a role for eIF3d in the induction of the integrated stress response as well as in Cryptococcal pathogenesis. Further work will investigate the specific mRNAs that are regulated by eIF3 in response to host-relevant stressors in C. neoformans .
    DOI:  https://doi.org/10.64898/2026.01.12.698982
  24. Methods Mol Biol. 2026 ;3013 91-108
    Poly(A) Profiling for Euglenozoans Using Oxford Nanopore Direct RNA Sequencing, Illustrated by the Example of Euglena gracilis.
    Natalia Gumińska, Agnieszka Czarnocka-Cieciura, Bożena Zakryś, Rafał Milanowski.
      There are numerous methods to study polyadenylation. These techniques offer insights into mRNA abundance and the dynamic regulation of poly(A) tail length and nucleotide content. The Oxford Nanopore Technologies (ONT) platform is particularly noteworthy among them. It allows analysis of the whole transcriptome at the single-molecule level without the amplification biases introduced by PCR-based methods.Most current studies in this area have focused on well-established model organisms such as humans, yeast, Arabidopsis, and Caenorhabditis elegans. In contrast, the poly(A) dynamics remains largely unexplored in non-model organisms like euglenids. These organisms possess a range of unique evolutionary traits, and investigating their poly(A) metabolism may elucidate the evolution of the enzymatic machinery that controls mRNA processing, stability, and turnover.Here, we present a step-by-step protocol for measuring poly(A) tail lengths and characterizing the nucleotide makeup of poly(A) tails in Euglena gracilis using ONT Direct RNA Sequencing.
    Keywords:  Direct RNA sequencing; Euglena gracilis; Euglenids; Nanopore; Non-adenosine; Poly(A)
    DOI:  https://doi.org/10.1007/978-1-0716-5142-1_6
  25. Chembiochem. 2026 Feb 12. 27(3): e202500799
    Structure-Guided Synthetic Peptide Targeting Nucleolus and Neural Progenitor Protein Nuclear Import Impairs Ribosome Biogenesis and Cancer Cell Proliferation.
    Abhishek Kumar, Suvam Saha, Yogendra Pratap Mathuria, Mukesh Kumar, Shailesh Kumar Gupta, Debasish Kumar Ghosh.
      Nucleolus and neural progenitor protein (NEPRO) is a nucleolar factor required for 40S ribosomal subunit maturation and is therefore essential for the high translational demand of proliferating cancer cells. Here, we identify a bipartite nuclear localization signal (NLS; aa 74-96) in NEPRO and show that residues in both basic clusters are required for nuclear targeting. A disease-associated mutation within the C-terminal cluster, R94C, abolished NEPRO nuclear localization and markedly reduced binding to importin-α1 in vitro and in cells. Importin-α1-NLS complexes revealed that R94 forms persistent hydrogen bonds, salt bridges, and hydrophobic contacts with importin-α1 residues (A269, W273, P308, T311, P312, N350), explaining its central role in NLS recognition. Guided by these insights, we designed a rational synthetic hexapeptide inhibitor (H2N-AWPTPD-COOH) that is soluble, monodisperse, shows intrinsic fluorescence and is non-amyloidogenic. AWPTPD peptide binds wild-type NEPRO but not the R94C variant, and ab initio modeling shows peptide engagement of the R94 surface. Cellular delivery of the synthetic peptide significantly mislocalized NEPRO to the cytoplasm, reduced polysome abundance, decreased collagen secretion/deposition and clonogenicity, and induced cell-cycle arrest with upregulation of senescence markers: p16INK4A and p21WAF1/CIP1. These results validate R94 as a targetable hotspot in NEPRO's NLS and demonstrate a peptide-based approach to perturb ribosome biogenesis and suppress cancer cell growth.
    Keywords:  cancer cell growth inhibition; nuclear localization signal; nucleolus and neural progenitor protein; peptide inhibitor; ribosome biogenesis
    DOI:  https://doi.org/10.1002/cbic.202500799
  26. bioRxiv. 2026 Jan 18. pii: 2026.01.16.700031. [Epub ahead of print]
    Struct2SeQ: RNA inverse folding with Deep Q-Learning.
    Shujun He, Qing Sun.
      RNA molecules play critical roles in biology and therapeutics, with their function intimately tied to their secondary structure. Designing RNA sequences that reliably fold into desired secondary structures, especially those with complex pseudoknots, remains a fundamental challenge. Here, we present Struct2SeQ, a reinforcement learning framework that leverages deep Q-learning to generate RNA sequences conditioned on target secondary structures and SHAPE reactivity constraints. By formulating RNA design as a sequential decision-making process, our model learns to construct sequences that not only fold into the intended structures but also exhibit experimentally consistent SHAPE profiles. Evaluated with experimental data from the OpenKnot 240mer pseudoknot design challenges, Struct2SeQ significantly outperformed humans and other automated design methods while generating diverse solutions that explore a broader sequence space compared to human players. The incorporation of SHAPE-informed rewards further enhances the chemical validity of generated sequences, as evidenced by improved OpenKnot scores. Our results demonstrate the potential of reinforcement learning for RNA design tasks, opening avenues for engineering RNAs with complex structures and functions.
    DOI:  https://doi.org/10.64898/2026.01.16.700031
  27. RNA. 2026 Feb 05. pii: rna.080910.125. [Epub ahead of print]
    Regulation of mRNA decay and translation during the mammalian cell cycle.
    Jimmy Ly, Ekaterina Khalizeva, Yi Fei Tao, Iain M Cheeseman.
      Cell cycle progression requires cells to continually remodel their gene expression programs as they transition through distinct functional states. Although transcriptional and post-translational mechanisms have long dominated our understanding of this regulation, recent work additionally highlights the essential contribution of cell cycle-specific mRNA decay and translational control. Across G1, S, G2, and mitosis, cells dynamically modulate global and transcript-specific mRNA stability and translation to coordinate processes including DNA replication, growth, checkpoint signaling, and chromosome segregation. Mitosis presents a particularly striking challenge: transcription is silenced, necessitating that cells rely on post-transcriptional mechanisms to sustain mitotic functions and preserve viability. In this review, we highlight how these coordinated layers of post-transcriptional regulation collectively contribute to cell cycle control.
    Keywords:  Cell cycle; Gene expression; Mitosis; Translation; mRNA decay
    DOI:  https://doi.org/10.1261/rna.080910.125
  28. Biochem Biophys Res Commun. 2026 Feb 03. pii: S0006-291X(26)00166-X. [Epub ahead of print]805 153402
    RALY promotes Epithelial-mesenchymal transition in Hepatocellular carcinoma by regulating Snail.
    Hee-Won Kim, Jungsoo Kim, Jeong-Heon Ko, Jeong Gu Kang.
      RALY, a heterogeneous nuclear ribonucleoprotein, binds to nascent RNA and participates in multiple aspects of RNA metabolism, including transport, splicing, transcription, and translation. Recent studies have revealed that RALY is overexpressed in various cancers, such as breast, uterine, and liver cancers. This overexpression has been associated with poor patient survival and uncontrolled carcinoma cell proliferation. In this study, we demonstrate that RALY functions as a key regulator of cell proliferation, migration, and invasion in the hepatocellular carcinoma (HCC) cell lines Hep3B and HepG2. Mechanistically, RALY promotes epithelial-mesenchymal transition (EMT) through regulation of the transcription factor Snail. RALY directly binds to Snail mRNA, thereby enhancing its stability. In addition, RALY modulates the TGF-β signaling pathway to promote Snail transcription. Together, our findings establish a functional link between RALY and EMT and reveal a previously unrecognized role of RALY in cancer cell metastasis. Accumulating evidence, including the results presented here, suggests that RALY represents a potential therapeutic target for cancer treatment.
    Keywords:  Epithelial-mesenchymal transition (EMT); Hepatocellular carcinoma; RALY; RNA binding protein; Snail; TGF-β
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153402
  29. bioRxiv. 2026 Jan 19. pii: 2026.01.19.700400. [Epub ahead of print]
    Ribosomal Protein bL27 Protects Translating Ribosomes from tmRNA-SmpB.
    Divyasorubini Seerpatham, George Wanes, Chathuri Pathirage, Mynthia Cabrera, Edu Usoro, Kristin Koutmou, Christine M Dunham, Paul C Whitford, Kenneth C Keiler.
      Bacterial ribosomal protein bL27 is universally conserved and its amino terminus is adjacent to the peptidyl transfer center, yet its role in translation remains unclear. Combining genetics, biochemistry and molecular dynamics, we show that bL27 has an unexpected role in preventing trans -translation, the bacterial ribosome rescue mechanism, from interfering with protein synthesis. Deletion of the bL27 gene causes a 10,000-fold decrease in viability and this defect is partially rescued by deletion of the gene encoding tmRNA, a critical molecule for trans -translation. Molecular dynamics simulations also indicate that bL27 can slow the movement of tmRNA on the ribosome. These data link trans -translation and bL27, and support a model in which the amino terminus of bL27 acts as a gatekeeper to prevent tmRNA from sterically interfering with tRNA on the ribosome.
    DOI:  https://doi.org/10.64898/2026.01.19.700400
  30. Mamm Genome. 2026 Feb 03. 37(1): 32
    m5c-modified LINC01094 participates in epithelial-mesenchymal transition and metastasis of cervical cancer cells via the ZNF582-SIRT1/p53 axis.
    Xia Lu, Lili Yao, Xu Xu, Mayinuer Guli Rexiti, Xiaoli He, Yanyan Yang.
      Cervical cancer (CC) remains a significant global health burden despite advances in prevention and screening. Emerging evidence highlights the critical role of long non-coding RNAs (lncRNAs) and RNA modifications in tumorigenesis. Here, we identified LINC01094 as a highly expressed lncRNA in CC through TCGA analysis and clinical specimens. Functional studies, including CCK-8 method, flow cytometry, Transwell and Western blot assays, demonstrated that LINC01094 knockdown suppressed cell proliferation, migration, and epithelial-mesenchymal transition while promoting apoptosis in CC cells (Caski and SiHa). Mechanistically, NSUN2-mediated 5-methylcytosine methylation stabilized LINC01094, enhancing its expression in CC. Furthermore, LINC01094 facilitated ZNF582-dependent transcriptional activation of SIRT1, promoted the deacetylation and degradation of p53. Rescue experiments confirmed that ectopic expression of either LINC01094 or SIRT1 reversed the tumor-suppressive effects of NSUN2 or LINC01094 knockdown, respectively. Collectively, NSUN2-mediated stabilization of LINC01094 upregulated SIRT1 expression, thereby suppressing the p53 pathway and accelerating CC progression. These findings uncover a novel NSUN2/LINC01094/SIRT1 axis as an epigenetic-transcriptional driver of CC, offering potential therapeutic targets.
    Keywords:  5-methylcytosine; Cervical cancer; Epithelial-mesenchymal transition; LINC01094; Metastasis
    DOI:  https://doi.org/10.1007/s00335-026-10200-z
  31. Biochem Biophys Rep. 2026 Mar;45 102464
    TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.
    Panjiao Pang, Mingyang Yu, Huixin Ma, Longkai Wei, Jiali Huang, Lingxin Zhao, Ying-Hua Zhang.
      The localization and translation of mRNAs play crucial roles in maintaining cellular phenotype and function, with RNA-binding protein (RBP) contributing significantly to these processes. TAR DNA-binding protein of 43 kDa (TDP-43) is an RNA/DNA-binding protein that is primarily localized in the nucleus, where it performs essential functions in pre-mRNA splicing, mRNA transport, and the stabilization and localized translation of mRNA. Its mis-localization from the cytoplasm, as well as mutations, protein misfolding, and posttranslational modifications, is closely linked to a reduction in its RNA-binding ability. This functional impairment is implicated in the initiation and progression of neurodegenerative diseases and cancer. In this review, we begin with a retrospective analysis of the molecular mechanism by which distinct domains of TDP-43 contribute to the initiation and progression of disease, particularly because its overexpression in tumors significantly influences disease progression. We subsequently elucidate the classical mechanisms of mRNA localization and translation, while clarifying the role of TDP-43 in these processes. Finally, we summarize the mechanisms by which TDP-43 facilitates the formation of ribonucleoprotein particles and this protein's involvement in mRNA localization and translation, as well as its associated molecular pathways. In conclusion, this review highlights the critical roles of TDP-43 and subsequent therapeutic strategies for treatment of neurodegenerative diseases and tumors.
    Keywords:  Liquid-liquid phase separation; Local translation; Molecular mechanism; Protein aggregation; TDP-43; mRNA localization
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102464
  32. bioRxiv. 2026 Jan 12. pii: 2026.01.12.699007. [Epub ahead of print]
    Starvation-independent alarmone production inhibits translation through GTP depletion.
    Kevin A England, Aude Trinquier, Leah K McKinney, Jue D Wang, Heather A Feaga.
      Bacteria produce the alarmone nucleotides (p)ppGpp during stress to affect replication, transcription, translation, and metabolism. Recently, pGpp was identified as a third alarmone that is produced from the hydrolysis of (p)ppGpp. Although pGpp is a major component of bacterial stress responses, its precise role in mediating these responses is poorly understood. ppGpp and pppGpp bind translation GTPases and therefore directly affect translation to conserve resources during periods of stress. Here, we show that while pGpp is a weaker inhibitor of protein synthesis than ppGpp and pppGpp in vitro , pGpp production in the model Gram-positive bacterium Bacillus subtilis leads to faster translation inhibition in vivo . Faster translation inhibition is accompanied by greater levels of disengaged ribosomal subunits and hibernating ribosome dimers, suggesting that translation initiation is strongly inhibited. We show that alarmone production in vivo causes a severe depletion of GTP, which is sufficient for translation inhibition. Finally, we find that pGpp production also causes more robust transcriptome remodeling than (p)ppGpp production. This work supports a model that implicates all three alarmones in translation inhibition via GTP depletion.
    DOI:  https://doi.org/10.64898/2026.01.12.699007
  33. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699605. [Epub ahead of print]
    Ribosome-associated quality control of aberrant protein production during amino acid limitation.
    Alicia M Darnell, Christopher Chidley, Victoria Paradise, Danica S Cui, Kristian Davidsen, Sarah C Lincoln, Keene L Abbott, Ryan Elbashir, Campbell P Vander Heiden, Peter K Sorger, Lucas B Sullivan, Joseph H Davis, Matthew G Vander Heiden.
      Amino acids can become limiting for protein synthesis through depletion of charged tRNAs, leading to ribosome stalling and disruption of translation elongation at specific codons. To assess whether this is a mechanism by which amino acid availability can directly influence gene expression, we designed a reporter library to measure translation disruption across all sense codons in the context of amino acid limitations. We found that arginine limitation consistently impairs translation at the arginine codon AGA, resulting in synthesis of proteins from endogenous transcripts. In contrast, GCN2 pathway activation suppresses translation disruption following depletion of most other amino acids. Genome-wide screens revealed that the ribosome quality control trigger (RQC-T) and RQC pathways, which resolve ribosome collisions on defective mRNAs, catalyze ribosome splitting and premature fall-off in response to arginine depletion. Additionally, the E3 ubiquitin ligase RNF14, recently shown to clear ribosome A-site obstructions, promotes translation disruption through both ribosome fall-off and frameshifting during arginine limitation. Together, these data show that the RQC machinery is engaged by tRNA-limited ribosomes and identify a new role for RNF14 as a regulator of translation upon arginine limitation.
    DOI:  https://doi.org/10.64898/2026.01.14.699605
  34. J Biol Chem. 2026 Feb 02. pii: S0021-9258(26)00092-X. [Epub ahead of print] 111222
    Phosphorylation-dependent regulation of serine/arginine-rich proteins and U2AF1 interactions in early spliceosome assembly.
    Zihan Zhang, Puspa Kunwar, Yanbao Yu, Peter Prevelige, Jun Zhang.
      Early-stage spliceosome assembly is critical to constitutive and alternative pre-mRNA splicing. This process is orchestrated by serine/arginine-rich (SR) proteins (SRSF1-SRSF12) and SR-related proteins U1-70K and U2AF1. SR proteins recognize exonic splicing enhancers and interact with U1-70K and U2AF1 to recruit the U1 and U2 snRNP complexes to the 5' and 3' splice sites, respectively. However, the molecular basis of the interaction between SR proteins and U2AF1 has remained poorly understood, largely due to the poor solubility of full-length U2AF1. Here, we successfully refold and solubilize U2AF1 and confirm its structural integrity. This enables investigation of its interaction with SRSF1, a prototypical SR protein. We show that the U2AF1 C-terminal RS domain (RSU2AF1) is essential for binding to the phosphorylated RS domain of SRSF1 (RSSRSF1), and that RSU2AF1 is phosphorylated in cells. Notably, phosphorylation of RSU2AF1 significantly reduces its affinity for SRSF1, revealing a phosphorylation-dependent regulatory mechanism. The SRSF1-U2AF1 interaction closely parallels that of SRSF1 and U1-70K, hinting at a general principle in which phosphorylated RS interacts with unphosphorylated ones. Inspired by this discovery, we further find the interaction between phosphorylated and unphosphorylated SRSF1, providing a mechanistic explanation of long observed self-interactions within SR proteins. Our MD simulations further reveal that the salt-bridges between phosphoserine and arginine dominate these interactions, and the interaction strength depends on net charges of RS regions. Together, our findings provide new molecular insights into how phosphorylation modulates splicing factor interactions and highlight a conserved mechanism that regulates early spliceosome assembly.
    Keywords:  RNA splicing; SRSF1; U2AF1; U2AF35; phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2026.111222
  35. J Egypt Natl Canc Inst. 2026 Feb 02. 38(1): 3
    Significance of MALAT1 long non-coding RNA and miR-20a-5p in regulating epithelial mesenchymal transition in luminal breast cancer patients.
    Gehad Tarek, Manar Fouda, Mohamed Omran, Gehan Safwat, Mahmoud Kamel, Abdel Hady Abdel Wahab.
       BACKGROUND: Luminal breast cancer (LBC) is the most common subtype of breast cancer affecting women worldwide. Although luminal breast cancer typically has a better prognosis, it mostly responds poorly to neoadjuvant chemotherapy. Non-coding RNAs, especially long non-coding RNAs and microRNAs are crucial in regulating biological processes that contribute to breast cancer development. MALAT1, a long non-coding RNA, is pivotal in the progression of breast cancer. Epithelial-mesenchymal transition (EMT) is critical for cell movement during embryonic development. Clarifying this role could pave various avenues for developing innovative strategies for combating this subtype of malignancy. The present study aimed to investigate the expression profiles and clinical relevance of MALAT1 level and EMT-related miRNAs (miR-17-5p, miR-20a-5p, miR-93-5p, miR-135b-5p, and miR-146a-5p) alongside EMT markers (E-cadherin, N-cadherin, vimentin, fibronectin, twist, SNAI1, Slug, ZEB1, and ZEB2) in LBC patients.
    METHODS: Fresh tissues were collected from fifty patients and twenty noncancerous controls. Differential expression of the markers was evaluated using qRT-PCR assay. Spearman Rho test assessed the relationship between the expression levels. Linear regression test evaluated the correlation between the parameters and various clinico-pathological features.
    RESULTS: Our results revealed an overall upregulation of MALAT1 in breast cancer tissues although this increase did not reach statistical significance. Overexpression of miR-20a-5p, miR-135b, and ZEB2 was reported, whereas miR146a-5p, ZEB1 and Vimentin levels were suppressed. Correlation analysis demonstrated that miR-20a-5p was positively correlated with SNAI1, E-cadherin, N-cadherin and Slug also it was significantly associated with family history and tumor laterality.
    CONCLUSIONS: Our findings suggest that miR-20a-5p plays an oncogenic role in luminal breast cancer by promoting EMT, while MALAT1 may contribute to disease progression through indirect regulatory mechanisms. Finally, MALAT1 and miR-20a-5p might serve as potential therapeutic and prognostic targets in LBC.
    Keywords:  Breast cancer; Luminal subtype; MALAT1; MicroRNA; Non-coding RNA; miR-20a-5p
    DOI:  https://doi.org/10.1186/s43046-026-00339-w
  36. RNA. 2026 Feb 03. pii: rna.080638.125. [Epub ahead of print]
    Distribution and structural diversity of Type IV internal ribosome entry sites.
    Katherine Elizabeth Segar, Madeline E Sherlock, Jeffrey Scott Kieft.
      Internal ribosome entry sites (IRESs) are RNA sequences that facilitate cap- and end-independent translation initiation in eukaryotes. Type IV IRESs, which include the hepatitis C virus IRES, directly bind the 40S ribosomal subunit and require only a subset of canonical initiation factors to function. As the full extent of diversity and species distribution of Type IV IRESs was unknown, we sought to identify and classify the architectural variation of all members. Using a secondary structure homology-based search method, we identified 163 putative Type IV IRESs from viruses with diverse hosts and phylogeny, including the first example in a double stranded viral genome. Clustering analysis based on the presence and overall size of secondary structure elements yielded three distinct groups, differentiated by substantial expansions and deletions. Chemical probing of representative IRES RNAs from each cluster confirmed predicted secondary structures. Subsequent in vitro translation assays suggested that structural differences produce functional variation. Our findings reveal distinct structural adaptations and patterns within the Type IV IRESs that may influence IRES function and mechanism.
    Keywords:  Internal Ribosome Entry Site; RNA Homology searches; RNA chemical probing; RNA structure
    DOI:  https://doi.org/10.1261/rna.080638.125
  37. Plant J. 2026 Feb;125(3): e70719
    Maize ZmBCCIP facilitates cleavage at the A3 site in pre-rRNA processing and is crucial to seed development and vegetative growth.
    Feng Sun, Pan-Pan Jiang, Shihao Liu, Xu Zhang, Nan Wu, Wenxin Liu, Yue Li, Gong Ao, Yafeng Zhang, Chunhui Xu, Bao-Cai Tan.
      The precise cleavage and processing of precursor rRNA (pre-rRNA) are essential for ribosome biosynthesis, a fundamental process for cell proliferation and growth. However, the molecular mechanisms underlying pre-rRNA processing in plants remain incompletely understood. In this study, we report the role of ZmBCCIP in pre-rRNA processing, which facilitates cleavage at the A3 site in the "ITS1-first" pathway by interacting with components of the mitochondrial RNA processing (MRP) endoribonuclease complex. ZmBCCIP is a nucleolar protein that is highly conserved across yeast, humans, and plants. A loss of ZmBCCIP function delays both maize seed development and seedling growth. Analysis of pre-rRNA processing in zmbccip mutants revealed an inhibition of cleavage at the A3 site of 35S pre-rRNA, leading to a reduction in the levels of 27S-A3, P-A3, and P'-A3 pre-rRNA intermediates, and an accumulation of 35S, 33S, and 27S-A2 intermediates. The decreased cleavage at the A3 site primarily impacts the processing of mature 25S rRNA, thereby hindering 60S ribosome assembly while exerting a lesser effect on the production of 18S rRNA and the formation of 40S ribosomes. The processing of 18S rRNA is maintained due to the compensatory effects of the "5'ETS-first" pathway, highlighting the adaptive advantage of having dual rRNA processing pathways in plants. ZmBCCIP interacts with ZmRPL23, which has a conserved role in shuttling and also associates with SHREK1, a WD40 protein involved in A3 cleavage, along with several components of the RNase MRP complex that mediates A3 cleavage in yeast. These findings highlight the role of BCCIP in facilitating A3 site cleavage during pre-rRNA processing and its crucial function in maize seed development and plant growth.
    Keywords:  A3 site; BCCIP; maize; rRNA processing; ribosome
    DOI:  https://doi.org/10.1111/tpj.70719
  38. J Biol Chem. 2026 Feb 02. pii: S0021-9258(26)00090-6. [Epub ahead of print] 111220
    AHCY: A Metabolic Gatekeeper at the Interface of Methylation, Redox Balance, and Cellular Stress Response.
    Sarah C Stanhope, Vikki M Weake.
      S-Adenosylhomocysteinase (AHCY, also known as SAHH) is a highly conserved enzyme that catalyzes the reversible hydrolysis of S-adenosylhomocysteine (SAH) into adenosine and homocysteine. As the sole enzyme capable of catalyzing this reaction, AHCY modulates cellular methylation potential required for DNA, RNA, and protein methyltransferase activity. Recent discoveries, however, expand its role well beyond this canonical function, positioning AHCY as a metabolic gatekeeper that integrates one-carbon metabolism with epigenetic regulation, RNA processing, nucleotide balance, and redox signaling. This review brings together mechanistic, structural, and regulatory insights into AHCY while critically evaluating diverse biochemical and biophysical methods for assaying its activity. Comparative structural analyses uncover conserved tetrameric organization alongside species-specific adaptations in oligomeric state, NAD+ pocket accessibility, and C-terminal dynamics that shape enzyme catalytic efficiency and regulation. AHCY function is further fine-tuned through a wide spectrum of post-translational modifications and small-molecule interactions, linking it to transcriptional control, stress adaptation, and viral infection. By linking SAH turnover to methylation capacity and adenosine/homocysteine flux, AHCY coordinates metabolism with chromatin regulation and stress responses. These cross-cutting roles highlight how a single metabolic enzyme bridges catalysis, regulation, and disease. In doing so, AHCY exemplifies the broader principle that metabolic enzymes can have a central role as regulators of metabolic flux and cellular regulation, offering both mechanistic depth and translational promise as a therapeutic target.
    Keywords:  S-Adenosylhomocysteinase (AHCY); S-Adenosylhomocysteinase Hydrolase (SAHH); enzymatic regulation; methylation potential; one-carbon metabolism; redox homeostasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.111220
  39. Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2511555123
    Nuclear speckles are regulatory hubs for viral and host mRNA expression during HSV-1 infection.
    Shani Nadav-Eliyahu, Chaya Bohrer, Alon Boocholez, Noa Kinor, Vesa Aho, Jennifer I C Benichou, Salla Mattola, Sami Salminen, Henri Niskanen, Minna U Kaikkonen, Maija Vihinen-Ranta, Yaron Shav-Tal.
      Herpes simplex virus type 1 (HSV-1) infection remodels the host nucleus, marginalizing chromatin and forming viral replication compartments (VRCs). Nuclear speckles, nuclear bodies enriched in RNA-processing factors, reposition around VRCs and undergo structural changes. While viral mRNAs are transcribed in VRCs and host transcription is largely suppressed, the nuclear routes used by viral and upregulated host transcripts and their relationship with nuclear bodies remain unclear. We show that immediate-early (IE) viral transcripts uniquely accumulate in nuclear speckles prior to export, unlike early or late transcripts, revealing a selective nuclear speckle-dependent pathway. Similarly, host mRNAs upregulated during infection traffic into nuclear speckles after transcription. Moreover, nuclear speckles are structurally remodeled, marked by the long non-coding RNA (lncRNA) MALAT1 removal and increased dynamics of the nuclear speckle core protein SRRM2. Finally, we found that blocking mRNA export causes IE transcripts to accumulate in nuclear speckles and that nuclear speckle disassembly severely impairs IE mRNA export, preventing downstream viral gene expression. These findings establish nuclear speckles as dynamic regulatory hubs that selectively facilitate the processing and export of IE viral mRNAs during HSV-1 infection.
    Keywords:  HSV-1; RNA FISH; RNA expression; nuclear organization; nuclear speckles
    DOI:  https://doi.org/10.1073/pnas.2511555123
  40. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699749. [Epub ahead of print]
    Human CCR4-NOT suppresses pervasive transcription and retrotransposable elements.
    Shardul Kulkarni, Alexis Morrissey, Aswathy Sebastian, Oluwasegun T Akinniyi, Cheryl A Keller, Istvan Albert, Shaun Mahony, Joseph C Reese.
      CCR4-NOT regulates multiple steps in gene regulation and has been well studied in budding yeast. Although primarily cytoplasmic, where it plays an essential role in mRNA degradation, the human complex has poorly characterized nuclear functions. Here, we used auxin-induced degradation to rapidly deplete the scaffold subunit CNOT1 and the E3 ligase CNOT4, and characterized the transcriptional functions of the human CCR4-NOT complex. Using transient transcriptome profiling (TT-Seq) to measure ongoing transcription, we found widespread activation of RNA synthesis in depleted cells across genic and intergenic regions. Interestingly, fewer genes were repressed, including KRAB-Zinc-Finger-protein (KZNF) genes, especially those on chromosome 19. KZNFs repress genes and retrotransposable elements (rTEs), and consistent with decreased KZNF expression, rTEs, mainly Long Interspersed Nuclear Elements (LINEs), were activated. Full-length active LINEs and rTEs lying outside of genes were activated, suggesting that the increased transcription is not the direct result of transcription of the genes the rTEs are embedded in. We found that most activated transcription events were in proximity to KZNF binding sites, suggesting that KZNF regulation contributes to the suppression of genic and rTE transcription. Finally, we demonstrate that CCR4-NOT regulates the stability of rTE RNAs, indicating that the complex tightly controls transposon expression by repressing transcription and targeting their RNAs for decay.
    DOI:  https://doi.org/10.64898/2026.01.16.699749
  41. Biogerontology. 2026 Feb 06. 27(2): 53
    Critical roles of m6A demethylase FTO in ovarian aging.
    Saba Hadi, Seyed Hossein Khoshraftar, Amir Hossein Kiani Darabi, Hamid Reza Nejabati.
      Ovarian aging, recognized as one of the initial signs of systemic aging, is marked by a progressive reduction in both the number and quality of oocytes, which has a profound effect on female fertility. In spite of the advancements in assisted reproductive technologies, these methods fail to tackle the fundamental molecular mechanisms that drive ovarian senescence. Recent surveys have underscored the significant role of epitranscriptomic regulation, especially the N6-methyladenosine (m6A) modification, in regulating RNA stability, translation, and cellular functionality. Fat mass and obesity-associated (FTO), a m6A demethylase, has been identified as a crucial regulator of granulosa cell homeostasis, influencing pathways related to oxidative stress, mitochondrial integrity, apoptosis, and cellular senescence. A decrease in FTO expression in aging ovaries is associated with increased m6A levels, destabilization of heterochromatin, dysregulation of transposable elements, and the upregulation of senescence-associated genes such as FOS. Moreover, regulation of genes such as MFN2, MMP2, and P53 by FTO has been shown to sustain mitochondrial function, uphold ERK signaling, and prevent apoptosis in granulosa cells. In summary, these discoveries position FTO as a pivotal element in the molecular framework governing ovarian aging, presenting promising opportunities for therapeutic strategies aimed at preserving female reproductive capacity.
    Keywords:  FTO; Fertility; Ovarian aging
    DOI:  https://doi.org/10.1007/s10522-026-10401-8
  42. J Mol Histol. 2026 Jan 31. 57(1): 66
    Exosomal CeRNAs from the tumor microenvironment: hidden drivers of colorectal cancer progression.
    Faris Anad Muhammad, Abdulkareem Shareef, S Renuka Jyothi, Priya Priyadarshini Nayak, J Bethanney Janney, Gurjant Singh, Aashna Sinha, Nodira Rabbimova, Hayder Naji Sameer, Ahmed Yaseen, Rasim M Salih, Mohaned Adil.
      Colorectal cancer (CRC) remains a major global health burden, with rising incidence and mortality, particularly in developing countries. The tumor microenvironment (TME) plays a critical role in CRC progression by facilitating angiogenesis, immune evasion, and metastasis through complex intercellular communication. Among the key mediators of this communication are exosomes-nano-sized extracellular vesicles-that transport a variety of bioactive molecules, including competing endogenous RNAs (ceRNAs). These ceRNAs, such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and mRNAs, act as molecular sponges for microRNAs (miRNAs), thereby regulating gene expression and influencing cancer-related pathways like Wnt/β-catenin and PI3K/Akt. This review explores the emerging role of exosomal ceRNAs derived from the TME in CRC progression, emphasizing their involvement in promoting tumor cell proliferation, invasion, metastasis, and resistance to therapy. By elucidating the intricate crosstalk between exosomal ceRNAs and the TME, we highlight their potential as novel biomarkers and therapeutic targets, offering new avenues for personalized treatment strategies in colorectal malignancies. Despite growing interest in exosomes and non-coding RNAs in colorectal cancer (CRC), limited attention has been given to the specific role of exosomal ceRNAs derived from the tumor microenvironment (TME). Existing reviews have predominantly addressed broader aspects of exosomal non-coding RNAs (e.g., miRNAs, lncRNAs, and circRNAs in general CRC progression, metastasis, or as biomarkers) or focused on exosomal communication in other malignancies. However, the intricate mechanisms by which TME-derived exosomal ceRNAs establish regulatory networks to drive CRC pathology-particularly through miRNA sponging in stromal-tumor crosstalk-remain underexplored and insufficiently synthesized. This review addresses these critical gaps by uniquely emphasizing exosomal ceRNAs sourced from the TME (including CAFs, macrophages, and other stromal components), elucidating their convergent roles in orchestrating proliferation, invasion, immune evasion, and chemoresistance. By integrating recent evidence into a TME-centric framework, we provide novel insights into potential diagnostic and therapeutic applications, advancing beyond general exosomal RNA overviews toward targeted strategies for CRC.
    Keywords:  CircRNA; Colorectal cancer; Exosomal CeRNAs; Exosomal biomarkers; LncRNA
    DOI:  https://doi.org/10.1007/s10735-026-10724-3
  43. bioRxiv. 2026 Jan 20. pii: 2026.01.20.700650. [Epub ahead of print]
    Programmed Double-stranded RNA Formation Enables Meiotic Stage Transitions.
    Hao Wu, Xinan Liu, Yihan Xiong, Yun Bai, Kevin M Weeks.
      Cell fate transitions rely on extensive transcriptional activation mediated by transcription factors, yet the equally important processes that ensure the selective removal of pre-existing mRNAs remain elusive. We uncover widespread formation of double-stranded RNA (dsRNA) during early-to-middle meiosis using quantitative RNA structure analysis, and validate hundreds of natural antisense transcripts (NATs) through long-read sequencing. These NATs are induced by meiosis-specific transcription factors, including Ndt80p, and pair with sense mRNAs to drive cytoplasmic aggregation of the resulting dsRNAs. These dsRNA aggregates are subsequently transported to the vacuole for clearance, likely via autophagy. This pathway selectively eliminates mRNAs before metaphase I, including NDJ1 , which encodes a meiotic cohesion protein that would otherwise block chromosome segregation. Our study reveals a physiological role for large-scale dsRNA formation, and highlights a simple but powerful model: the same transcription factors that activate mRNAs required for a specific developmental stage also program the synthesis of NATs that promote removal of transcripts from the preceding stage, thereby driving bidirectional transcriptome reprogramming.
    DOI:  https://doi.org/10.64898/2026.01.20.700650
  44. mSystems. 2026 Feb 06. e0049325
    Transcriptional and metabolic stasis define desiccation-induced dormancy in the soil bacterium Arthrobacter sp. AZCC_0090 until water vapor initiates resuscitation.
    Paul Carini, Adriana Gomez-Buckley, Christina R Guerrero, Melanie R Kridler, Isabella A Viney, Roya AminiTabrizi, Malak M Tfaily, Peter Moma, Laura K Meredith, Katherine B Louie, Benjamin P Bowen, Trent R Northen, Oona Snoeyenbos-West, Ryan P Bartelme.
      Microbes inhabiting soils experience periodic water deprivation. The effects of desiccation on DNA, protein, and membrane integrity are well-described. However, the effects of drying and rehydration on the composition of cellular RNA and metabolites are still poorly understood. Here, we describe how slow drying and rehydration with water vapor influence the composition of RNAs and metabolites in a soil Arthrobacter. While drying reduced cultivability relative to hydrated controls, water vapor rehydration fully restored it. Ribosomal RNA proportions remained constant throughout all treatments, and mRNA profiles showed stable composition during desiccation-changing only during transitions into and out of desiccation-induced dormancy. Six transcriptional modules displayed distinct expression patterns in desiccated-rehydrated samples relative to hydrated controls, including desiccation-rehydration responsive and rehydration-specific profiles. Targeted intracellular metabolomics revealed similarly static profiles during desiccation, with a cluster of ribonucleosides and nucleobases increasing in response to desiccation and returning to baseline levels upon rehydration with water vapor. These findings demonstrate that both mRNA and metabolite profiles remain essentially frozen in desiccated Arthrobacter, with dynamic changes occurring only during state transitions. These results have important implications for environments with frequent drying cycles where stable mRNA in dormant cells combined with intracellular RNA recycling may obscure interpretations of RNA-based environmental analyses that use RNA as a marker of microbial activity. Our results suggest that RNA-based activity assessments in periodically dry environments require careful consideration of dormancy-associated molecular preservation.IMPORTANCEMetabolic activity quickly ceases in drying bacteria as they enter desiccation-induced dormancy. We show that mRNA and metabolite profiles were variable during drying and rewetting but did not change while desiccated. Additionally, water vapor stimulated the shift from the static to active state when exiting desiccation-induced dormancy. These shifts coincided with increased cultivability, indicating water vapor resuscitated dry cells. Because RNAs are transient, labile molecules that are turned over rapidly in growing bacteria, the presence of RNA in the environment is used as a marker for microbial activity. Our research shows this assumption may not hold for desiccated cells, indicating reliance on RNA as a marker of activity in environments that experience drying may obscure estimates of in situ microbial activity.
    Keywords:  Arthrobacter; RNA-seq; desiccation tolerance; dormancy; drought survival; dryland microbiology; metabolomics; microbial activity assessment; soil bacteria; transcriptional stasis
    DOI:  https://doi.org/10.1128/msystems.00493-25
  45. Phytopathology. 2026 Feb 01.
    Characterization of the Citrus Leaf Blotch Virus AlkB Domain and Its Involvement in Viral Accumulation.
    Junna Han, Yuting Jiang, Yuqian Yan, Ying Wang, Aijun Huang.
      Chemical modifications are prevalent on the genomic and messenger RNAs of RNA viruses. The AlkB family proteins are a class of demethylases that have the capacity to modulate the abundance and distribution of chemical modifications on nucleic acids in a dynamic manner, thereby dictating the functional competence of viral RNAs and, ultimately, affecting viral infectivity and replication. A subset of positive-sense RNA viruses harbour an AlkB domain within their polyproteins; however, whether this domain displays enzymatic activity equivalent to that of canonical AlkB enzymes, and thus participates in virus-host interactions, remains unresolved. Here, we characterized the biological role of the AlkB domain embedded in ORF1 of citrus leaf blotch virus (CLBV). Site-directed mutagenesis of catalytic core residues within the domain did not abolish infectivity in Nicotiana benthamiana, but markedly delayed cell-to-cell movement, reduced viral accumulation in emerging leaves, and attenuated plant stunting. Moreover, m6A peaks in total RNA were significantly more abundant, and their distribution patterns on both host mRNAs and the viral genomic RNA were altered, in plants inoculated with the AlkB-mutated infectious clone. Collectively, these data suggest that the CLBV-encoded AlkB domain likely possesses m6A demethylase activity that is analogous to that of cellular AlkB proteins. The results of the present study provide the first functional characterisation of a viral AlkB domain and provide a critical reference for future mechanistic interrogation of AlkB-domain function across viral systems.
    Keywords:  Virology
    DOI:  https://doi.org/10.1094/PHYTO-08-25-0275-R
  46. RNA. 2026 Feb 04. pii: rna.080791.125. [Epub ahead of print]
    The repertoire of binding specificities for two repeats in the RNA-binding domain of Drosophila Pumilio.
    Tammy H Wharton, Robin P Wharton.
      The PUF domain of Drosophila Pumilio consists of eight homologous repeats that act in a modular fashion to recognize Nanos Response Elements (NREs) in targeted mRNAs, each repeat interacting with a single base of the NRE. Most of the sequence specificity of binding is thought to be driven by interactions between residues 12 and 16 of each repeat with the edge of the appropriate RNA base. In this report, we investigate the repertoire of amino acids at positions 12 and 16 that are capable of mediating high affinity binding for two of the PUF repeats, R6 and R5. We generate plasmid libraries in which the codons for residues 12 and 16 are randomized, transform these into a suitable yeast strain, and screen for variants that recognize an NRE in three hybrid RNA-binding experiments. We find that the two repeats have very different capabilities. Relatively few amino acid combinations in R6 are functional and these exhibit a limited array of binding specificities; in contrast, approximately 24% of the edge-on amino acid combinations in R5 are functional, and these exhibit a variety of novel specificities. These results support the idea that R6 (in part) defines NRE target sites, while R5 selects among NREs to allow differential regulation in vivo. We also show that R5 binding modules generally cannot be functionally swapped into R6. Thus, although binding of the Pumilio PUF domain is modular, the R6 and R5 modules are not readily interchangeable, consistent with studies of other PUF domains.
    Keywords:  PUF domain; Pumilio; RNA-binding protein; intrinsically disordered region
    DOI:  https://doi.org/10.1261/rna.080791.125
  47. Neurobiol Dis. 2025 Dec;pii: S0969-9961(25)00363-8. [Epub ahead of print]217 107146
    Molecular messengers of the brain: tRNA-derived small RNAs at the crossroads of brain development and neurodevelopmental disorders.
    Renqiuguo Li, Xiao Li, Hao Wang, HongYuan Chu, Meiyu Dong, Junjiao Zhang, Kai Gao, Jianxiong Gui, Yuwu Jiang.
      Brain development is tightly regulated by different modulators and mechanisms. Disruptions in these processes underlie a spectrum of neurodevelopmental disorders. Among non-coding RNAs, which usually act as key regulators of brain development, tRNA-derived small RNAs (tsRNAs) have recently emerged as functional regulators, rather than mere degradation byproducts. Abundantly and dynamically expressed in the brain, tsRNAs influence translation, epigenetics, and RNA-protein interactions, suggesting roles in neurogenesis, synaptic development, and synaptic plasticity. This review synthesizes current knowledge on tsRNA biogenesis, classification, and molecular functions, with a particular focus on their roles in brain development and neurodevelopmental disorders. We highlight how tsRNAs may act as modulators, serve as potential biomarkers, and represent novel therapeutic targets in these conditions. By integrating emerging findings and identifying key knowledge gaps, we aim to establish tsRNAs as pivotal players in both brain health and disease.
    Keywords:  Biomarkers; Brain development; Epilepsy; Intellectual disability; Neurodevelopmental disorders; tRNA-derived small RNA
    DOI:  https://doi.org/10.1016/j.nbd.2025.107146
  48. bioRxiv. 2026 Jan 16. pii: 2026.01.16.699960. [Epub ahead of print]
    Neural microexons contain lengthened sequence and extended RNA structure between the branchpoint and splice site motif.
    Alexandra Randazza, Kathryn E Howe, John R McCoy, Abigail Hatfield, Tara Doucet-O'Hare, Lela Lackey.
      Microexons are extremely short exons that are highly conserved in vertebrates and are essential for normal brain development. Their small size poses a challenge for canonical exon-definition splice site recognition, which typically relies on spliceosomal interactions across standard length exons. Here, we determine the sequence and RNA structural features of neural microexons in humans in comparison with chickens. We find that both human and chicken neural microexons share intronic features that extend the functional distance between the branchpoint and the 3' splice site, including distal positioning and lengthening of polypyrimidine tracts. Using experimental RNA structure-probing on a subset of neural microexons, we show that the human branchpoint-to-splice site region is unusually accessible and relatively unpaired compared to other exon classes. However, we find little support for shared RNA secondary structures between orthologous human and chicken precursor RNAs despite high sequence conservation. Using the chick embryo as a developmental model, we demonstrate that a subset of neural microexons undergo dynamic, stage-specific regulation during brain development that correlates with expression of known microexon regulators, SRRM4 and NOVA1 . Our data suggest that neural microexon splicing fluctuates during brain development and may rely on an extended polypyrimidine tract and structural accessibility for splicing efficiency, rather than conserved secondary structures.
    DOI:  https://doi.org/10.64898/2026.01.16.699960
  49. PLoS One. 2026 ;21(2): e0340367
    Mapping SBiP1 protein-protein interactions in Symbiodinium microadriaticum CassKB8 using the Yeast Two-Hybrid assay and structural prediction.
    Estefanía Morales-Ruiz, Tania Islas-Flores, Marco A Villanueva.
      BiP chaperones are central regulators of protein folding, endoplasmic reticulum homeostasis, and stress response across eukaryotes, but their client networks remain largely uncharacterized in Symbiodiniaceae. Here, we performed an initial yeast two-hybrid screening using a spliced-leader-based cDNA library to explore the interactome and regulatory dynamics of the Symbiodiniaceae BiP homolog, SBiP1, from Symbiodinium microadriaticum CassKB8. Using this approach, we identified eight candidate interactors with functions in translation, redox balance, RNA processing, and photosynthesis. AlphaFold2 structural modeling and Foldseek similarity analysis supported the plausibility of these candidates as BiP clients, revealing shared structural features such as globular folds and exposed hydrophobic or basic surfaces. Notably, two of the eight candidates, POX18 and TARBP1 were recovered in multiple independent clones, and even unannotated candidates displayed BiP-compatible surfaces. Gene expression analysis by RT-qPCR revealed dynamic transcriptional regulation of SBiP1, HSP70, and POX18 over an 18-day growth time course. All three genes peaked between days 6 and 12, suggesting coordination with intrinsic cellular cycles. SBiP1 expression was not significantly affected by light availability while HSP70 showed a modest but statistically significant increase following cycloheximide treatment, indicating transcript stabilization. In contrast, SBiP1 and POX18 expressions under the latter condition remained stable, suggesting their regulation may occur post-transcriptionally. Together, our findings highlight SBiP1 as a central player in ER proteostasis, bridging multiple cellular pathways essential for stress resilience. This work provides the first structural and functional map of a BiP-centered interaction network in a photosynthetic dinoflagellate, contributing to our molecular understanding of stress adaptation in these microorganisms.
    DOI:  https://doi.org/10.1371/journal.pone.0340367
  50. Mol Plant. 2026 Jan 29. pii: S1674-2052(26)00010-9. [Epub ahead of print]
    Structure under stress: conserved RNA structure in plant interaction with the environment.
    Dolly Mehta, Dominique Jacques-Vuarambon, Borys Alexander León Alcivar, Jingmin Hua, Chen Xiao, Lazara Aline Simoes Silva, Rodrigo S Reis.
      Plants have evolved sophisticated molecular mechanisms to sense and respond to their environment. There has been growing realization that RNA structure is a key player in this process, such as acting as sensor of temperature changes and nutrient availability, modulator of immune response, and regulator of diverse stress-response pathways (reviewed in Zhang and Ding, 2025). It is now possible to interrogate in vivo RNA secondary structure at nucleotide resolution across the entire transcriptome, which has enabled unprecedented insights into their biological function. However, the evolutionary conservation of functional RNA structures is still poorly understood in plants. Indeed, most reports either do not attempt to assess structural conservation or do not apply appropriate methods. Hence, it is difficult to know whether and how findings in model plants can be translated to crop improvement. This Opinion article briefly discusses previous attempts to assess RNA structural conservation in plants and proposes the need for more rigorous, structure-aware approaches.
    DOI:  https://doi.org/10.1016/j.molp.2026.01.009
  51. Nucleic Acids Res. 2026 Jan 22. pii: gkag062. [Epub ahead of print]54(3):
    PCLIPtools: a robust framework for identifying RNA-protein interaction sites from PAR-CLIP experiments.
    Ahsan H Polash, Markus Hafner.
      PAR-CLIP is a widely used method for identifying binding sites of RNA-binding proteins (RBPs) transcriptome-wide. A characteristic T-to-C transition in the sequenced complementary DNA pinpoints the site of RBP-RNA crosslinking and is induced by the use of a photoreactive uridine analogue, 4-thiouridine (4SU). As with other system-wide methods, PAR-CLIP, too, is prone to false discoveries, as the T-to-C signal might result from systematic noise, pre-existing SNPs, and polymerase chain reaction errors. Therefore, rigorous statistical methods are required for analyzing PAR-CLIP data. The few existing tools to analyze PAR-CLIP data lack updates and sufficient documentation, and often fail to process current higher-depth sequencing data. Here, we report PCLIPtools, a lightweight, customizable suite for analyzing PAR-CLIP data. PCLIPtools considers the read depth, T-to-C transitions, and the other mutations to statistically estimate high-confidence interaction sites. Benchmarking shows that PCLIPtools identifies more functionally significant targets than the current standard tool, PARalyzer, without losing high-confidence sites and outperforming it in runtime. Exploratory analyses show PCLIPtools' specific targets are enriched for read depth and T-to-C conversion, supporting their validity. With simplicity, robustness, and speed, PCLIPtools improves the precision of PAR-CLIP data analysis while being accessible to experimental RNA biologists.
    DOI:  https://doi.org/10.1093/nar/gkag062
  52. PLoS One. 2026 ;21(2): e0342107
    Regulation of tension-dependent localization of LATS1 and LATS2 to adherens junctions.
    Chamika De Silva, Brian A Kelch, Dannel McCollum.
      The LIM domain protein LIMD1 is a critical regulator of the Hippo signaling pathway, acting to sequester the kinases LATS1/2 to adherens junctions (AJs) in response to mechanical strain. Here, we identify the molecular basis for LIMD1 binding and recruitment of LATS1/2 to AJs. We show that while the LIM domains of LIMD1 are sufficient for AJ localization and binding to LATS1/2, recruitment of LATS1 to AJ requires both the intrinsically disordered region (IDR) in the N-terminus as well as the LIM domains. We further dissected the LIM domains and found that LIM1 and LIM2, but not LIM3, are necessary for LATS1 AJ localization. Point mutations that disrupt strain sensitivity in either the first or second LIM domain disrupt both binding and recruitment of LATS1/2 to AJs. Mechanistically, LIMD1 binds LATS1/2 through a conserved linear motif, the LATS-LATCH, which we identified by AlphaFold modeling and confirmed by biochemical and localization assays. The LATS-LATCH is required for mechanical strain-dependent recruitment of LATS1 and LATS2 to AJs. Further analysis of the LATS2-LATCH showed that it is sufficient for binding to LIMD1 and localization to AJs. Mutation of predicted contact residues within the LATS2-LATCH both disrupts its binding to LIMD1 and localization to AJs. These findings define a bipartite mechanism for LIMD1-dependent recruitment of LATS1/2 involving LIM domain-LATCH interactions and N-terminal IDR functions, providing insight into how mechanical signals are transduced through the Hippo pathway.
    DOI:  https://doi.org/10.1371/journal.pone.0342107
  53. Nature. 2026 Feb 04.
    Cleavage of mRNAs by a minority of pachytene piRNAs improves sperm fitness.
    Katharine Cecchini, Mina Zamani, Nandagopal Ajaykumar, Joel Vega-Badillo, Ayca Bagci, Shannon Bailey, Phillip D Zamore, Ildar Gainetdinov.
      Animals use 18-33-nucleotide PIWI-interacting RNAs (piRNAs) to silence transposons in germ cells1-3. In addition to transposon-silencing piRNAs, placental mammals make pachytene piRNAs4,5, an abundant class of testis-specific small RNAs derived from long noncoding RNA precursors. Although the sites of pachytene piRNA precursor transcription are often conserved among placental mammals, the sequences of the piRNAs themselves are rapidly diverging, even in the human population6. Consequently, the biological function and mechanism of action of pachytene piRNAs remain debated. Here we report that most mouse pachytene piRNAs have no biological function but instead 'selfishly' promote their own production. Our data suggest that pachytene piRNAs direct endonucleolytic cleavage of partially complementary targets and neither activate nor repress mRNA translation. Although many pachytene piRNAs guide cleavage of specific mRNAs, few alter the steady-state abundance of their targets. The minority of pachytene piRNAs that reduce target mRNA abundance enhance sperm fitness, thereby ensuring production of the entire pachytene piRNA repertoire. Together, our findings explain the lack of conservation of most pachytene piRNA sequences and suggest that these 'selfish' small RNAs persist in mammalian evolution because target cleavage by a tiny minority of piRNAs supports male fertility.
    DOI:  https://doi.org/10.1038/s41586-026-10102-9
  54. J Biochem. 2026 Feb 03. pii: mvag010. [Epub ahead of print]
    The eIF5-Mimic Protein 5MP1: A Regulator of Translation Stringency and a Multifaceted Oncogene.
    Abhineet Banerjee, Grant Brooke, Susumu Ishiguro, Katsura Asano.
      Accurate initiation of eukaryotic translation is essential for proteome integrity, yet the process is intrinsically challenged by the potential use of non-AUG start codons. The eIF5-mimic protein 5MP1 (also known as BZW2) has emerged as a pivotal regulator that enhances stringency in start codon selection by competing with eIF5 and eIF2B for binding to eIF2 and eIF3. This competition suppresses non-AUG and repeat-associated non-AUG (RAN) translation and remodels the dynamics of the scanning preinitiation complex. Beyond its biochemical role, accumulating evidence since the first report of BZW1/5MP2 as an oncogene in 2009 indicates that 5MP1/2 proteins promote proliferation, metastasis, and poor prognosis across diverse cancer types. However, the downstream effectors and mechanistic pathways linking translation control to tumorigenesis remain incompletely defined. This review summarizes current biochemical understanding of 5MP1 in translation initiation and synthesizes evidence supporting its tumor-promoting activities, outlining key questions and future directions.
    Keywords:  Translational control; cancer; non-AUG translation; oncogenic signaling; translation initiation
    DOI:  https://doi.org/10.1093/jb/mvag010
  55. Int J Biol Macromol. 2026 Feb 02. pii: S0141-8130(26)00612-4. [Epub ahead of print]346 150686
    K92 Lactylation of YBX1 orchestrates m5C RNA recognition to facilitate colorectal Cancer progression.
    Siche Chen, Xinyu Wang, Yanbin Chen, Yinbiao Qiao, Xinye Hu.
      RNA 5-methylcytosine (m5C) methylation is a vital epitranscriptomic mark involved in regulating numerous cellular and disease processes. A central effector of m5C-modified transcripts is Y-box binding protein 1 (YBX1), a key RNA-binding factor that modulates multiple aspects of RNA metabolism. Here, we identify lysine 92 (K92) as a predominant and previously unrecognized site of lactylation on YBX1, installed by the acyltransferase p300 and erased by the delactylase SIRT2. Although K92 lactylation has little effect on YBX1's cellular localization or stability, it significantly promotes its ability to associate with m5C-modified transcripts. Further analysis reveals that the RNA-binding protein G3BP2 preferentially interacts with lactylated YBX1, facilitating its engagement with m5C-modified RNAs. This interaction proves functionally critical, as K92 lactylation is required for YBX1-driven malignant behaviors in colorectal cancer (CRC). Clinically, analysis of a small set of CRC specimens suggests elevated YBX1 lactylation, consistent with its potential pathological relevance. Together, these results uncover a lactylation-dependent mechanism that governs m5C RNA recognition and contributes to YBX1's oncogenic activity.
    Keywords:  Colorectal cancer; G3BP2; Lactylation; YBX1
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150686
  56. Mol Med Rep. 2026 Apr;pii: 111. [Epub ahead of print]33(4):
    Circular RNAs in intervertebral disc degeneration: Current insights into mechanisms and therapeutic potentials (Review).
    Luyan Wang, Ke Yang, Houjun Zhu, Dachuan Wang, Feng Wang, Xianfa Du.
      Low back pain (LBP) is a leading cause of productivity loss worldwide and a major contributor to disability, imposing an economic burden on society. Intervertebral disc degeneration (IVDD) as a principal pathological driver of LBP remains a formidable therapeutic challenge, given that existing conservative and surgical interventions frequently fall short of achieving long‑term efficacy or halting disease progression. Advancements in molecular biology have revealed that circular RNAs (circRNAs) play a pivotal role in the intricate gene regulatory networks governing IVDD. The most extensively studied function of circRNAs is their ability to act as microRNA sponges. In addition, they participate in protein interactions, regulate gene transcription and serve as templates for protein translation. The present review provided a comprehensive overview of the current understanding of circRNA characteristics and functions, elucidated their involvement in IVDD pathogenesis and examined the therapeutic potential of emerging biomaterials for IVDD treatment. By consolidating existing research, the aim of this review was to offer theoretical foundations for innovative therapeutic strategies targeting IVDD.
    Keywords:  circular RNA; intervertebral disc degeneration; mechanisms; nucleus pulposus; therapeutic potentials
    DOI:  https://doi.org/10.3892/mmr.2026.13821
  57. Angew Chem Int Ed Engl. 2026 Feb 05. e26098
    Chemical Biology Tools for Decoding the Cell Surface GlycoRNA.
    Xinming Zhang, Yingying Zhu, Xiangli Shao, Haoyue Dong, Michiel Noe, Yuan Ma.
      The discovery of glycosylated RNAs (glycoRNAs) on the outer surface of mammalian cells, represents a spatial awakening in RNA biology. This identification redefines the spatial boundaries of RNA biology, possibly extending its role beyond the nucleus and cytoplasm to the extracellular membrane interface. This unexpected localization and the presence of glycosylation modifications challenge longstanding conventional paradigms and raise new questions about the biosynthetic pathways, structural diversity, and signaling functions of glycoRNAs in the intercellular environment. Chemical biology tools are central to their discovery, further identification, and future exploration, enabling enrichment, imaging, and functional analysis of glycoRNAs in both physiological and pathological contexts. In this review, we highlight how these technologies have driven the discovery of glycoRNAs and revealed new principles of RNA localization and membrane-related functions. We further discuss several challenges and future directions in decoding the RNA-centric membrane biology.
    Keywords:  RNA; cell surface RNA; chemical biology; glycosylation
    DOI:  https://doi.org/10.1002/anie.202526098
  58. Front Genet. 2025 ;16 1683576
    Genome-wide analysis of long non-coding RNAs and mRNAs in lung adenocarcinoma with pulmonary thromboembolism.
    Maryamgvl Ahmat, Gvzalnur Alim, Zhu Zhu, Chao Chen, Guolei Cao, Qin Luo.
       Introduction: Pulmonary thromboembolism (PTE) is a serious complication in patients with lung adenocarcinoma (LUAD), yet its molecular mechanisms remain poorly understood. This study aimed to investigate the expression profiles of long non-coding RNAs (lncRNAs) and mRNAs in LUAD patients complicated by PTE.
    Methods: Peripheral blood samples were collected from LUAD patients with PTE and from three control groups (LUAD-only, PTE-only, and healthy controls). RNA sequencing was performed to identify differentially expressed lncRNAs and mRNAs among groups.
    Results: RNA sequencing revealed significant dysregulation of transcripts. Compared with LUAD-only patients, 725 lncRNAs and 2,052 mRNAs were differentially expressed in the LUAD + PTE group. Compared with PTE-only patients, 932 lncRNAs and 2,206 mRNAs were differentially expressed, while comparison with healthy controls identified 1,190 lncRNAs and 3,001 mRNAs. Key dysregulated transcripts included MERGE.31027.6, ENST00000318988, MERGE.30976.2, and ENST00000397519. Enrichment analyses highlighted immune response-related pathways, cytokine signaling, and the NF-κB signaling pathway.
    Conclusion: These findings suggest that aberrant lncRNA and mRNA expression may contribute to the pathogenesis of LUAD complicated by PTE and may serve as potential biomarkers and therapeutic targets for prognosis and treatment.
    Keywords:  Kyoto Encyclopedia of Genes and Genome; RNA sequencing; long non-coding RNA; lung adenocarcinoma complicated by pulmonary thromboembolism; mRNA
    DOI:  https://doi.org/10.3389/fgene.2025.1683576
  59. Science. 2026 Feb 05. eads0960
    Live-cell single-molecule dynamics of eukaryotic RNA polymerase machineries.
    Yick Hin Ling, Chloe Liang, Sixiang Wang, Carl Wu.
      Eukaryotic gene expression is orchestrated by RNA polymerases (RNAPI, II, and III) and associated factors, yet their real-time dynamics remain obscure. Using single-molecule tracking in living yeast, we quantified the kinetics of 58 proteins encompassing three RNAP machineries. RNAPI and RNAPIII pre-initiation complexes (PICs) engage in long-lived chromatin interactions, contrasting with transient RNAPII PIC. We further report kinetics of RNAPII-associated factors for elongation, histone modification, C-terminal domain (CTD) modification, RNA processing, and termination. Many elongation factors show brief rather than persistent association, suggesting dynamic interactions with factor exchange, allowing a potential repertoire of regulatory events. CTD truncation reduces U1 snRNP residence time and intron retention in ribosomal protein genes, providing insights into co-transcriptional splicing. Our findings establish a framework of dynamic interactions of RNAP machineries.
    DOI:  https://doi.org/10.1126/science.ads0960
  60. Med Oncol. 2026 Feb 05. 43(3): 136
    LncRNA TMPO-AS1 aggravates the cisplatin resistance in cervical cancer via miR-140-5p/DNMT1 axis-mediated DNA methylation of KLK10.
    Jian Yang, Zhouhong Shi, Ting Song, Yurui Shao, Shunyu Hou, Chen Cheng, Baoquan Liang, Xiaojun Yang.
      Cisplatin resistance severely limits the efficacy of chemotherapy for cervical cancer (CC), and its molecular mechanisms remain incompletely understood. While epigenetic alterations such as DNA methylation are recognized as important contributors, the upstream regulatory networks, particularly the role of long non-coding RNAs (lncRNAs), are still unclear. This study aimed to explore novel mechanisms influencing cisplatin resistance in cervical cancer. Cisplatin-resistant CC cells (HeLa and SiHa) were established. A comprehensive approach employing mRNA and lncRNA microarrays, RT-qPCR, methylation-specific PCR (MSP-PCR), chromatin immunoprecipitation, luciferase reporter assays, RNA pull-down, RNA immunoprecipitation, cellular functional assays, and a mouse subcutaneous xenograft tumor model was utilized. The study found that Kallikrein 10 (KLK10) expression was significantly downregulated in cisplatin-resistant CC cells due to promoter hypermethylation mediated by DNA methyltransferase 1 (DNMT1). LncRNA microarray analysis revealed that TMPO-AS1 was the most significantly upregulated lncRNA in resistant cells. Functional assays confirmed that TMPO-AS1 promoted cisplatin resistance, proliferation, migration, and invasion of CC cells. Mechanistically, TMPO-AS1 acted as a competitive endogenous RNA (ceRNA) by sponging miR-140-5p, thereby relieving its inhibitory effect on DNMT1 mRNA, upregulating DNMT1 expression, enhancing KLK10 promoter methylation, and leading to its silencing. In vivo experiments further demonstrated that silencing TMPO-AS1 inhibited tumor growth. This study unveils a novel TMPO-AS1/miR-140-5p/DNMT1/KLK10 regulatory axis that plays a critical role in cisplatin resistance in CC, providing a potential therapeutic target for overcoming chemoresistance.
    Keywords:  Cervical cancer; Cisplatin resistance; DNA methylation; KLK10; TMPO-AS1
    DOI:  https://doi.org/10.1007/s12032-025-03233-y
  61. bioRxiv. 2026 Jan 16. pii: 2026.01.15.699768. [Epub ahead of print]
    Small RNA sequencing of human sural nerves identifies widespread microRNA dysregulation and Schwann cell-localized miR-21-5p in diabetic peripheral neuropathy.
    Sneha A Gummadi, Ryan R Ju, Victoria Pastor, Eric C Meyers, Shai M Rozen, Diana Tavares-Ferreira.
      Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with no disease modifying treatments. Despite the prevalence, the molecular mechanisms of DPN are not fully characterized. Among the various molecular regulators, microRNAs (miRNAs) control protein synthesis and are essential for normal development and homeostasis, with dysregulation implicated in cancer and neurodegenerative diseases. In this study, we performed small RNA-sequencing to profile the miRNA landscape of human sural nerves from individuals with and without DPN. Our analysis revealed that nearly 10% of all miRNAs detected are dysregulated and among those 74% are significantly downregulated in DPN. Target gene enrichment analysis of the differentially expressed miRNAs yielded pathways significantly associated with nerve regeneration, metabolic dysfunction, and immune cell activity. In particular, miR-21-5p is significantly upregulated in DPN, showed a positive association with axonal loss severity, and localizes to Schwann cells, consistent with its broader role as an injury- and inflammation-responsive miRNA that shifts from early pro-regenerative functions to maladaptive, inflammation-amplifying effects that impair Schwann cell mediated nerve repair. These results suggest that miRNAs may contribute to peripheral nerve degeneration by promoting inflammation, apoptosis, oxidative stress, and impaired nerve regeneration, while also opening potential avenues for biomarker discovery and therapeutic intervention.
    Article highlights: We undertook this study to address the limited understanding of molecular changes contributing to diabetic peripheral neuropathy (DPN) in humans.We sought to profile microRNAs (miRNAs), key post-transcriptional regulators of gene expression, in human sural nerves and developed a dedicated computational pipeline for robust miRNA quantification, differential expression, and target enrichment analysis.Our analyses revealed widespread miRNA dysregulation in DPN, with most altered miRNAs downregulated and miR-21-5p significantly upregulated in DPN, highly correlated with axonal loss severity and localized to Schwann cells.These findings suggest that miRNA imbalance, including elevated Schwann cell miR-21-5p, may contribute to nerve dysfunction in DPN and provide new opportunities for biomarker development and therapeutic targeting.
    DOI:  https://doi.org/10.64898/2026.01.15.699768
  62. Chemistry. 2026 Feb 05. e00025
    A Bifunctional Small Molecule Degrader of the Long Noncoding RNA MALAT1 Triplex.
    Christian A T Brega, Benjamin A Craig, Sigitas Mikutis, Rupert S J Proctor, Yuliia Vyborna, Maria Eleftheriou, Kostas Tzelepis, Mo Yang, Shaifaly Parmar, Javier Bonet-Aleta, John S Schneekloth, Gonçalo J L Bernardes.
      The targeted degradation of RNA, particularly long noncoding RNAs (lncRNAs), holds immense potential for therapeutic interventions in diseases associated with aberrant RNA regulation. Here, we introduce a novel Proximity-Induced Nucleic Acid Degrader (PINAD-1), a first-in-class small molecule that selectively induces the degradation of MALAT1, a lncRNA implicated in the regulation of metastatic processes. PINAD-1 is designed by conjugating a binder specific for the triple helix structure of MALAT1 to an imidazole-based RNA-degrading warhead, enabling specific cleavage of the MALAT1 transcript in vitro and in cellulo, with minimal off-target effects on the structurally similar NEAT1 lncRNA. Through mechanistic studies, we show that effective RNA degradation is not solely dependent on proximity but requires a precise structural context, as demonstrated by the differential activity of PINAD-1 compared to the structurally analogous but functionally inert conjugate PINAD-2. Our findings underscore the importance of binder-induced destabilization and RNA geometry in facilitating RNA degradation. This work lays the foundation for the design of bifunctional small-molecule RNA degraders as powerful tools for the modulation of structured noncoding RNAs, offering potential applications in RNA-based therapeutics.
    Keywords:  MALAT1; RNA; degraders; proximity induced; small‐molecule
    DOI:  https://doi.org/10.1002/chem.202600025
  63. J Vis Exp. 2026 Jan 16.
    NEAT1/miR-181a-5p/HMGB1 Axis Regulates Macrophage Polarization and Inflammation in Sepsis Models.
    Kuo Wang, Yancun Liu, Yanfen Chai.
      Sepsis is characterized by a dysregulated host immune response and remains a leading cause of mortality worldwide. Long non-coding RNA NEAT1 has been implicated in inflammatory diseases, but its specific role in macrophage polarization during sepsis has not been fully defined. Here, we systematically examine the NEAT1/miR-181a-5p/HMGB1 axis across clinical samples, cultured macrophages, and a CLP mouse model. Quantitative PCR, western blotting, dual-luciferase reporter assays, and RNA pull-down experiments are used to confirm the competitive endogenous RNA (ceRNA) interaction among NEAT1, miR-181a-5p, and HMGB1. Functional assays, including immunofluorescence, transwell migration, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, are applied to assess macrophage polarization, migration, and apoptosis. In vivo, the CLP model combined with ELISA and histopathology validates the impact of NEAT1 knockdown on cytokine profiles and organ injury. NEAT1 and HMGB1 are upregulated, whereas miR-181a-5p is downregulated, in patients with sepsis and in lipopolysaccharide-stimulated macrophages. Silencing NEAT1 promotes M2 macrophage polarization, reduces pro-inflammatory cytokines, impairs macrophage migration, and alleviates tissue damage in septic mice via the miR-181a-5p/HMGB1 axis. To our knowledge, this is the first integrated protocol to characterize the lncRNA-microRNA-HMGB1 regulatory circuit in sepsis using harmonized clinical, in vitro, and in vivo approaches. It provides a methodological framework for targeting NEAT1-related ceRNA networks as potential therapeutic strategies.
    DOI:  https://doi.org/10.3791/69802
  64. bioRxiv. 2026 Jan 23. pii: 2026.01.22.698893. [Epub ahead of print]
    Super-resolved, three-dimensional spatial transcriptomics reveals cell-type and brain-region-specific modulation of key epitranscriptomic switches following adolescent alcohol exposure.
    Jamuna Tandukar, Anam Islam, Emir Malovic, Bisma Afzal, Huaibo Zhang, Subhash C Pandey, Ruixuan Gao.
      Epitranscriptomic mechanisms dynamically regulate neuronal function through gene expression, but their precise roles in neuropsychiatric and neurological disorders remain to be fully elucidated. A major obstacle to advancing such studies is the absence of a methodology for precise, cell-type and brain-region-specific quantification of critical epitranscriptomic regulators under these complex brain conditions. To overcome this challenge, we developed a super-resolved, three-dimensional spatial transcriptomics method to quantify key epitranscriptomic switches in intact brains. Using this method, we quantified the expression of Mettl3 , an N6-methyladenosine (m6A) methyltransferase enzyme recently shown to be upregulated in the amygdala after adolescent intermittent ethanol (AIE) exposure in rats. We observed a significant increase in cytoplasmic Mettl3 mRNA in neurons, but not in astrocytes or microglia, within the adult central amygdala and the CA1 and dentate gyrus of hippocampus following AIE. In contrast, no significant changes were observed across neurons, astrocytes, or microglia within the basolateral amygdala or the hippocampal CA3. Additionally, we found both the cytoplasmic density and subcellular localization of Mettl3 mRNA were dependent on the specific cell types and brain subregions examined. These results suggest that AIE increases Mettl3 expression in a highly cell-type-specific and spatially heterogeneous manner, underscoring the necessity of high-resolution spatial transcriptomics methods for studying transcriptomic and epitranscriptomic regulations under neurological conditions.
    Significance Statement: Epitranscriptomics plays a crucial role in neuronal functions by influencing the splicing, stability, and translation of genes. However, the exact role of epitranscriptomic mechanisms, such as m6A RNA methylation, in brain disorders remains unclear, particularly in a cell-type and circuitry-specific manner. Here we developed a super-resolved, three-dimensional spatial transcriptomics method and applied it to a model of alcohol exposure. We found differential cell-type- and brain-region-specific modulation of Mettl3 , a key m6A enzymatic switch, across major brain regions following adolescent intermittent ethanol exposure in adulthood. Our findings, coupled with our pipeline, are expected to address existing methodological limitations and knowledge gaps, thereby accelerating brain transcriptomic and epitranscriptomic studies under various psychiatric and neurological conditions.
    DOI:  https://doi.org/10.64898/2026.01.22.698893
  65. bioRxiv. 2026 Jan 20. pii: 2026.01.16.699780. [Epub ahead of print]
    Systematic fusion transcript discovery in mantle cell lymphoma using long-read sequencing.
    Lael Pasipamire, Jacob Rashid, Caiden Lukan, Nandita Das, Jie Li, Chioniso Patience Masamha.
      Fusion transcripts are composed of hybrid RNA consisting of transcripts from two distinct genes and can arise from physical linking of genes at the DNA level, splicing or read-through transcription. In addition, there are also fusion transcripts that can occur between a protein coding gene and long non-coding RNAs. Systemic detection of all fusion transcripts at the RNA-level is important in the identification of potential therapeutic drug targets as well as biomarkers for detection, classification, and subtyping of cancer. We used long-read third-generation sequencing of RNA, Iso Sequencing to identify fusion transcripts in Mantle Cell Lymphoma (MCL) cell lines. Our results revealed widespread transcript diversity in MCL. The majority of the long-read transcripts were novel. Some of the thousands of novel transcripts we identified were fusion transcripts. These fusion transcripts had some of the longest transcripts in the MCL transcriptome. We identified the fusion junction of several select fusion transcripts involving protein coding genes including the well-known and widely expressed CTBS::GNG5 and validated their presence using other techniques. Furthermore, we also identified and validated a novel fusion transcript between the multifunctional, m6A methylation 'writer', RBM15, and LAMTOR5:AS, a long noncoding RNA. Use of the chemical compound, JT-607, an inhibitor of CPSF73/CPSF3 which affects both alternative polyadenylation and read-through transcription resulted in increased expression of the RBM15::LAMTOR5:AS fusion transcript. Our analysis suggests that RBM15::LAMTOR5:AS and many fusion transcripts we identified are intrachromosomal. Since the origin, significance and impact of many fusion transcripts remain unknown, our results support using an unbiased approach to identify fusion transcripts. This will help us to fully comprehend the complexity of the human transcriptome in normal biology and in disease.
    DOI:  https://doi.org/10.64898/2026.01.16.699780
  66. Int J Biol Macromol. 2026 Feb 04. pii: S0141-8130(26)00679-3. [Epub ahead of print] 150753
    circIRES-DAF: A dual-attenuation fusion framework for identification of internal ribosome entry sites in circular RNAs.
    Zheng Wang, Lian Liu, Xiujuan Lei.
      Internal ribosome entry sites (IRESs) in circular RNAs (circRNAs) are key elements that drive cap-independent translation, and their accurate identification is crucial for understanding circRNA function. Currently, most IRES prediction models are designed for linear RNA sequences, and models specifically for circRNAs still show suboptimal performance. To address this, we proposed a dual-attenuation fusion framework, circIRES-DAF, specifically designed for predicting IRES in circRNAs. The model captures sequence features and local contextual information through a dual-channel sequence feature extraction module; meanwhile, it integrates a graph neural network to model RNA secondary structure. Furthermore, the model introduces a dual-attenuation fusion strategy based on local feature quality evaluation and global modality importance weighting. This strategy effectively suppresses noise and enhances discriminative capability. Ablation experiments demonstrate that sequence and structural features provide complementary information, and the dual-attenuation fusion mechanism significantly improves model performance. On independent test sets, circIRES-DAF outperforms existing mainstream methods. Furthermore, interpretability analysis reveals several potential consensus motifs associated with IRES elements, providing a powerful computational tool and biological insights for circRNA research.
    Keywords:  Circular RNAs; Dual-attenuation fusion; Internal ribosome entry site
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150753
  67. PLoS Biol. 2026 Feb;24(2): e3003598
    Epimutations driven by RNAi or heterochromatin evoke transient antimicrobial drug resistance in pathogenic Mucor fungi.
    Ye-Eun Son, Carlos Pérez-Arques, Joseph Heitman.
      Antimicrobial resistance (AMR) is a global health threat emerging through microbe adaptation, driven by genetic variation, genome plasticity or epigenetic processes. In this study, we investigated how the Mucor circinelloides species complex adapts to the antifungal natural product FK506, which binds to FKBP12 and inhibits calcineurin-dependent hyphal growth. In Mucor bainieri, most FK506-resistant isolates (90%) were found to be unstable and transient, readily reverting to being drug sensitive when passaged without drug, and with no associated DNA mutations. In half of the isolates (50%), FK506-resistance was conferred by RNAi-dependent epimutation in which small interfering RNAs (siRNAs) silenced the fkbA encoding FKBP12 post-transcriptionally. In contrast, most of the remaining FK506-resistant isolates (40%) were found to have undergone heterochromatin-mediated silencing via H3K9 dimethylation, transcriptionally repressing fkbA and neighboring genes. In these heterochromatic epimutants, only minimal enrichment of siRNA to the fkbA locus was observed, but in three of the four examples, siRNA was significantly enriched at a locus distant from fkbA. A similar mechanism operates in Mucor atramentarius, where FK506 resistance was mediated by ectopic heterochromatin silencing of fkbA and associated genes with siRNA spreading across the region. Heterochromatin-mediated fkbA epimutants exhibited stability during in vivo infection, suggesting epimutation could impact pathogenesis. These findings reveal that antifungal resistance arising through distinct, transient epimutation pathways involving RNAi or heterochromatin, highlighting adaptive AMR strategies employed by ubiquitous eukaryotic microbes.
    DOI:  https://doi.org/10.1371/journal.pbio.3003598
  68. Adv Biomed Res. 2025 ;14 133
    LNC01089-LINC00963/miR-1244-5p/IGF1 ceRNA Axis Regulate FOXO Signaling Pathway in Breast Cancer Patients: A Biomarker Discovery Investigation.
    Mohammad Rezaei, Ramin Masoudi Marghmaleki, Farzaneh Sanati Boroujeni, Abbas Shahriari, Shadi Omidghaemi, Mansoureh Azadeh.
       Background: Breast carcinoma (BC) ranks as one of the most prevalent illnesses among women, and a variety of factors, including inherited and environmental factors, can impact its start and progression. In this study, we tried to analyze the expression patterns of mRNAs and long noncoding RNAs and find novel biomarkers for the diagnosis and prognosis of BC during a systems biology approach.
    Materials and Methods: Microarray analysis was performed to find novel potential BC biomarkers. Using miRWalk, lncRRIsearch, STRING, and Cytoscape, noncoding and protein interaction analysis was utilized and visualized. Pathway enrichment and gene ontology analyses were performed to find accurate biological mechanisms of selected RNAs. qRT-PCR was established on 50 tumor samples compared to 50 control samples for validation of bioinformatics analyses and understanding of the diagnosis capability of selected RNAs.
    Results: IGF1 expression level had a significant reduction in BC based on microarray and qRT-PCR experiments. LINC00963 and LNC01089 also have significant decreases in expression levels based on GEPIA2 and qRT-PCR. LNC01089 and LINC00963 could represent suitable BC diagnostics (depending on receiver operating characteristic analysis) and prognosis (clinicopathological analysis) biomarkers. The two mentioned lncRNAs have direct interaction with IGF1 mRNA. miR-1244-5p as a potential upregulated oncogene of BC suppresses the expression level of LNC01089, LINC00963, and IGF1.
    Conclusion: LINC00963 and LNC01089 could regulate the FOXO signaling pathway through direct interaction with IGF1 mRNA. miR-1244-5p might also have a critical role in FOXO regulation through suppression of IGF1 and two mentioned lncRNAs.
    Keywords:  Breast cancer; IGF1 protein; long noncoding RNA; microRNA; systems biology
    DOI:  https://doi.org/10.4103/abr.abr_490_23
  69. Chembiochem. 2026 Jan;27(2): e202500774
    Transcript-Level Modulation of O-GlcNAc Transferase for Aging-Related Neurodegenerative Diseases.
    Florian Malard.
      The O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.
    Keywords:   O‐GlcNAc transferase; O‐GlcNAcylation; RNA therapeutics; alternative splicing; antisense oligonucleotide; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/cbic.202500774
  70. Noncoding RNA Res. 2026 Jun;18 12-21
    Noncoding RNAs are indispensable architects and regulators of biomolecular condensates.
    Shiyuan Chen, Canchen Wang, Junyi Hu, Ting Luo, Qian Li, Hui Shen.
      Liquid-liquid phase separation (LLPS) is a biophysical mechanism by which certain biomolecules demix from the cytosol or nucleoplasm to form membraneless organelles. These droplet-like assemblies are dynamic and reversible, allowing selective enrichment of specific proteins and nucleic acids while excluding others. Classical examples include the nucleolus, P-bodies, and stress granules, all of which exhibit liquid-like behaviors such as rapid fusion, fission, and molecular exchange. Most importantly, the LLPS property has been implicated with a plethora of physiological and pathological processes. Historically, research on LLPS focused on protein drivers, especially RNA-binding proteins (RBPs) with low complexity domains or intrinsically disordered regions, contributing to multivalent weak interactions. However, it is now clear that RNA molecules especially noncoding RNAs are integral components and often active modulators of these condensates. Noncoding RNAs, including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), and others, can serve as scaffolds, regulators, or clients within the LLPS droplets, thereby influencing both normal cellular organization and disease processes. This review provides an overview of current research on how ncRNAs contribute to LLPS across different cellular localizations and contexts, covering physiological condensates, disease linked phase separation, underlying molecular mechanisms, and emerging therapeutic implications.
    Keywords:  Non-coding RNA; RNA-binding protein; condensates; liquid-liquid phase separation
    DOI:  https://doi.org/10.1016/j.ncrna.2026.01.003
  71. BMC Musculoskelet Disord. 2026 Jan 30.
    The METTL3-IGF2BP3 axis drives osteosarcoma progression by enhancing ID1 mRNA stability.
    Rongbing Shu, Qiuxin Cheng, Zhuanyi Yu, Huaqiang Zhou, Mingchao Lin, Minghong Shi, Jianhe Chen, Jingxiang Chen, Min Zhao.
       OBJECTIVE: Osteosarcoma (OS) is a highly aggressive malignant bone tumor. While ID1 plays a critical role in OS progression, the underlying mechanisms remain unclear. This study investigates the METTL3-IGF2BP3 axis-mediated N6-methyladenosine (m6A) modification in regulating ID1 mRNA stability and its functional implications in OS.
    METHODS: RNA-binding proteins (RBPs) associated with ID1 were predicted using the ENCORI database. Differentially expressed RBP genes (RBP-DEGs) were screened via the GSE253548 dataset, and core RBP-DEGs were identified using machine learning algorithms. m6A modification sites on ID1 mRNA were predicted by SRAMP, while the interaction between METTL3/IGF2BP3 and ID1 was analyzed via the RM2Target database. Functional experiments including CCK-8, colony formation, wound healing, and Transwell assays were performed to assess OS cell proliferation, migration, and invasion. Mechanistic insights were validated through MeRIP-qPCR, RIP-qPCR, RNA stability assays, and dual-luciferase reporter experiments. Additionally, a subcutaneous xenograft mouse model of OS was established to evaluate tumor growth, with tumor volume/weight and Ki67 expression monitored.
    RESULTS: Bioinformatics analysis identified METTL3 and IGF2BP3 as core regulators of ID1, with elevated ID1, IGF2BP3, and METTL3 expression observed in OS cells. Mechanistically, IGF2BP3 enhanced ID1 mRNA stability by binding to m6A-modified ID1 transcripts, while METTL3 catalyzed ID1 mRNA m6A modification to strengthen IGF2BP3-ID1 interaction. Cellular assays demonstrated that the METTL3-IGF2BP3 axis significantly promoted OS cell proliferation, migration, and invasion via m6A-dependent ID1 stabilization. In vivo studies further confirmed that this axis accelerated OS tumor growth by upregulating ID1 expression.
    CONCLUSION: The METTL3-IGF2BP3 axis facilitates OS progression by enhancing ID1 mRNA stability and expression, highlighting its potential as a therapeutic target.
    Keywords:  ID1; IGF2BP3; METTL3; Osteosarcoma; m6A; mRNA stability
    DOI:  https://doi.org/10.1186/s12891-026-09527-0
  72. Physiology (Bethesda). 2026 Feb 05.
    mRNA translation and proteasomal degradation in health and neurological disease.
    Alinny R Isaac, Danielle Cozachenco, Beatriz de A Wagner, Mariana G Chauvet, Mychael V Lourenco.
      The homeostasis of cellular proteins, i.e., proteostasis, is critical for neuronal function and brain processes. Proteostasis comprises a set of cellular mechanisms that control protein synthesis, folding, post-translational modification and degradation. Mounting evidence indicates that disruptions in such mechanisms may underlie several neurological diseases, including neurodevelopmental, neurodegenerative and psychiatric diseases. In this review, we discuss molecular pathways involved in protein synthesis and degradation that are altered in several brain diseases, possible pharmacological approaches to correct these defects, and future perspectives for the field.
    Keywords:  mental health; neurodegenerative diseases; proteostasis; translational control
    DOI:  https://doi.org/10.1152/physiol.00023.2025
  73. Res Sq. 2026 Jan 19. pii: rs.3.rs-8523796. [Epub ahead of print]
    Genome-wide profiling of RNA 2'-O-methylation in neurons and identification of orphan snoRNA targets.
    Gordon Carmichael, Xuan Ye, Yaling Liu, Yinzhou Zhu, Saran Alshawi, Brittany Elliott, Christopher Holley, Jean-Denis Beaudoin, Brenton R Graveley.
      We have compared genome-wide patterns of RNA 2'- O -methylation (Nm) between two isogenic pairs of neurons. Each pair includes one line harboring a small deletion of orphan box C/D snoRNAs (SNORD116s) from the paternal chr15q11-q13 region. One isogenic pair also differs in expression of SNORD113/114 snoRNAs from chr14q32.2. Wild-type and modified cells were differentiated into cortical neurons, and genome-wide patterns of Nm identified. Neurons display a distinctive signature of rRNA modification compared to undifferentiated stem cells. We further identified thousands of shared Nm sites in mRNAs, lncRNAs and small RNAs. Most sites do not exhibit canonical complementarity to snoRNAs, but a number exhibit strong complementarity to U3 snoRNA, not previously shown to direct Nm. Evidence from cross-linking and sequencing of hybrids (CLASH) suggests that U3 is proximally associated with a subset of 2'- O -methylation events. Finally, we identify a number of apparent canonical targets of SNORD113, SNORD114 and SNORD116 snoRNAs. These data present a comprehensive characterization of the Nm landscape in neurons and, for the first time, allow the assignment of Nm sites targeted by specific orphan snoRNAs associated with neurodevelopmental and other disorders.
    DOI:  https://doi.org/10.21203/rs.3.rs-8523796/v1
  74. J Cell Biol. 2026 Apr 06. pii: e202501207. [Epub ahead of print]225(4):
    Cullin-3 adaptor SHKBP1 inhibits SQSTM1/p62 oligomerization and Keap1 sequestration.
    Lin Luan, Xiaofu Cao, Zijun Xia, Shivanshi Vaid, Manuel D Leonetti, Jeremy M Baskin.
      SQSTM1/p62 is a master regulator of the autophagic and ubiquitination pathways of protein degradation and the antioxidant response. p62 functions in these pathways via reversible assembly and sequestration of additional factors into cytoplasmic phase-separated structures termed p62 bodies. The physiological roles of p62 in these various pathways depend on numerous mechanisms for regulating p62 body formation and dynamics that are incompletely understood. Here, we identify a new mechanism for regulation of p62 oligomerization and incorporation into p62 bodies by SHKBP1, a cullin-3 E3 ubiquitin ligase adaptor, that is independent of its potential functions in ubiquitination. We map an SHKBP1-p62 protein-protein interaction outside of p62 bodies that limits p62 assembly into p62 bodies and affects the antioxidant response involving sequestration of Keap1 and nuclear translocation of Nrf2. These studies provide a non-ubiquitination-based mechanism for an E3 ligase adaptor in regulating p62 body formation and cellular responses to oxidative stress.
    DOI:  https://doi.org/10.1083/jcb.202501207
  75. Discov Oncol. 2026 Feb 04.
    The role of Alanyl-tRNA synthetase 1 lactylation in tumors and other diseases.
    Xiao-Yan Zhou, Xing-Ju Zhou.
      Tumorigenesis and progression are driven by dysregulated genes and signaling pathways, with cellular metabolic reprogramming being a hallmark that supports neoplastic growth. Alanyl-tRNA Synthetase 1 (AARS1), a key enzyme with dual roles in metabolism and gene expression regulation, has emerged as a critical focus in cancer and disease research. As a member of the aminoacyl-tRNA synthetase (AARS) family, AARS1 canonically catalyzes the attachment of alanine to its cognate transfer RNA (tRNA) to ensure fidelity in protein synthesis. Emerging evidence reveals non-canonical roles of AARS1 in tumor biology, including regulation of metabolic reprogramming, cell proliferation, apoptosis, and intracellular signal sensing-all of which directly impact tumor growth and patient prognosis. Beyond cancer, dysregulated AARS1 (via abnormal expression or pathogenic mutations) is linked to a spectrum of non-malignant disorders, including Charcot-Marie-Tooth (CMT) disease (a hereditary peripheral neuropathy), adult-onset leukoencephalopathy, recurrent acute liver failure, and sulfide dysplasia. These associations arise from disrupted cellular homeostasis and impaired physiological functions caused by AARS1-mediated pathway dysregulation. Notably, AARS1's ability to sense lactate and catalyze lysine lactylation-a newly identified post-translational modification (PTM)-represents a novel mechanism linking metabolic dysregulation to disease pathogenesis. Dysregulated AARS1 contributes to tumor initiation, progression, metastasis, and treatment resistance, while its mutations drive the onset of several neurodegenerative and metabolic disorders. Unraveling the molecular mechanisms of AARS1, particularly its lactylation-related functions, will deepen our understanding of cellular metabolism in disease and identify novel therapeutic targets for precise diagnosis and treatment of tumors and other disorders. Furthermore, AARS1 holds significant promise as a diagnostic biomarker and therapeutic target, offering new avenues for precision medicine in both oncology and non-malignant conditions.
    Keywords:  AARS1; Charcot-Marie-Tooth disease; Lysine lactylation; Metabolic reprogramming; Protein synthesis; Tumor
    DOI:  https://doi.org/10.1007/s12672-026-04549-5
  76. Biosci Biotechnol Biochem. 2026 Feb 04. pii: zbag015. [Epub ahead of print]
    Re‑thinking translation quality control in bacteria: from trans‑translation to collided‑disome surveillance.
    Hiraku Takada.
      Cells must recycle stalled ribosomes while preventing the accumulation of aberrant nascent chains. In bacteria, this is achieved by overlapping pathways with distinct substrates: ribosome-rescue systems act mainly on non-stop mRNAs, whereas ribosome-associated quality control (RQC) targets mid-ORF arrests. Work in Gram-positive bacteria defined an RQC mechanism that appends C-terminal degrons to stalled peptides, yet the full set of bacterial substrates and splitting factors remains unresolved, and enteric bacteria notably lack a canonical RQC elongation factor. This review traces the field from the discovery of tmRNA (also known as 10Sa RNA or SsrA RNA) through alternative rescue pathways to the current bacterial RQC framework. I summarize mechanisms across three layers-processing of 50S-peptidyl-tRNA, collision sensing and splitting, and downstream proteolysis-and compare species-level strategies and conservation patterns. I highlight how rescue and quality control intersect during phage infection, and outline key mechanistic uncertainties and experiments needed to resolve them.
    Keywords:  RQC; Ribosome; tmRNA; translation quality control
    DOI:  https://doi.org/10.1093/bbb/zbag015
  77. Am J Pathol. 2026 Feb 01. pii: S0002-9440(26)00029-5. [Epub ahead of print]
    Pseudogene-derived long non-coding RNAs GSM3P1/Gstm2-ps1 exacerbate sepsis-associated acute kidney injury by suppressing their parent gene translation.
    Jing Huang, Zheng Dong, Qingqing Wei.
      Long non-coding RNAs (lncRNAs) are emerging as critical regulators of acute kidney injury (AKI). In this study, we investigated the pathological role of pseudogene derived lncRNA GSTM3P1(human)/Gstm2-ps1(mouse) in sepsis-associated AKI (SA-AKI). GSTM3P1/Gstm2-ps1 was transiently upregulated in kidney proximal tubular cells at the early stage of SA-AKI in mice treated with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP), as well as in LPS-treated proximal tubular cells. Functionally, overexpression of GSTM3P1/gstm2-ps1 exacerbated LPS-induced proximal tubular cell apoptosis and oxidative stress. In contrast, proximal tubule-specific gstm2-ps1 knockout mice were significantly protected from LPS-induced AKI, as evidenced by improved renal function and reduced apoptosis, kidney injury markers, and reactive oxygen species. Similarly, these mice showed renal protective effects against CLP-induced AKI. Mechanistically, overexpression of GSTM3P1/Gstm2-ps1 in proximal tubular cells markedly suppressed parent gene GSTM3/GSTM2 protein but not mRNA expression, indicating a translational repression. Restoration of GSTM3/GSTM2 rescued proximal tubular cells from LPS-induced apoptosis. Furthermore, RNA pulldown assay revealed that Gstm2-ps1 bind to Human antigen R (HuR), a known post-transcriptional regulator for mRNA stability and translation. Overexpression of HuR antagonized Gstm2-ps1-mediated repression of GSTM2, associated with increased cell survival after LPS injury. In conclusion, the early induction of GSTM3P1/Gstm2-ps1 in SA-AKI exacerbates kidney injury by a novel mechanism to sequester HuR and inhibit the translation of parent gene GSTM3/gstm2 for oxidative stress detoxification.
    Keywords:  HuR; apoptosis; epigenetic regulation; lncRNA; oxidative stress; pseudogene; sepsis
    DOI:  https://doi.org/10.1016/j.ajpath.2026.01.004
  78. Nucleic Acids Res. 2026 Feb 05. pii: gkag080. [Epub ahead of print]54(4):
    AquIRE reveals the mechanisms of clinically induced RNA damage and the conservation and dynamics of glycoRNAs.
    Zijian Zhang, Zornitsa Vasileva Kotopanova, Kexin Dang, Xiangxu Kong, Nicole Simms, Tin Wai Yuen, Lan Lam, Lauren Forbes Beadle, Emma Hilton, Taqdees Qureshi, Marianna Coppola, Callum David Holmes, Kwan Ting Kan, Mark Ashe, Patrick Gallois, Hilary Ashe, Michael Braun, Mark Saunders, Paul Sutton, David J Thornton, John R P Knight.
      RNA is subject to many modifications, from small chemical changes like methylation to conjugation of biomolecules such as glycans. As well as endogenously written modifications, RNA is also exposed to damage induced by its environment. Certain clinical compounds are known to covalently modify RNA with a growing appreciation of how these impact clinical efficacy. To understand the regulation of these modifications, we need a reliable, sensitive, and rapid methodology for their quantification. Thus, we developed Aqueous Identification of RNA Elements (AquIRE) and applied it to the analysis of drug-induced RNA damage by 5FU, oxaliplatin, and temozolomide in clinically relevant cell models. We demonstrate that RNA damage is widespread and follows previously unappreciated temporal dynamics. AquIRE also provides a highly sensitive method to detect RNAs modified by glycans. We leverage this to expand the horizons of the glycoRNA world across the kingdoms of life as well as identifying cell-free glycoRNAs in multiple species. We demonstrate that glycoRNA expression is dynamic during embryo development, modulated during senescence, and elevated by RNA-damaging agents. Finally, we use RNA digestion to demonstrate that cell surface or cell-free RNA promotes the cytotoxicity of RNA-damaging chemotherapy. Together, the AquIRE platform provides an intrinsically flexible method to study diverse RNA modifications from any sample.
    DOI:  https://doi.org/10.1093/nar/gkag080
  79. PeerJ. 2026 ;14 e20538
    Integrative analysis for identification of key miRNA-mRNA regulatory axes in esophageal cancer and preliminary validation of the regulatory role of miR-15b-5p/BTG2 therein.
    Wenyuan Hong, Chaoyang Xia, Gao Li.
       Background: Esophageal cancer (ESCA), a leading cause of cancer-related mortality, lacks reliable biomarkers for early detection and prognosis. Dysregulated microRNAs (miRNAs) have emerged as pivotal regulators of tumor progression, yet their context-specific roles and interactions with target genes in ESCA remain underexplored.
    Methods: Multi-omics data from The Cancer Genome Atlas-esophageal cancer (TCGA-ESCA) and Gene Expression Omnibus (GEO) datasets were integrated to identify differentially expressed miRNAs and mRNAs. A miRNA-mRNA regulatory network was constructed using FunRich and validated through functional assays, including dual-luciferase reporter, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in vitro proliferation/migration/invasion experiments. Prognostic signatures were developed using Cox regression, least absolute shrinkage and selection operator (LASSO)-Cox and nomogram analysis.
    Results: We identified 1,131 differentially expressed mRNAs and 69 miRNAs in ESCA. The miR-15b-5p/BTG2 axis emerged as a central regulatory hub. miR-15b-5p was significantly upregulated in ESCA tissues and showed an inverse correlation with B-cell translocation gene 2 (BTG2) expression. Survival analyses established both molecules as independent prognostic factors. Mechanistically, miR-15b-5p directly targeted BTG2 3'UTR, suppressing its expression. Functional studies demonstrated that miR-15b-5p overexpression promoted proliferation, migration and invasion in ESCA cells, whereas BTG2 restoration reversed these effects. A prognostic nomogram integrating miR-15b-5p, BTG2 and clinical parameters demonstrated robust predictive accuracy (C-index: 0.78).
    Conclusions: The miR-15b-5p/BTG2 axis represents a novel regulatory mechanism in ESCA progression with significant potential as both a prognostic biomarker and therapeutic target.
    Keywords:  Esophageal cancer; Functional genomics; Prognostic biomarker; miR-15b-5p/BTG2; miRNA-mRNA network
    DOI:  https://doi.org/10.7717/peerj.20538
  80. Antonie Van Leeuwenhoek. 2026 Feb 03. 119(2): 46
    The role of non-coding RNAs in Staphylococcus aureus infections: mechanisms, biomarkers, and therapeutic implications.
    Tahereh Barati, Fatemeh Ghaffarian Sayeli, Ali Nazari-Alam.
      Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play crucial roles in regulating the host's response to Staphylococcus aureus (S. aureus) infections. These ncRNAs are involved in various biological processes, including immune regulation, inflammation, tissue repair, and apoptosis, and their dysregulation often contributes to the severity of S. aureus-induced diseases. Recent studies have highlighted the significance of ncRNAs in controlling both innate and adaptive immune responses, as well as their potential as biomarkers for disease diagnosis and prognosis. Additionally, ncRNAs are emerging as promising therapeutic targets, especially in light of the growing prevalence of antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA). However, while ncRNAs show great promise in improving treatment outcomes, much remains to be understood about their exact mechanisms in S. aureus pathogenesis. Further research into ncRNA-based therapeutic strategies is crucial to developing novel approaches for combating S. aureus infections and addressing the challenges posed by antibiotic resistance. This review emphasizes the potential of ncRNAs in S. aureus infections and their application in future therapeutic interventions.
    Keywords:   Staphylococcus aureus ; Biomarker; Infection; MRSA; circRNA; lncRNA; miRNA
    DOI:  https://doi.org/10.1007/s10482-026-02256-3
  81. FASEB J. 2026 Feb 15. 40(3): e71518
    Nucleolar Protein Nop2 Promotes Neural Differentiation by Regulating Ribosome Biogenesis-Related Processes.
    Tingting Yang, Jiancong Wen, Xiaoyu Li, Xunjie Ma, Liang Zhang, Guozhu Ning, Jingjing Zhang.
      The NOP2 nucleolar protein (NOP2) serves pivotal functions in ribosome biogenesis, cell cycle regulation and embryonic development, yet its spatiotemporal dynamics and mechanistic contributions to neural development remain elusive. Through CRISPR/Cas9-mediated knockout modeling in zebrafish, we demonstrated that NOP2 nucleolar protein homolog (yeast) (nop2) deficiency induced embryonic lethality within 3-5 days post-fertilization (dpf), accompanied by pathognomonic microcephaly and cerebral edema. Mechanistic analysis suggested that nop2 ablation triggered differentiation impairment in neural progenitors, which accumulated extensively in brain tissue and led to impaired generation of neurons and glial cells. In addition, nop2 deficiency activated p53-dependent apoptosis in neural cells. Biochemical characterization revealed compromised pre-ribosomal particle processing in mutants, establishing defective ribosome biogenesis as the primary molecular lesion. Ribosome profiling (Ribo-seq) uncovered aberrant regulation of nervous system processes and activation of p53-mediated apoptosis in neural cells. Genetic epistasis experiments demonstrated that tp53 mutation partially rescued neurogenic defects and reduced cerebral edema, but failed to rescue microcephaly. These findings provide evidence supporting the role of Nop2 as a significant regulator in neural development. Our results demonstrate that Nop2 promotes neural differentiation by regulating ribosome biogenesis-related processes, thereby extending our previous research on rRNA metabolism-related genes in neurodevelopment. Moreover, our study provides critical insights into developing early interventions against neurodevelopmental disorders associated with ribosomopathies.
    Keywords:   nop2 ; CRISPR/Cas9; neural development; p53; ribosome biogenesis; zebrafish
    DOI:  https://doi.org/10.1096/fj.202503338RR
  82. J Biochem Mol Toxicol. 2026 Feb;40(2): e70726
    Exosome-Derived Circular RNAs in Colorectal Cancer: Emerging Roles in Tumorigenesis, Diagnosis, and Therapy.
    Amir Mohammad Aghaie, Fereydoun Rahmani, Nazila Fathi Maroufi, Vahid Zarezade, Soleyman Bafadam, Mostafa Mostafazadeh.
      Circular RNAs (circRNAs) are a class of non-coding RNAs characterized by their covalently closed loop structures, which confer remarkable stability. Recent studies have highlighted the role of exosomal circRNAs, which are encapsulated within extracellular vesicles known as exosomes, in intercellular communication and tumor progression. In colorectal cancer (CRC), exosomal circRNAs have been implicated in various oncogenic processes, including cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. These molecules exhibit dysregulated expression patterns in CRC tissues and bodily fluids, making them promising candidates for non-invasive biomarkers. Moreover, their functional roles in modulating signaling pathways and the tumor microenvironment suggest their potential therapeutic applications. This review summarizes our current understanding of exosomal circRNA biology, highlights their roles in the CRC development and progression, and discusses their clinical significance as diagnostic, prognostic and therapeutic tools.
    Keywords:  colon cancer; exosomal circular RNAs; liquid biopsy; miRNA sponge; tumor microenvironment
    DOI:  https://doi.org/10.1002/jbt.70726
  83. Plant J. 2026 Feb;125(3): e70685
    Nuclear DNA of plastid origin (NUPTs), neglected driver of genome variation and evolutionary innovation.
    Lorenzo Carretero-Paulet, Juan Pablo Marczuk-Rojas, Aaron Gálvez-Salido.
      Plant nuclear genomes contain a variable, though typically minor, fraction of DNA sequences of plastid origin known as NUPTs. Unlike the massive transfer of DNA and genes from the proto-organelle genome to the nucleus that occurred during the endosymbiotic event that gave rise to plastids, the formation of NUPTs is an ongoing process that does not imply concomitant DNA loss. Although NUPTs are generally considered to be potentially deleterious insertions that are continuously generated and rapidly eliminated at near-constant turnover rates, accumulating evidence reveals alternative evolutionary trajectories. In this review, we discuss recent findings that highlight the episodic formation of NUPTs, their subsequent proliferation, and their eventual long-term fixation within the nuclear genome. We also explore their non-random spatial association with specific genomic elements. NUPTs show preferential overlap with specific superfamilies of transposable elements, which may facilitate their proliferation and dispersal throughout the nuclear genome. Regarding protein-coding genes, the contribution of NUPTs varies among species. In contrast, NUPTs are found to be consistently enriched among certain classes of non-coding RNA genes, notably rRNA, tRNA, and specific regulatory RNA families, suggesting that they are involved in the evolution of gene regulation and translational machinery. Overall, these findings underscore the unexpected complexity of the mechanisms underlying NUPT formation and support the idea that they are a significant source of genome variation and evolutionary innovation. Further research is necessary to fully elucidate the mechanisms underlying NUPT formation, as well as to determine their potential adaptive significance in plant genome evolution.
    Keywords:  NUPTs; genome evolution; new gene origin; plastids; rRNA genes; regulatory RNA genes; tRNA genes; transposable elements
    DOI:  https://doi.org/10.1111/tpj.70685
  84. Physiol Plant. 2026 Jan-Feb;178(1):178(1): e70773
    Tomato RING Type E3 Ligases, SlRGLGs, Positively Regulate the Dehydration Stress Response.
    Yeongil Bae, Chae Woo Lim, Dae Sung Kim, Sung Chul Lee.
      The ubiquitin-proteasomal protein degradation system is a key regulatory process mediating the dehydration stress response in plants, and RGLG proteins, a subfamily of the RING E3 ligases, are well known to modulate this response. In this study, we isolated four SlRGLG proteins (Solanum lycopersicum RING domain ligase) from tomato plants and characterized their functions at the molecular and biological levels. We found that these four SlRGLGs have the conserved VWA and RING domains and high amino acid sequence identities with RGLGs from Arabidopsis thaliana and pepper plants. The transcript levels of SlRGLGs were found to be responsive to several environmental stimuli, including dehydration, mannitol, and abscisic acid, which are believed to be associated with the presence of different stress-associated cis-regulatory elements in the respective promoter regions. Subcellular localization studies of SlRGLGs-GFP fusion proteins revealed distinct subcellular distribution patterns, and all four MBP-SlRGLGs recombinant proteins exhibited robust E3 ligase activities in vitro. To elucidate their biological roles in the dehydration stress response, we generated SlRGLGs-silenced tomato plants and SlRGLGs-overexpressing (OE) Arabidopsis plants. Notably, all SlRGLGs-silenced tomato plants were found to have dehydration-sensitive phenotypes with increased transpirational water loss and lipid peroxidation of cell membranes and decreased expression of dehydration stress-responsive genes. However, all SlRGLGs-OE Arabidopsis plants showed the dehydration-tolerant phenotypes, compared to control plants. Collectively, these findings indicate a positive role for all four SlRGLGs in the dehydration stress response of tomato.
    Keywords:  E3 ligase; RGLG; dehydration; tomato; ubiquitination
    DOI:  https://doi.org/10.1111/ppl.70773
  85. Anticancer Res. 2026 Feb;46(2): 787-795
    POM121 Drives Gastric Cancer Progression via the mTOR/p70S6K Signaling Axis.
    Hong-Beum Kim, Seong-Hun Kim, Hye-Hwa Lee, Hee-Jeong Lee, Sang-Gon Park.
       BACKGROUND/AIM: Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. This study aimed to clarify the oncogenic function of POM121 and its involvement in signaling pathways driving tumor progression.
    MATERIALS AND METHODS: POM121 expression was analyzed in six GC cell lines and one normal gastric epithelial cell line, as well as in clinical datasets. Functional consequences of POM121 knockdown were assessed in AGS and KATO-III cells using cell proliferation, migration, soft agar colony formation, proteomic profiling, and in vivo xenograft models. Phosphorylation of p70S6 kinase at Thr389 and Thr421/Ser424 was examined to determine downstream signaling.
    RESULTS: POM121 was consistently found to be upregulated in GC tissues and cell lines. Silencing of POM121 significantly inhibited proliferation, migration, anchorage-independent growth, and tumorigenicity in vivo. Proteomic analysis revealed that suppression of POM121 attenuated phosphorylation of p70S6K at Thr389 and Thr421/Ser424, indicating impaired mTOR-p70S6K signaling.
    CONCLUSION: POM121 promotes GC progression by enhancing proliferative and invasive phenotypes through p70S6 kinase-mediated signaling. These findings establish POM121 as a novel oncogene, prognostic biomarker, and potential therapeutic target in GC.
    Keywords:  GC; POM121; mTOR signaling; p70S6 kinase signaling; prognostic biomarker; tumor progression
    DOI:  https://doi.org/10.21873/anticanres.17987
  86. bioRxiv. 2026 Jan 14. pii: 2026.01.14.699521. [Epub ahead of print]
    Single-nucleus transcriptomics reveal stress-related prefrontal activation in Tourette disorder.
    Philip Moos, Caterina Branca, Marco Bortolato.
       BACKGROUND: Tics are sudden, partially controllable motor or vocal events that arise from disruptions within cortico-striatal-thalamo-cortical circuits. Within this network, converging evidence implicates the dorsolateral prefrontal cortex (DLPFC) as an important cortical node supporting voluntary tic control. This region is critical for top-down regulation and is particularly sensitive to stress, raising the possibility that molecular vulnerabilities within the DLPFC may influence the capacity to suppress tics. However, the underlying cellular and molecular architecture remains poorly defined.
    METHODS: To address this gap, we conducted the first single-nucleus RNA sequencing analysis of postmortem DLPFC tissue from men with Tourette disorder (TD) and age-matched neurotypical controls.
    RESULTS: Overall cell-type proportions did not differ significantly between groups. In contrast, gene ontology analyses revealed broad upregulation of transcripts involved in protein synthesis, most prominently in microglia, oligodendrocytes, and interneurons. Among neuronal lineages, these changes were most pronounced in superficial and middle-layer pyramidal neurons and vasointestinal peptide-positive interneurons. To determine whether these alterations reflect engagement of stress-related transcriptional programs, we compared TD-associated differentially expressed genes with published single-nucleus datasets from major depressive disorder and posttraumatic stress disorder. Across DLPFC cell populations, and especially within pyramidal neurons and interneurons, we observed significant enrichment for stress-associated gene signatures, including glucocorticoid-responsive transcripts and immediate early genes.
    CONCLUSION: Together, these findings identify the DLPFC in TD as a region of heightened stress responsivity and altered excitatory-inhibitory dynamics, offering new insight into cortical mechanisms that may constrain tic suppression.
    DOI:  https://doi.org/10.64898/2026.01.14.699521
  87. Mol Genet Genomics. 2026 Jan 31. 301(1): 28
    A combined computational and functional approach identifies FBLN5 as an amino acid metabolism-related gene and suppressing colorectal cancer progression.
    Jiezhi Chen, Yang Bai, Shiyi Liu, Changwei Lin.
      The importance of amino acid metabolism in regulating cancers progression was investigated by accumulating research. But the role of amino acid metabolism-related genes (AAMRGs) played in the colorectal cancer (CRC) progression remains unclear. We used Cox-LASSO analysis to construct an AAMRG prognostic signature and performed Gene set enrichment analysis (GSEA) for further investigation. Moreover, RT‒qPCR was adopted to estimate the expression of AAMRGs in clinical samples. Cell-based assays, including CCK-8, colony formation, and transwell assays were also performed to identify the roles of fibulin 5 (FBLN5) in CRC progression. We established a 10-AAMRG prognostic signature and stratified CRC samples into two risk groups, which showed significant differences in immune infiltration and EMT. RT-qPCR and human protein atlas data confirmed the mRNA and protein expression of these 10 AAMRGs, validating our bioinformatics findings. Importantly, functional assays revealed that FBLN5 overexpression suppressed CRC cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Our study establishes a novel 10-AAMRG signature as a promising predictor of therapeutic response and prognosis in CRC, and we identify FBLN5 as a pivotal protective factor in CRC progression, offering potential therapeutic value for targeted interventions.
    Keywords:  Acid metabolic reprogramming; Colorectal cancer; FBLN5; Prognostic signature; Tumor progression
    DOI:  https://doi.org/10.1007/s00438-025-02327-6
  88. Nucleic Acids Res. 2026 Feb 05. pii: gkag081. [Epub ahead of print]54(4):
    Exploring the regulatory potential of RNA structures in 202 cyanobacterial genomes.
    Adrian Sven Geissler, Elena Carrasquer-Alvarez, Christian Anthon, Niels-Ulrik Frigaard, Jan Gorodkin, Stefan Ernst Seemann.
      Cyanobacteria are one of the oldest and most abundant groups of prokaryotes and are crucial for research in climate, ecology, medicine, and agriculture. Despite intensive efforts in metabolic engineering of cyanobacteria, the mechanisms of gene regulation, particularly through regulatory RNA structures, are often ignored. We computationally searched 202 cyanobacterial genomes for putative conserved RNA structures (CRSs) in the upstream and downstream intergenic regions of 931 orthologous gene groups with the comparative genomics tool CMfinder. The predicted structures were scored according to their local phylogeny and filtered for a maximal false discovery rate of 10%. The screen identified 402 CRSs that match known RNA families (Rfam and Rho-independent bacterial terminators) and 409 novel CRSs. The structures are not limited to either low or high nucleotide conservation, and about half have a high level of significant covariation. The majority of novel CRSs are supported by transcription in at least one species in public RNA-seq data. The regulatory associations of CRSs are discussed in different metabolic pathways, such as photosynthesis, nitrogen fixation, and CO$_2$ metabolism. This resource will support future research on the regulatory mechanisms of RNA in cyanobacteria.
    DOI:  https://doi.org/10.1093/nar/gkag081
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