bims-ribost 2026-01-11 papers

bims-ribost

Biomed News

on Ribostasis and translation stress

Issue of 2026–01–11
fifty-five papers selected by
Cédric Chaveroux, CNRS

SARS-CoV-2 and MERS-CoV disrupt host protein synthesis via nsp1 with differential effects on the integrated stress response.
Detection and Characterization of the Eukaryotic Vacant Ribosome.
The nuclear cap-binding complex regulates subcellular RNA processing and surveillance of coding and noncoding RNAs.
In Vitro Reassociation Assay to Measure the Formation of 80S Ribosomal Particles Using Salt-washed Ribosomal Subunits.
RGG-motif protein Scd6 affects oxidative stress response by regulating cytosolic caTalase T1 (Ctt1).
Integrated Stress Response (ISR) Modulators in Vascular Diseases.
Eukaryotic initiation factor 3d Regulates Context-Dependent Pain Hypersensitivity Through the Integrated Stress Response.
The DinG exonuclease acts as a primary quality controller to remove unprocessed ribosomal RNAs.
Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling.
Crystal structures of Caenorhabditis elegans PUF-3 depict plasticity of RNA recognition that enables germline gene regulation.
The Conserved GTPase LepA May Contribute to the Final Proper Stabilization of the 3' Domain of the 30S Subunit During Ribosome Assembly.
Linking RNA methylation to structure: a biophysical perspective.
Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.
Translational landscape during seed germination revealed by ribosome profiling.
Binding of Glycyl-tRNA synthetase to Mengovirus RNA stimulates translation.
mRNA methylation at the crossroads of translation, transport, and decay in plant development and stress responses.
Bridging the gap: When transcription meets translation.
Defining the role of RNase E in the mycobacterial degradosome-like network.
p53 status determines the epigenetic response to demethylating agents azacitidine and decitabine.
Division of labor in trypanosome RNA processing and export through expanded Mex67 paralogs.
Halofuginone exerts broad-spectrum cytotoxic effects by regulating p-eIF2α-S100A8/A9-calcium signaling, inhibiting global protein synthesis, and reversing the resistance of idarubicin in acute myeloid leukemia.
This ribosome goes to 11.
H/ACA snoRNAs and snoRNPs Dysregulation Links rRNA Modification to Glioblastoma Progression.
Feedback from the Nascent Chain Triggers Ribosomal Frameshifting and Transcript Decay.
Mechanistic insights into recruitment and regulation of the RNA helicase UPF1 in replication-dependent histone mRNA decay.
Missing steps of mitochondrial translation initiation identified in plants.
Mutations in the Rab33b protein that lead to the skeletal disease Smith-McCort dysplasia result in unstable proteins and altered autophagy function.
Absence of MBP 3' UTR in Mice Disrupts mRNA Transport, Myelination, and Motor Learning.
Differential association of primary and alternative σ factors with RNA polymerase of Mycobacterium tuberculosis during transcription elongation.
Reversible cytoplasmic foci of RNA polymerase II subunits serve as proteostatic hubs orchestrating transcriptional reprogramming.
Targeted stress granule regulation by engineering a non-catalytic O-GlcNAc transferase.
Phosphoproteomic Profiling Reveals Overlapping and Distinct Signaling Pathways in Dictyostelium discoideum in Response to Two Different Chemorepellents.
Biochemical and structural characterization of the RlaP family nucleotidyltransferase potentially involved in RNA repair.
Reshaping cancer cell plasticity by P-body dynamics and protein translation.
ADAR1 upregulates the translation of cytochrome c via the inhibition of translocation into stress granules, facilitating apoptosis by an anticancer agent.
Systemic control of HNF1B-driven redox homeostasis by N6-adenosine methylation.
Initial spliceosomal U4/U6 di-snRNA formation occurs in the cytoplasm of Saccharomyces cerevisiae and requires a guard protein mediated quality control.
Split-APEX implicates splicing factor SRSF1 and splicing helicases in ribosomal biogenesis.
Sequence-dependent co-condensation of Lsr2 with DNA elucidates the mechanism of genome compaction in Mycobacterium tuberculosis.
N4BP1 acts as a potent negative regulator of IL-17 signaling by blocking the translation of Act1 mRNA.
A prelimbic molecular clock of protein synthesis for memory persistence.
A high throughput screen for nucleolar function reveals a role for the signaling protein, SPRR3, in ribosome biogenesis.
Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs.
Acute Cold Exposure Cell-Autonomously Reduces mTORC1 Signaling and Protein Synthesis Independent of AMPK.
RNA-Binding Proteins in Dinoflagellates.
Direct RNA Sequencing Reveals Stress-Dependent and Pathway-Specific rRNA Modification Reprogramming During 50S Biogenesis.
ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis.
The Role of DNA and RNA Methylation in Cancer: Mechanisms and Therapeutic Potential of Epigenetic and Epitranscriptomic Drugs
Membranous Interacting Partners of Phage-Type Plastid RNA Polymerase Have Limited Impact on Plastid Gene Expression During Chloroplast Development.
Characterization of RNA interference in the cnidarian Nematostella vectensis reveals partial target silencing but lack of small RNA amplification.
A dietary pan-amino acid dropout screen in vivo reveals a critical role for histidine in T-ALL.
Delamanid and pretomanid have comparable bactericidal activity but pretomanid potently inhibits Mycobacterium tuberculosis ribosomal rRNA synthesis.
Canine parvovirus infection affects host cell nucleolar organization and ribosome biogenesis.
Low complexity (A/C)GG Repeats and m1 A Methylation Sites in 5` UTRs Regulate Gene Expression.
Emerging roles of tRNA modification-mediated codon-specific translational reprogramming in cancer biology.

bioRxiv. 2025 Dec 29. pii: 2025.12.28.696697. [Epub ahead of print]

SARS-CoV-2 and MERS-CoV disrupt host protein synthesis via nsp1 with differential effects on the integrated stress response.

Nicholas A Parenti, Renee Cusic, David M Renner, Nathaniel Jackson, Chengjin Ye, Li Hui Tan, Jessica J Pfannenstiel, Anthony R Fehr, Noam A Cohen, Luis Martinez-Sobrido, James M Burke, Susan R Weiss.

Coronaviruses pose a serious threat to public health, driving the need for antiviral therapeutics and vaccines. Therefore, it is paramount to understand how this family of viruses evades cellular antiviral responses and establishes productive infection. The conserved coronavirus non-structural protein (nsp)1 has been shown to inhibit host protein synthesis and promote host mRNA degradation while viral mRNAs are protected. We showed previously that SARS-CoV-2 induces activation of host integrated stress response (ISR) kinases PKR and PERK, which promote phosphorylation of eIF2α and consequent inhibition of host protein synthesis. In contrast, eIF2α remains unphosphorylated during MERS-CoV infection. To investigate the interactions of nsp1 and the ISR kinases, we utilized recombinant SARS-CoV-2 and MERS-CoV expressing nsp1 with mutations in each of two conserved domains. Upon infection with SARS-CoV-2 nsp1 mutants, translation was shut down in wildtype (WT) and PKR knockout (KO) cells but rescued in PERK KO cells, likely due to reduced p-eIF2α. In contrast, translation was rescued during infection with the analogous MERS-CoV nsp1 mutants even in WT cells. Moreover, SARS-CoV-2 WT suppressed expression of GADD34, a negative regulator of eIF2α phosphorylation, while SARS-CoV-2 nsp1 mutants induced GADD34. In contrast MERS-CoV WT induced GADD34. Utilizing single-molecule fluorescence in situ hybridization, we found that SARS-CoV-2 and MERS-CoV nsp1 promote host mRNA degradation during WT, but not nsp1 mutant, infection. Finally, while SARS-CoV-2 WT suppressed stress granule formation, nsp1 mutants induced stress granules containing host RNA. Thus, SARS-CoV-2 and MERS-CoV differ in interactions with the ISR and nsp1 control of host protein synthesis.
Significance: Coronaviruses cause disease across a wide range of animal species, and the human coronaviruses SARS-CoV-2 and MERS-CoV have caused epidemics of severe respiratory illness. Thus, it is imperative to understand how these viruses antagonize host responses and cause lethal disease. We show here that the betacoronavirus non-structural protein (nsp)1 promotes shutdown of host protein synthesis while preserving viral protein synthesis and, in addition, promotes degradation of host mRNAs. However, SARS-CoV-2 and MERS-CoV differ in their ability to manipulate the host integrated stress response, indicating that it is important to understand detailed coronavirus-host interactions and how they differ even between lethal coronaviruses. Such insights will inform the development of antiviral therapeutics to treat and prevent current and future coronavirus outbreaks.

DOI: https://doi.org/10.64898/2025.12.28.696697
Int J Mol Sci. 2025 Dec 27. pii: 308. [Epub ahead of print]27(1):

Detection and Characterization of the Eukaryotic Vacant Ribosome.

Colin E Delaney, Attila Becskei.

  Upon transcription, most mRNAs associate with the small ribosomal subunit, after which a fully translating ribosome assembles. Under starvation or stress, however, mRNA-ribosome associations are blocked and many mRNAs are instead sequestered with specific RNA-binding proteins into stress granules or other subcellular condensates, a process that has been extensively studied. In contrast, much less attention has been paid to the fate of ribosomes under these same conditions. Ribosomes can remain fully assembled but unbound to mRNA, entering an inactive, dormant state. Dormancy is often supported by specific protein factors which protect ribosomes from degradation and facilitate reactivation once growth conditions improve. In this review, we highlight that dormant ribosome states are well defined in prokaryotes, in part because they possess distinct and experimentally tractable features, such as stable vacant 100S dimers. In eukaryotes, by contrast, analogous disomes are largely absent, making their discovery more indirect and method-dependent. We therefore focus on how evidence for eukaryotic dormant ribosomes has been assembled through multiple independent findings and how their interpretation depends critically on the experimental approaches used to study them. Finally, we consider atypical ribosomal states, such as translationally inactive polysomes in neurons, which underscore the context-dependent nature of ribosome activity.

Keywords:  80S ribosome; CCDC124; Lso2; SERBP1; Saccharomyces cerevisiae; Stm1; YfiA; heat-shock; monosome; neuron; polysome; starvation

DOI:  https://doi.org/10.3390/ijms27010308
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1467. [Epub ahead of print]54(1):

The nuclear cap-binding complex regulates subcellular RNA processing and surveillance of coding and noncoding RNAs.

Diep R Ganguly, Brian D Gregory.

RNA cleavage is essential for processing and regulating all classes of RNA. Current methods profiling genome-wide RNA cleavage are biased towards cytoplasmic events and ignore compartmentalized differences. Here, we couple subcellular RNA fractionation with degradome profiling to detect genome-wide nucleoplasm- and cytoplasm-enriched RNA cleavage in Arabidopsis thaliana. While messenger RNA (mRNA) cleavage dominated cytoplasmic fractions, we captured a diverse array of nucleoplasm-enriched RNA cleavage events. These included pre-mRNA cleavage and noncoding RNA processing, including for microRNAs, ribosomal RNAs, small nucleolar RNAs, enhancer-associated RNAs, and retrotransposon-derived RNA. Furthermore, our findings suggest that CAP-BINDING PROTEIN80/ABA HYPERSENSITIVE1 regulates mRNA surveillance within the perinuclear cytoplasm during the pioneer round of translation. Our data also emphasized its role in stabilizing nucleoplasmic RNAs (e.g. mRNA-associated antisense RNAs) and affecting cytoplasmic mRNA cleavage. Overall, our results highlight the diversity of compartmentalized RNA cleavage and reveal that the nuclear cap-binding complex has numerous functions in subcellular RNA processing and surveillance.

DOI: https://doi.org/10.1093/nar/gkaf1467
J Vis Exp. 2025 Dec 16.

In Vitro Reassociation Assay to Measure the Formation of 80S Ribosomal Particles Using Salt-washed Ribosomal Subunits.

Anette Hallik, Analiis Veeremaa, Tiina Tamm.

Ribosomes are molecular machines that are responsible for protein synthesis in all living cells. All ribosomes consist of two subunits. In eukaryotes, the 40S and 60S subunits interact during translation initiation to form the functional 80S ribosomal particles. These subunits are joined by contacts known as intersubunit bridges. To investigate how damage or mutations affect ribosome functionality, the in vitro reassociation of ribosomal subunits can be employed. In this method, eukaryotic ribosomes are first isolated, then the subunits are dissociated under high-salt condition using sucrose density gradient ultracentrifugation. The purified, salt-washed ribosomal subunits can subsequently be reassociated at different magnesium concentrations to monitor the formation of 80S particles. As an example, the formation of 80S particles using the purified 60S subunits from a Saccharomyces cerevisiae strain lacking the ribosomal protein eL24 is analyzed. Thus, this method enables the investigation of the structural integrity of the purified ribosomal subunits. Additionally, the method enables the evaluation of the roles of ribosomal proteins and rRNA in ribosomal subunit joining outside of the translational context.

DOI: https://doi.org/10.3791/69529
RNA Biol. 2026 Dec;23(1): 1-23

RGG-motif protein Scd6 affects oxidative stress response by regulating cytosolic caTalase T1 (Ctt1).

Sweta Tiwari, Chitra Togra, Sudharshan Sj, Purusharth I Rajyaguru.

  In response to stress, cells undergo gene expression reprogramming to cope with external stimuli. Cells utilize a conserved stress response mechanism called global downregulation of translation, leading to the storage of translationally repressed mRNAs in RNA granules. During oxidative stress induced by H2O2, genes responsible for combating oxidative stress, such as catalases, are strongly induced. However, the post-transcriptional regulatory events affecting these genes during H2O2 stress are not well-explored. Scd6, an RGG-motif-containing protein in yeast, acts as a translational repressor through its interaction with eIF4G1. This study identifies the role of Scd6 in oxidative stress response by regulating cytoplasmic catalase T1 (CTT1). We observe that peroxide stress induces the assembly of Scd6 puncta, which do not colocalize with P-bodies or stress granules. Scd6 overexpression increased sensitivity, while deletion enhanced tolerance to H2O2 treatment. Increased ROS accumulation and decreased Ctt1 protein levels were observed upon Scd6 overexpression due to translation repression of CTT1 mRNA. CTT1 mRNA interacts with Scd6. smFISH analysis and RNA immunoprecipitation studies reveal that localization of Scd6 to puncta upon peroxide stress reduces its interaction with CTT1 mRNA, allowing derepression. The role of Scd6 in peroxide stress response is conserved since the human homolog LSm14A also localizes to puncta upon H2O2 stress, and its overexpression reduces survival in response to peroxide stress. Overall, this study identifies a unique example of translation regulation whereby stress-induced localization of the translation repressor protein to puncta leads to derepression of the target mRNA.

Keywords:  Post-transcriptional control; Scd6; catalase; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1080/15476286.2026.2613892
Cells. 2025 Dec 19. pii: 2. [Epub ahead of print]15(1):

Integrated Stress Response (ISR) Modulators in Vascular Diseases.

Alexander Kalinin, Ekaterina Zubkova, Irina Beloglazova, Yelena Parfyonova, Mikhail Menshikov.

  Vascular dysfunction lies at the core of cardiovascular diseases-the leading cause of global morbidity and mortality. Despite their prevalence, therapeutic options remain limited, in part due to an incomplete understanding of the molecular mechanisms driving vascular pathology. The integrated stress response (ISR), an evolutionarily conserved signaling network activated by diverse stressors, represents a critical but underexplored mechanism in vascular biology. This review examines the dual roles of the core ISR kinases-PERK, GCN2, HRI and PKR-in vascular homeostasis and pathology, including atherosclerosis, pulmonary hypertension, and angiogenesis. We develop a conceptual framework in which the ISR functions as a context-dependent, double-edged sword: while PERK and PKR promote inflammation, apoptosis, and vascular re-modeling, GCN2 mediates protective effects. The outcome of ISR activation is shaped by cell type, stress duration and intensity, and downstream signaling bias (e.g., ATF4 vs. CHOP dominance). We further discuss pharmacological ISR modulators-including 2-aminopurine, C16, salubrinal, halofuginone, GSK2606414, and GSK2656157-which have demonstrated beneficial effects in preclinical models by suppressing inflammation, reducing apoptosis, and attenuating disease progression. Collectively, the ISR emerges as a critical regulatory node in vascular pathophysiology, and its selective, context-aware modulation represents a promising avenue for therapeutic intervention.

Keywords:  GCN2; PERK; PKR; cardiovascular diseases; integrated stress response; pulmonary arterial hypertension; pulmonary capillary hemangiomatosis; pulmonary veno-occlusive disease; restenosis; thrombosis

DOI:  https://doi.org/10.3390/cells15010002
bioRxiv. 2025 Dec 23. pii: 2025.12.21.695844. [Epub ahead of print]

Eukaryotic initiation factor 3d Regulates Context-Dependent Pain Hypersensitivity Through the Integrated Stress Response.

Subhaan M Mian, Sera I Nakisli, Brodie J Woodall, Pooja J Patel, Aariz Nackvi, Noura Elhamadany, Kree Goss, Nwasinachi Adriana Ezeji, Muhammad Saad Yousuf.

Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a noncanonical cap binding protein implicated in selective mRNA translation under stress conditions. Here, we investigate the contribution of eIF3d to pain processing using a heterozygous eIF3d knockout (eIF3d +/- ) mouse model. We first validated this model, confirming substantial reductions in eIF3d mRNA and protein levels in dorsal root ganglia. Baseline assessments revealed no differences in mechanical, thermal, cold, or spontaneous pain behaviors between eIF3d +/- (HET) and eIF3d +/+ (WT) mice, indicating intact basal nociceptive function. In pain models involving peripheral inflammation and metabolic stress, including methylglyoxal injection, IL-6 administration and paw incision, HET mice displayed significantly reduced mechanical and cold hypersensitivity. In contrast, HET mice exhibited increased second phase nocifensive behavior in the formalin test, possibly indicating enhanced central sensitization. Hyperalgesic priming was comparable between HET and WT mice following IL-6 exposure. Experimental autoimmune encephalomyelitis (EAE) induced mice were unaffected by eIF3d reduction. These findings demonstrate that eIF3d selectively modulates nociceptive plasticity under defined stress conditions and suggests a context dependent role in the regulation of inflammatory and central pain sensitization.
Highlights: Baseline mechanical, thermal, cold and spontaneous pain are intact in eIF3d +/- mice Methylglyoxal-evoked ISR activation and mechanical pain is blunted in eIF3d +/- mice IL-6-evoked mechanical and cold pain are reduced without altered priming Mechanical hypersensitivity is reduced in eIF3d +/- mice with paw incision EAE pain is unaltered but increased pain in phase II formalin pain in eIF3d +/- mice.

DOI: https://doi.org/10.64898/2025.12.21.695844
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1446. [Epub ahead of print]54(1):

The DinG exonuclease acts as a primary quality controller to remove unprocessed ribosomal RNAs.

Karolis Vaitkevičius, Jörgen Johansson.

Bacteria lacking DEAD-box RNA-helicases often show reduced growth and aberrant maturation of ribosomal subunits resulting in fewer active ribosomes. Here, we show that the slow growth observed in a strain lacking the RNA-helicase CshC in the bacterial pathogen Listeria monocytogenes can be suppressed by mutations in the exonuclease DinG. A strain lacking both CshC and DinG increased the number of mature and active ribosomes compared to the parental ΔcshC mutant. DinG acts as a 3'- to 5'-exoribonuclease, targeting immature, unprocessed ribosomal RNA in vitro and in vivo while leaving processed rRNA undisturbed. In addition, DinG directly or indirectly interferes with the ribonuclease M5 mediated pre-5S rRNA processing. We suggest that DinG acts as a primary ribosome quality control ribonuclease that initiates degradation of unprocessed rRNA.

DOI: https://doi.org/10.1093/nar/gkaf1446
Int J Mol Sci. 2026 Jan 01. pii: 455. [Epub ahead of print]27(1):

Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling.

Giovanni Luca Cipriano, Alessia Floramo, Veronica Argento, Salvatore Oddo, Osvaldo Artimagnella.

  Altered protein synthesis plays a key role in ageing and multiple neurodegenerative diseases. In Alzheimer's disease and other tauopathies, the intracellular accumulation of hyperphosphorylated Tau disrupts several cellular processes, including mRNA translation. Although Tau interacts with ribosomal proteins and modulates translational selectivity, its effects on global protein synthesis remain poorly understood. Studies report reduced translation in later disease stages but increased translation early in pathology. To clarify Tau's impact in human neurons, we used SH-SY5Y cells overexpressing the P301L mutant form of Tau and quantified global protein synthesis using the SUnSET (Surface Sensing of Translation) puromycin-incorporation assay. We found that Tau-P301L expression greatly increased global translation by upregulating mTOR/S6 pathway. These effects were abolished by rapamycin treatment, indicating that Tau-driven translational upregulation is mTOR-dependent. Given that impaired translational control can disrupt synaptic plasticity and memory, Tau-induced alterations in protein synthesis may contribute to tauopathy progression and identify mTOR signalling as a potential therapeutic target.

Keywords:  SH-SY5Y; Tau; mTOR pathway; neurons; protein translation

DOI:  https://doi.org/10.3390/ijms27010455
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1431. [Epub ahead of print]54(1):

Crystal structures of Caenorhabditis elegans PUF-3 depict plasticity of RNA recognition that enables germline gene regulation.

Yingying Zhang, Franklin D Kennedy, Traci M Tanaka Hall.

Prototypical PUF proteins are known for modular, sequence-specific RNA recognition. A single PUF protein in Drosophila melanogaster Pumilio and two closely related proteins in mammals, PUM1 and PUM2, are representative. In contrast, Caenorhabditis elegans PUF proteins have evolved to include four subfamilies of single-stranded RNA-binding proteins that recognize distinct sequence elements. Here, we provide an in-depth structural and biochemical analysis of C. elegans PUF-3, a member of the subfamily lacking structural information. We determined crystal structures of PUF-3 in complex with RNAs representing three classes of binding elements. These structures and quantitative RNA-binding assays fine-tune the features of PUF-3 RNA recognition and demonstrate how PUF-3 binds to varied target RNA elements by accommodating divergent sequences between conserved features. Our analyses here and published biological data suggest that PUF-3 may redundantly regulate RNA targets with other PUF proteins. We determined the in vitro binding affinities of C. elegans PUF protein subfamily representatives for the range of corresponding RNA elements. We find that PUF-3 and FBF-2 have broader RNA recognition, whereas PUF-8 and PUF-6 are highly selective. These subfamily recognition properties and protein expression patterns support a working model for PUF protein activities in different regions of the C. elegans germline.

DOI: https://doi.org/10.1093/nar/gkaf1431
Int J Mol Sci. 2026 Jan 03. pii: 489. [Epub ahead of print]27(1):

The Conserved GTPase LepA May Contribute to the Final Proper Stabilization of the 3' Domain of the 30S Subunit During Ribosome Assembly.

Olesya Kravchenko, Elena Maksimova, Timur Baymukhametov, Irina Eliseeva, Elena Stolboushkina.

  The function of the highly conserved GTPase LepA, a homolog of elongation factor EF-G, remains unknown in translation. However, there is biochemical data that it implicates in the 30S ribosomal subunit biogenesis. Here, using cryo-electron microscopy, we characterized 30S subunits isolated from an Escherichia coli strain with a deleted lepA gene. The cryo-EM maps for ∆lepA 30S particles were divided into classes corresponding to consecutive assembly intermediates: from particles characterized by unformed helices h44/h45 of the central decoding center (CDR) and highly flexible head, through intermediates with a distorted CDR and a partial stabilization of the head, to near-mature 30S subunits with correctly docked h44 in the CDR, accessible 3' end of 16S rRNA for translation but significant flexibility in head domain. Cryo-EM analysis of ΔlepA 30S intermediates revealed that they predominantly proceed to nearly mature functional state and exhibit suboptimal flexibility in the head domain. This finding suggests that LepA likely contributes to the final proper stabilization of the 3' domain of the 30S subunit during ribosome assembly.

Keywords:  30S subunit maturation; LepA; cryo-EM; ribosome assembly

DOI:  https://doi.org/10.3390/ijms27010489
FEBS J. 2026 Jan 08.

Linking RNA methylation to structure: a biophysical perspective.

Bünyamin Akgül, Günnur Güler, Buket Sağlam, Onur Akkuş, Azime Akçaöz-Alasar.

  Recent epitranscriptomic studies show that ribonucleic acids (RNAs) are coated with an array of chemical modifications that dictate their cellular fate. Genetic, biochemical, and genomic approaches have been employed to elucidate the molecular details of RNA methylation, one of the most prevalent types of RNA modifications with significant implications for health and disease. Various biochemical approaches have been developed to identify RNA methylations both at the global and nucleotide resolution levels. However, simpler detection methods are needed to assess the global methylation status of synthetic or cellular RNAs. Although significant progress has been made in elucidating the factors involved in writing, erasing, or reading methylated epitopes or structures, the impact of these methyl moieties on the secondary structure of RNAs or macromolecular interactions remains to be fully understood. Typically, biophysical approaches, such as Fourier transformed-infrared (FT-IR) spectroscopy, circular dichroism (CD), and Raman spectroscopy, have been used to study the structures and interactions of macromolecules, including DNA and proteins. Although RNAs harbor similar chemical modifications or structure-mediated functions, the number of RNA studies that employ biophysical approaches is scarce. In this viewpoint article, we present a biophysical perspective that links RNA methylation to structure and propose that FT-IR analyses can be employed to examine global changes in the abundance of cellular RNA m6A marks. Additionally, we discuss the potential applications of biophysical approaches that may be employed to gain insight into methylation-mediated changes in RNA structures.

Keywords:  CD spectroscopy; FT‐IR spectroscopy; RNA conformation; RNA methylation; epitranscriptomics

DOI:  https://doi.org/10.1111/febs.70393
Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01013-5. [Epub ahead of print]86(1): 6-8

Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.

Yury S Bykov, Johannes M Herrmann.

In this issue of Molecular Cell, Zhu et al.1 show that mitochondria of cancer cells rely on the import of glutamine not only to fuel metabolite synthesis via the tricarboxylic acid cycle but also to charge mt-tRNAGln to allow mitochondrial protein synthesis and respiration.

DOI: https://doi.org/10.1016/j.molcel.2025.12.014
Plant J. 2026 Jan;125(1): e70663

Translational landscape during seed germination revealed by ribosome profiling.

Bing Bai, Run Qi, Wei Song, Harm Nijveen, Leónie Bentsink.

  Seed germination is crucial for agricultural reproduction. A deep understanding of this process can secure healthy growth at the early phases of plant development and therefore yield. Recent research indicates that germination is a complex process involving translational regulation. A large group of seed-stored mRNAs together with newly synthesized transcripts are regulated by post-transcriptional mechanisms and selectively translated at different stages to support the germination process. To investigate the mechanism of translational control, we performed ribosome profiling on mRNAs of distinct physiological stages during Arabidopsis thaliana seed germination. The presence of ribosome association on mRNAs with three-nucleotide periodicity indicates their capacity for translation. Dry seeds, in which translation is on hold, are characterized by a unique ribosome association landscape with a higher ribosome association at the 5' and 3' UTR, compared with physiological stages that show active translation. Start codon-specific stalling of ribosomes in dry seeds is associated with an adenine-enriched sequence motif. Throughout germination, codons encoding glycine, aspartate, tyrosine, and proline are the most frequent ribosome pausing sites. Moreover, the non-coding ribosome-associated RNAs that we identified are indeed translated, as was revealed by investigating total seed proteome data. Seed-specific upstream open reading frames (uORFs) have been identified that may play a role in translational regulation of early seed germination. Altogether, we present a first ribosome profiling analysis across seed germination that illuminates various regulatory mechanisms that potentially contribute to the seed's survival strategy.

Keywords:  Arabidopsis thaliana; long non‐coding RNAs; ribosome profiling; seed germination; translational control; upstream open reading frame (uORF)

DOI:  https://doi.org/10.1111/tpj.70663
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1451. [Epub ahead of print]54(1):

Binding of Glycyl-tRNA synthetase to Mengovirus RNA stimulates translation.

Fabian Droß, Tim Gödert, Selena A Fuchshuber, Dimitar V Nachev, Dmitri E Andreev, Markus Fricke, Muriel Ritsch, Gesche K Gerresheim, Simeon Repp, Yannic Noe, Oliver Rossbach, Manja Marz, Patrick Barth, Alexander Goesmann, Uwe Linne, Axel Weber, Michael Kracht, Ivan N Shatsky, Michael Niepmann.

Picornaviruses are small viruses with a plus-strand RNA genome in which RNA secondary structures bind cellular proteins to support viral translation and replication. Here, we characterize tRNA anticodon stem-loop-like structures in the 5'- and 3' untranslated regions (UTRs) of the RNA of Mengovirus, a member of the Cardiovirus group in the Picornaviridae family. These RNA elements specifically bind cellular Glycyl-tRNA synthetase (GARS). Mutation of the conserved CCA motifs in the loops of these GARS binding elements (GBEs) impairs binding, as does deletion of the anticodon binding domain of GARS. Mutation of the 3'-UTR GBE reduces Mengovirus translation early after transfection, independent of viral polymerase activity. The 3'UTR GBE is a stronger GARS binding site, and in reporter RNAs with the Mengovirus 5'- and 3'-UTRs, the 3'UTR GBE strongly contributes to recruitment of translation factors and ribosomes, thereby stimulating translation. In contrast, the 5'UTR GBE is a weaker GARS binding site, but its mutation has a stronger effect on translation. Therefore, we hypothesize that a GARS dimer binds strongly to an "anchor" site in the 3'UTR with one monomer, while the other monomer interacts with the 5'UTR to stimulate recruitment of translation factors and ribosomes.

DOI: https://doi.org/10.1093/nar/gkaf1451
Curr Opin Plant Biol. 2026 Jan 07. pii: S1369-5266(25)00165-7. [Epub ahead of print]89 102851

mRNA methylation at the crossroads of translation, transport, and decay in plant development and stress responses.

Yihan Dong, Wenna Zhang, Veli Vural Uslu.

Modified nucleotides on RNAs have been investigated for over six decades for their potential role in regulating gene expression and protein synthesis across a wide range of organisms, from animals to plants and fungi, as well as in viral genetic materials. Among them, mRNA methylation stands out with its dynamic nature, which underscores the adaptability of the epitranscriptome in developmental transitions and response to environmental stress, especially in plants. Advances in next-generation sequencing methods have revealed the specific sequence contexts of mRNA methylation, uncovering their involvement in gene regulatory networks. Additionally, genetic perturbations on the writers, erasers, and readers of m6A and m5C expanded our understanding of the physiological function and the mode of action of these modifications. In this review, we highlight recent advances in understanding how mRNA fate decisions, mainly determined by m6A and m5C RNA methylation, shape stress response and development in plants.

DOI: https://doi.org/10.1016/j.pbi.2025.102851
FEBS J. 2026 Jan 10.

Bridging the gap: When transcription meets translation.

Huma Rahil, Albert Weixlbaumer.

  Recruitment of the small ribosomal subunit (30S) to messenger RNA (mRNA) marks a key step in bacterial translation initiation. Recruitment begins with a 30S standby site binding single-stranded mRNA regions at or near the translation initiation region (TIR). Subsequently, the mRNA is accommodated into the 30S mRNA binding channel to initiate translation. An essential part of accommodation is the recognition and proper positioning of the start codon to establish the correct reading frame. This is often facilitated by the Shine-Dalgarno (SD) sequence. Recent structural and biochemical studies provided snapshots of the first steps of 30S recruitment to a nascent mRNA preceding accommodation, which likely reflect similar events for fully transcribed mRNAs. These studies suggest that a transcribing RNA polymerase (RNAP) promotes 30S recruitment to the nascent mRNA via two distinct pathways. In one, RNAP cooperates with ribosomal protein bS1, which captures the mRNA and channels it toward the anti-Shine-Dalgarno (aSD) sequence for base pairing. In the other, direct coupling between RNAP and the 30S, mediated by transcription factor NusG, facilitates an alternative mRNA delivery pathway. We explore the current understanding of mRNA delivery, highlighting different modes of 30S recruitment to the nascent mRNA, the role of bS1, and how this leads to the establishment of transcription-translation coupling.

Keywords:  E. coli; coupling; cryo‐EM; prokaryotes; protein synthesis; transcription; translation; translation initiation

DOI:  https://doi.org/10.1111/febs.70396
bioRxiv. 2025 Dec 25. pii: 2025.12.24.696391. [Epub ahead of print]

Defining the role of RNase E in the mycobacterial degradosome-like network.

Abigail R Rapiejko, Ying Zhou, Vidhyadhar Nandana, Junpei Xiao, Jared M Schrader, Scarlet S Shell.

  mRNA degradation is a fundamentally important process that is regulated in response to stress in the globally important pathogen Mycobacterium tuberculosis. Several mycobacterial ribonucleases (RNases) are hypothesized to function together to coordinate mRNA degradation, but the interactions among them are mostly undefined. One of the rate-limiting enzymes, RNase E, contains intrinsically disordered regions (IDRs). Here, we aimed to define the interactions between major mycobacterial mRNA degradation enzymes and identify the function(s) of the two IDRs of RNase E in the nonpathogenic model Mycolicibacterium smegmatis. We found that the two IDRs differentially impact mRNA degradation rates in vivo but are largely functionally redundant in their impacts on steady-steady transcript abundance. In vitro, the IDRs are uninvolved in catalysis but play major roles in RNA binding and interactions with other mRNA degradation enzymes, namely PNPase, RNase J, and RhlE1. In vivo, these enzymes localize with RNase E, but its IDRs play only a minor role, suggesting substantial redundancy in subcellular localization mechanisms. Collectively, we propose a degradosome-like network model in mycobacteria, held together by dynamic, transient interactions among RNA degradation enzymes and RNA that can be disrupted during physiologically relevant stress to allow for adaptability.

Keywords:  RNase E; degradosome; degradosome-like network; mRNA decay; mRNA degradation; mRNA processing

DOI:  https://doi.org/10.64898/2025.12.24.696391
EMBO Rep. 2026 Jan 07.

p53 status determines the epigenetic response to demethylating agents azacitidine and decitabine.

Emma Langdale Hands, Arndt Wallmann, Gabrielle Oxley, Sophie Storrar, Rochelle D'Souza, Mathew Van de Pette.

  5'-Azacitidine (Aza) and 5-Aza-2'-deoxycytidine (Dac) are widely used demethylating drugs that directly integrate into nucleic acids. They are frequently used interchangeably, surprisingly as their selectivity is unique from the other, with no predictors of response or clinical biomarkers to indicate drug preference. Using these drugs to induce demethylation, we combine DRIPc-Seq, Immunostaining, RNA-Seq and Mass spectrometry to uncover unique cellular responses. Activation of p53, exclusively by Aza, sustains accumulation of R-loops in CpG islands of p53 target genes. This effect is abolished by the removal of p53, compounded by destabilisation of heterochromatin marks. Dac treatment induces global chromatin modification, sustaining DNA damage, which is heightened in the absence of p53. Rescue experiments reverse the changes observed in the epigenome, demonstrating a direct role for p53 in preserving H3K9me3 and H3K27me3. These insights further our knowledge of how cells recognize and respond to methylation changes and uncover novel roles for p53 in modulation of the epigenome. Further to this, we determine a first in kind biomarker in p53 status that may be relevant for clinical settings.

Keywords:  Azacitidine; Decitabine; Epigenetics; R-Loops; p53

DOI:  https://doi.org/10.1038/s44319-025-00678-0
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1443. [Epub ahead of print]54(1):

Division of labor in trypanosome RNA processing and export through expanded Mex67 paralogs.

Samson O Obado, Peter C Fridy, Eva Hegedűsová, Trevor van Eeuwen, Milana E Stein, Wenzhu Zhang, Bryan C Jensen, Connor Chung, Marc Brillantes, Lucy Glover, Zdeněk Paris, Brian T Chait, Mark C Field, Michael P Rout.

In animals and fungi, bulk messenger RNA (mRNA) export to the cytoplasm is mediated by the Mex67/Mtr2 (NXF1/NXT1) heterodimer and driven by an ATP-dependent remodeling machinery on the cytoplasmic side of nuclear pore complexes, the exclusive gateways of nucleocytoplasmic transport. Uniquely, we show that trypanosomes have three distinct Mex67 paralogs (TbMex67, TbMex67b, and TbMex67L); each having a different non-redundant role in ribosomal RNA (rRNA) processing and mRNA export. Specifically, TbMex67 and TbMex67b retain canonical roles in mRNA export, albeit associating with specific mRNA cohorts and differing protein and mRNA interactomes in the vertebrate host and insect vector forms of the parasite. Further, TbMex67 and TbMex67b paralogs associate with the GTPase Ran export machinery, rather than ATP-dependent helicases, demonstrating significant departure in RNA export mechanisms in trypanosomes. In contrast, TbMex67L is not involved in mRNA export but primarily associates with ribosome biogenesis factors. Thus, in trypanosomes Mex67 paralogs have diverse functionalities with implications for evolutionary origins and diversity of the control of gene expression.

DOI: https://doi.org/10.1093/nar/gkaf1443
Chin Med. 2026 Jan 06. 21(1): 7

Halofuginone exerts broad-spectrum cytotoxic effects by regulating p-eIF2α-S100A8/A9-calcium signaling, inhibiting global protein synthesis, and reversing the resistance of idarubicin in acute myeloid leukemia.

Liuzhi Shi, Min Zhao, Chen Meng, Min Li, Xuanyu Yu, Shixin Zhang, Shirui Yu, Xinyao Chen, Bin Zhou, Chongyun Xing, Jinjun Jia, Jingying Zhou, Shenmeng Gao.

   BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with poor overall survival (OS). Resistance to chemotherapeutic drugs such as idarubicin (IDA) remains a major cause of treatment failure. This study investigated the anti-leukemic activity of halofuginone (HF) a synthetic derivative of the natural compound from hydrangea Dichroa febrifuge and its potential to overcome IDA resistance in AML cells.
METHODS: Apoptosis, proliferation, cell cycle, and colony formation were assessed in AML cells treated with HF. RNA sequencing (RNA-seq) was performed to identify the potential molecular targets of HF. The anti-leukemic efficacy of HF was further assessed in NOD/SCID-IL2Rγ (NSG) mice xenografted with human relapsed/refractory (R/R) AML samples.
RESULTS: HF treatment significantly inhibited cell proliferation, reduced colony formation, and induced apoptosis in AML cells. By RNA-seq analysis, S100A8 and S100A9 (S100A8/A9) were identified as potential targets of HF, and HF treatment markedly suppressed their expression. Overexpression of S100A8/A9 abrogated the anti-leukemic effects of HF, indicating that S100A8/A9 are critical mediators of HF activity. Mechanistically, HF activated the amino acid starvation response (AAR), leading to phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (p-eIF2α), subsequent downregulation of S100A8/A9, and elevation of cytoplasmic Ca2⁺ levels. Knockdown of eIF2α prevented HF-induced downregulation of S100A8/A9, confirming that HF regulates S100A8/A9 expression via the eIF2α pathway. Furthermore, HF treatment inhibited global protein synthesis, enhanced the cytotoxicity of chemotherapeutic drugs, and reversed IDA resistance by suppressing S100A8/A9 expression. Finally, HF inhibits leukemic infiltration and extended OS in MLL-AF9-transduced AML mice and enhanced IDA-induced anti-leukemic effects in R/R AML-xenografted NSG mice model.
CONCLUSIONS: These findings reveal that HF exerts anti-leukemic effects by modulating the p-eIF2α-S100A8/A9-Ca2⁺ signaling axis in AML cells. HF represents a promising therapeutic candidate for AML, particularly for patients with IDA-resistant disease.

Keywords:  Acute myeloid leukemia; Halofuginone; S100A8; S100A9

DOI:  https://doi.org/10.1186/s13020-025-01278-9
Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01014-7. [Epub ahead of print]86(1): 1-2

This ribosome goes to 11.

Allen R Buskirk.

In this issue of Molecular Cell, Ishiguro et al.1 describe new RNA modifications near the active site of the E. coli ribosome that appear only under anaerobic conditions. These modifications enhance ribosome activity and increase anaerobic growth rates.

DOI: https://doi.org/10.1016/j.molcel.2025.12.015
Res Sq. 2025 Dec 11. pii: rs.3.rs-8079210. [Epub ahead of print]

H/ACA snoRNAs and snoRNPs Dysregulation Links rRNA Modification to Glioblastoma Progression.

Gabriela D A Guardia, Xiufen Lei, Christina Middle, Morgan Roos, Lea Damaschke, Sreenevash Ramesh, Stella Auth, Gabriel Lucas Fonseca, Nicole Acevedo, Frederico G C Oliveira, Nidhi Shah, Gary Schroth, Susanne Angelow, Andrew Brenner, Scott Kuersten, Pedro A F Galante, Luiz O Penalva.

Background. Small nucleolar RNAs (snoRNAs) are critical players in ribosome biogenesis and have essential roles in rRNA processing and modification (2'O methylation and pseudo-uridylation). snoRNAs define which nucleotides get modified by guiding small nucleolar ribonucleoprotein complexes (snoRNPs) to specific positions in rRNA via base pairing. Altered snoRNA expression has been reported in diverse biological and pathological contexts. In cancer cells, the dysregulation of snoRNAs can alter the rRNA modification landscape, potentially affecting ribosome composition and translation. In aggressive tumors, such as glioblastoma (GBM), snoRNA profiling is crucial for expanding our understanding of ribosome biogenesis and identifying novel biomarkers and therapeutic targets. Methods. We have developed an Ampliseq platform and analysis pipeline to measure the expression of 127 snoRNAs (mostly those containing H/ACA boxes) and Cajal body-specific RNAs (scaRNAs) and conducted a study in a panel of glioma stem cell (GSC), GBM, and normal neuronal lines/tissue. Results. The results of our Ampliseq analysis identified snoRNAs and scaRNAs (snoRNAs/scaRNAs) that were differentially expressed in GBM and GSC cells compared to normal neuronal cells/tissue, as well as snoRNAs/scaRNAs associated with stemness and differentiation. SnoRNAs with elevated expression in GSC and GBM lines (snoRA38, snoRA51, snoRA71, and snoRA75) have been previously implicated in cancer development. Components of the H/ACA snoRNP complex, which regulate snoRNA processing and rRNA pseudouridylation, were also found to be overexpressed in GBM and showed decreased levels during neuronal differentiation. Notably, high expression of Dyskerin (DKC1)-the pseudouridylation enzyme and a key H/ACA snoRNP component-correlates with poor survival in patients with high-grade gliomas. Finally, we assessed the therapeutic potential of targeting snoRNAs in GBM. Knockdown of two upregulated snoRNAs, snoRA46 and snoRA75, using antisense oligonucleotides significantly impaired GBM cell growth. Conclusions snoRNA/scaRNAs profiling revealed distinct alterations in snoRNA expression between glioblastoma and normal neuronal cells. These differences may contribute to the reprogramming of rRNA modification and ribosome composition in cancer cells. Moreover, our findings highlight the potential of antisense oligonucleotide-based targeting of overexpressed snoRNAs in GBM as a promising therapeutic strategy.

DOI: https://doi.org/10.21203/rs.3.rs-8079210/v1
bioRxiv. 2025 Dec 26. pii: 2025.12.23.696290. [Epub ahead of print]

Feedback from the Nascent Chain Triggers Ribosomal Frameshifting and Transcript Decay.

Patrick J Carmody, Caden R Sillman, Dyotima, Rohan Bhardwaj, Ali Farzam, Morvarid Golrokhmofrad, Braden Lewis, Wesley D Penn, Bryon S Drown, Charles P Kuntz, Jonathan P Schlebach.

Though ribosomes have several features that help them maintain their reading frame, these safeguards can be bypassed by RNA structures that promote -1 programmed ribosomal frameshifting (-1PRF). We recently found that conformational transitions in the nascent polypeptide can enhance -1PRF, though it's unclear whether this feedback plays a general role in translational recoding. Here we demonstrate that the translocation of nascent transmembrane domains is sufficient to induce -1PRF during the decoding of slippery heptamers. We identify thousands of motifs that potentially trigger -1PRF along with proteomic identifications of 33 predicted human frameshift products. We also identify thousands of splicing-dependent motifs and demonstrate that the splicing-mediated reconfiguration of transmembrane domains alters -1PRF. Finally, we show that most transcripts bearing these motifs are sensitive to the nonsense-mediated decay regulator UPF1, suggesting they modulate mRNA turnover. Our findings show that the misassembly of growing polypeptides can trigger -1PRF, premature termination, and transcript decay.

DOI: https://doi.org/10.64898/2025.12.23.696290
Nat Commun. 2026 Jan 03. 17(1): 155

Mechanistic insights into recruitment and regulation of the RNA helicase UPF1 in replication-dependent histone mRNA decay.

Alexandrina Machado de Amorim, Guangpu Xue, Wenxia He, Theresa Dittmers, Sarah Lewandowski, Cecilia Perez-Borrajero, Juliane Bethmann, Nevena Mateva, Clemens Krage, Vidhyadhar Nandana, Bernhard Loll, Tarek Hilal, Janosch Hennig, Henning Urlaub, William F Marzluff, Sutapa Chakrabarti.

Metazoan histone mRNAs are a unique class of mRNAs that lack the poly(A) tail present in all other eukaryotic transcripts. Instead, they end in a conserved stem-loop (SL) structure, necessitating a decay mechanism that is distinct from deadenylation-initiated degradation. Here, combining structural and functional approaches, we elucidate molecular mechanisms of initiation of histone mRNA decay. At the end of S-phase, the RNA helicase UPF1, the exoribonuclease 3'hExo and stem-loop binding protein SLBP all contribute to histone mRNA degradation, although how they are mechanistically coupled remained unknown. The cryoEM structure of an UPF1:SL RNA complex, presented here, shows that binding of UPF1 partially melts the RNA stem in the absence of ATP, harnessing the free energy derived from RNA-binding to unwind RNA. This melting event primes the SL-RNA for decay by 3'hExo. Using biochemical and cellular analyses, we demonstrate that SLBP directly engages the UPF1 helicase core to attenuate its unwinding activity and prevent premature degradation. Activation of UPF1 at a later stage promotes SL-RNA decay. We provide direct evidence that UPF1, SLBP and 3'hExo form a degradosome-like assembly that functionally couples SL unwinding and degradation, highlighting a dynamic and intricate network of UPF1-centric interactions that orchestrates timely histone mRNA decay.

DOI: https://doi.org/10.1038/s41467-025-67991-z
bioRxiv. 2025 Dec 30. pii: 2025.12.30.697032. [Epub ahead of print]

Missing steps of mitochondrial translation initiation identified in plants.

Vasileios Skaltsogiannis, Heddy Soufari, Philippe Giegé.

Translation initiation, the first step of the translation cycle, involves initiation factors (mtIF) 2 and 3 in mitochondria. mtIF3 release from the ribosomal small subunit was believed to be a prerequisite for the recruitment of the initiator tRNA. Here we use cryogenic electron microscopy to characterize plant mitochondria pre-initiation complexes and to reveal how plant mtIF3 binds the initiator tRNA and facilitates its accommodation in the decoding center.

DOI: https://doi.org/10.64898/2025.12.30.697032
Eur J Cell Biol. 2025 Dec 24. pii: S0171-9335(25)00053-6. [Epub ahead of print]105(1): 151528

Mutations in the Rab33b protein that lead to the skeletal disease Smith-McCort dysplasia result in unstable proteins and altered autophagy function.

Sofia R Parisi, Danielle Z Harte, Jeremy C Simpson.

  The human skeletal disease Smith McCort dysplasia is known to be caused by mutations in the RAB33B gene. Despite there being detailed genetic and medical studies about the patients carrying these mutated genes, there is a paucity of information about these mutations at the molecular and cellular level. The RAB33B gene encodes the small GTP binding protein Rab33b, which primarily localises to the Golgi apparatus in cells, and plays roles in membrane traffic and autophagy. In recent years, several different mutations in the RAB33B gene have been reported, potentially giving rise to both prematurely truncated proteins and also proteins containing single amino acid substitutions. Importantly, no work to date has examined the consequences of expression of these Rab33b variants in cells. In the study presented here we use a model cell culture system to seek to understand what the consequences might be to cells expressing five of the reported disease-causing Rab33b variants. We specifically examine the ectopic expression of two truncated and three single amino acid substitution variants in cultured cells. Our results reveal that all of these mutants show subcellular mislocalisation and fail to accumulate on Golgi membranes. We also demonstrate that each of these mutants are unstable and suffer from premature degradation in cells. Finally, overexpression of the single amino acid substitution variants in cells induced for autophagy causes a severe reduction in the number of autophagosomes as defined by the number of LC3B-positive puncta. Our results provide the first molecular insight into the cellular effects caused by five of the reported Rab33b mutants that give rise to Smith McCort dysplasia.

Keywords:  Autophagy; Golgi; Membrane traffic; Rab proteins; Rab33b; Skeletal dysplasia; Smith-McCort dysplasia

DOI:  https://doi.org/10.1016/j.ejcb.2025.151528
bioRxiv. 2025 Dec 25. pii: 2025.12.23.696264. [Epub ahead of print]

Absence of MBP 3' UTR in Mice Disrupts mRNA Transport, Myelination, and Motor Learning.

Joseph C Nowacki, Haidyn L Bulen, Lindsey M Meservey, Hunter Richardson, Alex Valenzuela, Huy Nguyen, Zhuanfen Cheng, Hong Zeng, Meng-Meng Fu.

Myelin sheath maturation requires compaction, a cellular phenomenon mediated by local translation of myelin basic protein (MBP), which acts as a molecular zipper to join adjacent membranes and extrude the cytoplasm. Contrary to decades-old microinjection experiments indicating that Mbp mRNA transport is restricted to microtubules, we now show using smFISH that endogenous Mbp mRNA granules indeed localize along actin. To validate the in vivo necessity of Mbp mRNA transport and its dependence on the 3' UTR (untranslated region), we replaced the endogenous Mbp 3' UTR with polyA tail sequences. Though these mice have decreased Mbp mRNA levels, this alone could not account for their striking phenotypes - hypomyelination, baseline tremors, and motor learning defects. Thus, we cultured oligodendrocytes from these mice and found defects in both Mbp mRNA localization and local translation. These results demonstrate that the 3' UTR of a locally translated structural protein is critical for both developmental and activity-induced myelination.

DOI: https://doi.org/10.64898/2025.12.23.696264
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1459. [Epub ahead of print]54(1):

Differential association of primary and alternative σ factors with RNA polymerase of Mycobacterium tuberculosis during transcription elongation.

Nilanjana Hazra, Jayanta Mukhopadhyay.

In response to environmental cues, bacteria alter gene expression by switching σ factor(s) that recognize a specific set of promoters. This 'σ-cycle', in which σ binds to RNA polymerase (RNAP) to initiate transcription and is released during transcription elongation, is thought to be an essential step for σ-switching. Studies in Escherichia coli provide evidence that σ70 is stochastically released from the elongation complex. This 'σ-cycle' became a general model for all σ factors of all bacteria. Here, using three distinct groups of σ factors in Mycobacterium tuberculosis, we show that although a significant fraction of σA and σE are stochastically or immediately released from RNAP during the transition from transcription initiation to elongation, most of σF are retained. We also show that NusA facilitates σA release from elongation complexes at specific genes but does not affect the release of σE and σF. Our results further indicate that σF remains bound at the elongation complex despite the displacement of σ4, as σ2 and σ3 remain associated with RNAP. Our study demonstrates that σ-release is not a universal phenomenon-the release or retention of σ factor depends on its domain architecture.

DOI: https://doi.org/10.1093/nar/gkaf1459
Int J Biol Macromol. 2026 Jan 05. pii: S0141-8130(26)00023-1. [Epub ahead of print] 150097

Reversible cytoplasmic foci of RNA polymerase II subunits serve as proteostatic hubs orchestrating transcriptional reprogramming.

Le Wang, Debao Xie, Xiangdong Zhao, Xizhe Sun, Mengdi Gao, Zehao Wu, Pan Li, Fanli Zeng.

  Prolonged defects in RNA polymerase II (RNAPII) assembly lead to the accumulation of its subunits in cytoplasmic foci, but the cellular consequences of this phenomenon remain unclear. Building on our previous discovery that GPN3 dysfunction induces reversible formation of Rpb1 foci, a process termed the RNAPII Assembly Stress Response (RASR), we examined whether RASR represents a general response to RNAPII assembly defects. Here, we show that inactivation of all three GPN proteins (Npa3/Gpn1, Gpn2, and Gpn3) results in reversible accumulation of Rpb1, Rpb2, and Rpb3 in cytoplasmic foci, establishing RASR as a conserved pathway triggered by impaired polymerase assembly. We also identify the molecular chaperone Hsp82 as a component that accumulates in these foci and partially colocalizes with them. Biochemical analyses indicate that the condensates are protein based and nucleic acid free, resist dissolution by 1,6-hexanediol, and show dynamic behavior in fluorescence recovery after photobleaching (FRAP) experiments. Transcriptomic profiling reveals coordinated regulation of ribosome biogenesis genes and metabolic pathways, including amino acid metabolism, the TCA cycle, and purine biosynthesis. Oxidative stress induced by H₂O₂ further increases foci formation, highlighting the redox sensitivity of this process. Together, these findings support a model in which RASR-induced cytoplasmic foci function as a proteostatic quality-control hub that integrates molecular chaperoning and metabolic adaptation during transcriptional stress, thereby helping to maintain the fidelity of eukaryotic gene expression.

Keywords:  Cytoplasmic foci; GPN family; Protein quality control; RNA polymerase II assembly

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150097
Nat Commun. 2026 Jan 07. 17(1): 163

Targeted stress granule regulation by engineering a non-catalytic O-GlcNAc transferase.

Na Wang, Fanjia Hou, Sihui Ma, Silan Liu, Haimei Wei, Weicheng Fang, Ke Zhang, Yun Ge.

Stress granules (SGs) are disease-relevant dynamic ribonucleoprotein condensates formed by liquid-liquid phase separation (LLPS) of proteins and mRNAs. Understanding their regulators and developing interventions are critical for therapeutic development. O-GlcNAc transferase (OGT) has been implicated in SG regulation, but functions beyond O-GlcNAcylation remain unclear. Here we uncover that, upon induced proximity, OGT suppresses LLPS of the SG marker G3BP1 and thereby SG assembly, independent of its catalytic activity. We repurpose OGT into an SG modulator by fusing its N-catalytic and intervening domains (NI) to induced-proximity modules. This inhibitory effect arises from targeted protein immobilization that rigidifies G3BP1 under prolonged stress. This tool recognizes G3BP1's domain organization, thus generalizes to four additional proteins featuring similar architectures, suppressing condensate formation with mobility reduction. This modular, genetically encoded strategy enables SG regulation and functional dissection by interfering material properties of critical SG proteins and illuminates the cryptic non-catalytic function of OGT.

DOI: https://doi.org/10.1038/s41467-025-66689-6
Cells. 2025 Dec 29. pii: 60. [Epub ahead of print]15(1):

Phosphoproteomic Profiling Reveals Overlapping and Distinct Signaling Pathways in Dictyostelium discoideum in Response to Two Different Chemorepellents.

Salman Zahir Uddin, Ramesh Rijal, Darrell Pilling, Richard H Gomer.

  Chemorepulsion mechanisms for eukaryotic cells are poorly understood. We performed proteomics and phosphoproteomics to elucidate how Dictyostelium discoideum responds to its two endogenous chemorepellent signals, the protein AprA and inorganic polyphosphate (polyP). AprA and polyP affected levels of more than 200 proteins, with an overlap of both upregulating 25 proteins and downregulating two proteins. Two proteins were upregulated by AprA but downregulated by polyP, while two others showed the opposite trend. Surprisingly, many of the AprA- and polyP-regulated proteins are associated with RNA metabolism and ribosomes. AprA increased phosphorylation of 15 proteins and decreased phosphorylation of 36 proteins. PolyP increased phosphorylation of 12 proteins and decreased phosphorylation of 12 proteins. As expected, the two chemorepellents affected phosphorylation of signal transduction/ motility proteins, but unexpectedly affected phosphorylation of RNA-associated proteins. Both AprA and polyP decreased phosphorylation of five proteins including the Ras-interacting protein RipA and guanine nucleotide exchange factors (GEFs) such as the RacGEF GxcT. Mutants lacking RipA or GxcT were unresponsive to both AprA and polyP chemorepulsion. Together, this work supports the idea that rather than activating the same chemorepulsion mechanism, AprA and polyP activate only partially overlapping chemorepulsion mechanisms, and identifies two new components that are used by both chemorepellents.

Keywords:  AprA; Dictyostelium discoideum; chemorepulsion; phosphoproteomics; polyphosphate; proteomics; small GTPases

DOI:  https://doi.org/10.3390/cells15010060
bioRxiv. 2025 Dec 30. pii: 2025.12.29.696909. [Epub ahead of print]

Biochemical and structural characterization of the RlaP family nucleotidyltransferase potentially involved in RNA repair.

Amy Carruthers, Shirin Fatma, Raven H Huang.

Nucleotidyltransferases (NTases) of Polβ superfamily are highly diverse and play many important biological functions. However, many families of NTases remain uncharacterized. Because of physical proximity of the genes encoding NTases of PF10127 family to those encoding RNA ligases involved in RNA repair, PF10127 family of NTases was named RlaP (RNA ligase-associating Polβ). Here we report comprehensive characterization of two RlaP from Pseudomonas fluorescens and Pseudomonas aeruginosa ( Pf RlaP and Pa RlaP), respectively. Our study showed that, among macromolecules isolated from E. coli cells, only RNAs are the substrates of RlaP. In vitro assays employing synthetic RNAs as substrates demonstrated that RlaP catalyzes addition of one or two nucleotide monophosphate (NMP) to the 3'-hydroxyl group of RNAs, with the damaged RNAs as the preferred substrates. The crystal structure of Pf RlaP provided insight into molecular recognition of RNA substrate and nucleotide triphosphate (NTP) by RlaP. Aminoacylation assays indicate that RlaP is required to restore biological function of the repaired tRNAs that have suffered excessive damage. Based on our studies, we propose an in vivo scenario where cell survival requires the involvement of RlaP in RNA repair to restore the biological function of the damaged RNAs.

DOI: https://doi.org/10.64898/2025.12.29.696909
Commun Biol. 2026 Jan 02.

Reshaping cancer cell plasticity by P-body dynamics and protein translation.

Emanuela Senatore, Laura Rinaldi, Francesco Chiuso, Antonio Giuseppe Bianco, Antonio Feliciello.

Processing bodies (P-bodies) are membrane-less organelles composed of condensed mRNAs and proteins that play essential role in mRNAs decay and storage, contributing to the translational control of cellular proteostasis. Regulation of P-body assembly/disassembly by signaling events, cellular stress or specific environmental conditions shapes the rate of RNA turnover and protein synthesis, controlling cell growth, differentiation and survival. Deregulation of protein translation is an important factor for tumor development and progression and cancer cells benefit from P-bodies to reshape their proteome to support specific metabolic needs and promote tumor development, progression and metastasis. Hence, understanding the composition and the regulation of P-bodies, both under physiological and pathological conditions, will define the mechanisms underlying cancer cell plasticity and develop novel therapeutic strategies to inhibit cancer growth and metastasis. Here, we will discuss the principal mechanisms of P-body regulation and function, with special focus on the role of these ribonucleoprotein condensates in cancer.

DOI: https://doi.org/10.1038/s42003-025-09439-0
Biochim Biophys Acta Mol Cell Res. 2026 Jan 06. pii: S0167-4889(25)00209-5. [Epub ahead of print] 120104

ADAR1 upregulates the translation of cytochrome c via the inhibition of translocation into stress granules, facilitating apoptosis by an anticancer agent.

Motoki Isono, Tomoka Yamakawa, Kyoka Nagaoka, Masataka Nakano, Tatsuki Fukami, Miki Nakajima.

  Adenosine-to-inosine (A-to-I) RNA editing catalyzed by adenosine deaminase acting on RNA (ADAR) 1 is the most abundant RNA modification in humans. We noticed that there are multiple A-to-I RNA editing sites in the 3'-UTR of cytochrome c (CYCS), a mitochondrial protein involved in the initiation of apoptosis. We aimed to clarify the impact of ADAR1 on the regulation of CYCS expression, its mechanism, and its biological and pharmacological significance. In human hepatocellular carcinoma-derived HepG2 or Huh-7 cells, siRNA-mediated knockdown of ADAR1 (siADAR1) reduced CYCS protein levels without affecting mRNA levels, suggesting that ADAR1 facilitates CYCS translation. Sanger sequence analysis showed that multiple adenosines in the 3'-UTR of CYCS are highly edited by ADAR1. The CYCS protein level in HepG2 CYCS 3'-UTR-deleted cells in which the 3'-UTR of CYCS was deleted by the CRISPR/Cas9 system was not decreased by siADAR1, indicating that the 3'-UTR is required for ADAR1-dependent translational regulation. The pulldown assay revealed that siADAR1 increases the binding of CYCS mRNA to RNA-binding proteins with disordered regions, suggesting that stress granules, a membrane-less organelle formed by such proteins with intrinsically disordered regions, might trap CYCS mRNA and suppress its translation. Treatment with ISRIB, an inhibitor of stress granule formation, attenuated the siADAR1-mediated decrease in CYCS protein levels. Interestingly, sorafenib-induced apoptosis in HepG2 cells was repressed by siADAR1, but this repression was not observed in HepG2 CYCS 3'-UTR-deleted cells. Collectively, this study clarified that ADAR1 upregulates CYCS translation by inhibiting stress granule formation and thereby can facilitate anticancer agent-induced apoptosis.

Keywords:  A-to-I RNA editing; ADAR1; Apoptosis; Cytochrome c; Stress granules

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120104
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1504. [Epub ahead of print]54(1):

Systemic control of HNF1B-driven redox homeostasis by N6-adenosine methylation.

Minji Park, Hwa-Ryeon Kim, Ji Hoon Park, YongHwan Kim, June-Ha Shin, Jueun Lee, Yeajin Ju, Geum-Sook Hwang, Dong-Myung Shin, Mi-Young Kim, Jae-Seok Roe.

Transcription factors are key regulators of gene expression and play essential roles in various diseases, yet their lack of small-molecule binding pockets makes them difficult to target with drugs. Internal RNA modifications, such as N6-methyladenosine, are widespread in mammalian cells, but how m6A-encoded epitranscriptomic information influences transcription factor activity and cellular function remains incompletely understood. Here, we demonstrate that m6A methylation directly regulates HNF1B and is essential for maintaining redox homeostasis in cancer cells. The METTL3/METTL14 methyltransferase complex deposits m6A marks within the 3'-untranslated regions of HNF1B messenger RNA (mRNA), stabilizing its expression and function. Genetic or chemical inhibition of METTL3-mediated m6A modifications disrupts HNF1B-driven glutathione metabolism, severely impairing the antioxidant capacity of cancer cells and rendering them vulnerable to oxidative stress. Notably, HNF1B loss induces oxidative stress-induced cell death across multiple cancer lineages, mirroring the metabolic dysfunction caused by m6A depletion and establishing HNF1B as a central regulator of redox defense in human cancer. By directly linking RNA modifications of a transcription factor to redox homeostasis, our findings identify the METTL3-HNF1B axis as a metabolic vulnerability in cancer and highlight its potential as a target for m6A-directed cancer therapies.

DOI: https://doi.org/10.1093/nar/gkaf1504
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1500. [Epub ahead of print]54(1):

Initial spliceosomal U4/U6 di-snRNA formation occurs in the cytoplasm of Saccharomyces cerevisiae and requires a guard protein mediated quality control.

Xiaoxiao Wang, Jian Guo, Jing Li, Heike Krebber.

Unlike mRNA surveillance, ncRNA quality control is less well understood. While mRNA maturation is monitored by guard proteins that allow nuclear export of correctly processed transcripts or retention and degradation of faulty RNAs, such surveillance system is unknown for ncRNAs. This study investigates the maturation process of the snRNA U6 in Saccharomyces cerevisiae, revealing that this RNAPIII transcript undergoes quality control by established guard proteins and the novel factor Lhp1 (human La), which ensures proper loading of the Lsm-ring in the nucleus. Subsequent Mex67 binding facilitates the nuclear export of pre-U6. In the cytoplasm, pre-U6 associates with Prp24 which assists in annealing with pre-U4. Defects in di-snRNP formation are identified by the guard proteins Npl3, Gbp2, and Hrb1. These proteins retain the RNA in the cytoplasm and recruit Dcp1 and Dcp2 for de-capping, along with Xrn1 for degradation of faulty pre-U6. Correctly assembled U4/U6 complexes are released from the guard proteins and imported back into the nucleus. This guard protein-mediated surveillance mechanism prevents faulty di-snRNPs to torpedo the spliceosome, underscoring the significance of the compartmented maturation and quality control of ncRNA. Additionally, the study illustrates that RNA surveillance mechanisms extend beyond coding RNAs and involve similar quality control mechanisms and proteins.

DOI: https://doi.org/10.1093/nar/gkaf1500
Front Mol Biosci. 2025 ;12 1714378

Split-APEX implicates splicing factor SRSF1 and splicing helicases in ribosomal biogenesis.

Vasileios Paschalis, Max F K Wills, Philippe De Gusmao Araujo, Christian Lucas, Sumera Tubasum, Shijie Cui, Hesna Kara, Carlos Bueno-Alejo, Marina Santana-Vega, Andrea Taladriz-Sender, Zhengyun Zhao, Alexander Axer, Cyril Dominguez, Alasdair W Clark, Glenn A Burley, Andrew J Hudson, Ian C Eperon.

  SR proteins are RNA-binding proteins with one or two RNA recognition motif (RRM)-type RNA-binding domains and a C-terminal region rich in arginine-serine dipeptides. They function in cellular processes ranging from transcription to translation. The best-known SR protein, SRSF1, modulates RNA splicing by stabilizing the binding of constitutive splicing factors, but there is also evidence that it participates in constitutive splicing reactions and is present in spliceosomal complexes. It has been shown recently that it interacts with DDX23, an RNA helicase that triggers the transition from complex pre-B to complex B during activation of the spliceosome. To identify in which other steps of spliceosome assembly and reaction it might be present, we have used split-APEX with SRSF1 and a number of helicases, each of the latter being involved in a particular step. Peroxidase activity should only be reconstituted if SRSF1 and the helicase were in contact, and the consequent biotinylation should reveal proteins in the vicinity. Our results show that all the helicases tested can complement SRSF1, but that the proximal proteins are very similar in all cases. Moreover, the proteins identified fall into two major classes: splicing-related proteins and ribosomal proteins. The results raise the possibility that SRSF1 and the canonical helicases have hitherto unsuspected collaborative roles in ribosomal assembly or translation.

Keywords:  RNA splicing helicases; SRSF1; ribosomal biogenesis; spliceosomal assembly; split-APEX

DOI:  https://doi.org/10.3389/fmolb.2025.1714378
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1428. [Epub ahead of print]54(1):

Sequence-dependent co-condensation of Lsr2 with DNA elucidates the mechanism of genome compaction in Mycobacterium tuberculosis.

Prakshi Gaur, Thejas Satheesh, Rohit Kumar Singh, Hussain Beig, Sneha Shahu, Saminathan Ramakrishnan, Mansi Srivastava, Shreyasi Neogi, Ayesha Dash, Amit Singh, Sandeep Choubey, Mahipal Ganji.

The xenogeneic silencer protein Lsr2 from Mycobacterium tuberculosis plays a critical role in its survival and pathogenesis. Lsr2 is a nucleoid-associated protein (NAP) that interacts with DNA in vivo and regulates many genes. Purified Lsr2 forms nucleoprotein filaments with DNA molecules, leading to highly compacted DNA conformations. However, the physical mechanism underlying Lsr2-mediated DNA compaction, resulting in gene regulation, remains elusive. We employed a combination of biochemical assay, single-molecule imaging, and molecular dynamics simulations to investigate the governing principles of Lsr2-mediated DNA compaction. We show that, while Lsr2 alone undergoes phase separation, addition of DNA substantially lowers the required concentration for its phase separation. Strikingly, our single-molecule and simulation data establish that Lsr2 forms condensates with long stretches of AT-rich DNA, providing strong evidence for sequence-dependent co-condensation. We further validate our findings by carrying out in vivo imaging of endogenously expressing Lsr2 tagged with eGFP in Mtb cells. This observation is contrary to the classical view of sequence-dependent binding of individual protein molecules to DNA; our findings rather suggest that protein-DNA co-condensates "sense" the average binding energy landscape. We present a physical model for Lsr2-mediated DNA compaction and gmycene regulation, describing a novel mechanism for NAP-mediated genome organization in bacteria.

DOI: https://doi.org/10.1093/nar/gkaf1428
Inflamm Res. 2026 Jan 08. 75(1): 14

N4BP1 acts as a potent negative regulator of IL-17 signaling by blocking the translation of Act1 mRNA.

Yanli Li, Zhuolong Xu, Xiaoyu Zhang, Zijian Zhang, Changsheng Ji, Xiaohong Guo, Jie Zhang, Peida Feng, Renfang Mao, Zhaoxiu Liu, Yang Lu, Yihui Fan.

   BACKGROUND: Interleukin 17 (IL-17) is a primary pathogenic cytokine, and antibodies blocking its function are clinically approved for treating psoriasis. Although Act1 (TRAF3IP2) is an essential multifunctional adaptor in IL-17 signaling, its regulatory mechanisms remain poorly understood. In this study, the role of endoribonuclease N4BP1 in regulating the IL-17 signaling pathway was characterized.
METHODS: N4BP1 was knocked out in both in vivo and in vitro experimental models to detect alterations in the IL-17 signaling pathway. Moreover, the specific mechanism by which N4BP1 exerts its regulatory effect was explored by examining the stability, degradation rate, transcription and translation rate of key proteins.
RESULTS: N4BP1 deficiency markedly enhanced IL-17-induced expression of proinflammatory mediators, including CXCL1, CCL20, and MMP9. Unexpectedly, the mRNA stability of CXCL1, CCL20, and MMP9 was largely unaffected by N4BP1 knockout. Further investigation revealed that N4BP1-deficient cells exhibited elevated MAPK phosphorylation, particularly of p38. Pharmacological inhibition of p38 substantially reduced CXCL1, CCL20, and MMP9 levels in N4BP1-deficient cells. This hyperactivation of MAPKs was attributed to an increased protein level of Act1 in N4BP1-deficient cells. Silencing of Act1 with shRNAs in N4BP1-deficient cells greatly diminished the upregulation of CXCL1, CCL20 and MMP9. The elevated Act1 protein level in N4BP1-deficient cells was not due to enhanced Act1 mRNA stability. Instead, polysome profiling demonstrated a pronounced enrichment of Act1 mRNA in the translationally active polysome fraction in N4BP1-deficient cells. In vivo, under pathological stimuli such as IMQ or aging, N4BP1-deficient mice exhibited increased Act1 protein, MAPK phosphorylation, and increased expression of IL-17 downstream genes, including CXCL1, CCL20, and MMP9. Pharmacological inhibition of Act1 ameliorates IMQ-induced skin damage, with a more pronounced therapeutic effect observed in N4BP1 KO mice.
CONCLUSIONS: These findings collectively establish that N4BP1 is a potent negative regulator of IL-17 signaling that suppresses the translation of Act1 mRNA.

Keywords:  Act1; IL-17 signaling; Inflammation; MAPK; N4BP1

DOI:  https://doi.org/10.1007/s00011-025-02159-5
bioRxiv. 2026 Jan 02. pii: 2026.01.02.697403. [Epub ahead of print]

A prelimbic molecular clock of protein synthesis for memory persistence.

J Iqbal, S Kim, S Lawal, A Shah, L Punepalle, H Sanghvi, A Gallagher, A Wilson, B Xu, P Shrestha.

Emotionally salient associative memories can endure for long periods, yet the mechanisms that determine their long-term stability remain unclear. Here we show that the prelimbic (PL) cortex integrates temporally structured translational programs to control both the consolidation and reconsolidation of cued threat memories. Using Pavlovian threat conditioning with in vivo fiber photometry, we found that PL calcium dynamics tightly track memory strength: discrete threat-predictive cues evoked robust activity during recent and single-timepoint remote retrieval, whereas prior retrieval selectively weakened remote expression, independent of contextual influences. Translational profiling of PL Camk2a ⁺ cells uncovered a biphasic consolidation program, with an early phase characterized by ER stress-linked translational repression and robust oligodendrocyte plasticity, followed by a delayed phase engaging synaptic growth pathways. Loss- and gain-of-function approaches demonstrated that eIF2α-regulated, cap-independent translation is essential for recent consolidation and for the enduring stabilization of remote memory, whereas retrieval-induced destabilization engages a mechanistically distinct, eIF4E-dependent translational pathway required for reconsolidation. These findings identify the PL cortex as a dynamic node in which discrete modes of translational control govern the long-term persistence of emotional memories.

DOI: https://doi.org/10.64898/2026.01.02.697403
J Biol Chem. 2026 Jan 07. pii: S0021-9258(26)00002-5. [Epub ahead of print] 111132

A high throughput screen for nucleolar function reveals a role for the signaling protein, SPRR3, in ribosome biogenesis.

Emily C Sutton, Carson J Bryant, Janina I S Gbenoba, Isabella R Lawrence, Susan J Baserga.

SPRR3 is a small, proline-rich protein that promotes cell proliferation. Overexpressed SPRR3 is associated with cancer and regulates AKT phosphorylation at serine 473. However, the specific cellular mechanisms by which SPRR3 drives proliferation are not fully understood. Using a genome-wide siRNA screen in MCF10A breast epithelial cells for decreased nucleolar number, we identified SPRR3 as a novel regulator of ribosome biogenesis. We used siRNA to deplete SPRR3 and found that it is required for transcription of the pre-ribosomal RNA (pre-rRNA), the earliest step in ribosome biogenesis. Furthermore, this reduction in pre-rRNA transcription triggers the nucleolar stress response (increased TP53 protein and CDKN1A mRNA levels) in both MCF10A cells and A549 lung carcinoma cells. Finally, SPRR3 depletion reduces AKT phosphorylation in both cell lines and correlates with lower levels of the RNAPI catalytic subunit POLR1A. In sum, we establish a new role for the non-nucleolar protein SPRR3 in ribosome biogenesis, specifically pre-rRNA transcription, via its ability to facilitate phosphorylation of AKT.

DOI: https://doi.org/10.1016/j.jbc.2026.111132
bioRxiv. 2025 Dec 23. pii: 2025.12.20.694502. [Epub ahead of print]

Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs.

Arun Krishnaraj, Xinrui Wei, Richi Thakral, Weiyi Guo, Siva Bala Subramaniyan, Xiaopei Zhang, Katelyn R Alley, Anqi Feng, Andrew Hoy, Douglas Kung, Purushottam B Tiwari, Aykut Üren, Rodrigo Maillard, Victoria J DeRose, Sreejith J Nair.

Small molecules developed to target proteins or DNA may also bind RNA, but the extent and biological significance of such interactions among oncology drugs remain poorly defined. Here, we systematically profiled RNA interactions of a cohort of clinically approved anticancer agents and uncovered widespread RNA off-targeting. Cisplatin, a frontline chemotherapeutic agent for solid tumors, has emerged as a prominent RNA-binding drug. While the primary mechanism of action of cisplatin has been attributed to DNA damage-induced apoptosis, it has also been shown to bind RNA molecules. However, the extent of RNA binding in cancer cells and its functional relevance in platinum-based chemotherapy remained unknown. To map specific RNA targets of cisplatin in vivo , we developed PlatRNA-seq, a click-chemistry-enabled transcriptome-wide assay. Using this approach and integrated genomic, biophysical, and computational analysis, we show that cisplatin binding is enriched at guanine-rich regions of transcripts, with a pronounced affinity for RNA G-quadruplexes (rG4s) secondary structures. Cisplatin accumulates preferentially near the 5' ends of transcripts associated with R-loop formation and RNA pol II stalling. Mechanistically, cisplatin binding to rG4s modulates their formation and stability. Importantly, we provide evidence that cisplatin-induced cytotoxicity is mediated in part through its binding to RNA, revealing a noncanonical RNA-based mechanism of action. Analysis of single-cell RNA-seq data from tumor biopsies of treatment-naïve ovarian cancer patients further shows that the expression of rG4-enriched cisplatin-RNA targets predicts platinum sensitivity, underscoring the prognostic and clinical relevance of drug-RNA interactions. Together, these results demonstrate that RNA off-targeting by small molecules is not passive but can modulate therapeutic outcomes and may be leveraged to overcome current limitations of chemotherapeutic agents. Our findings highlight the importance of systematically investigating RNA interactions of clinically used small molecules to better inform therapeutic and prognostic strategies.

DOI: https://doi.org/10.64898/2025.12.20.694502
Cells. 2025 Dec 30. pii: 65. [Epub ahead of print]15(1):

Acute Cold Exposure Cell-Autonomously Reduces mTORC1 Signaling and Protein Synthesis Independent of AMPK.

Benjamin Y Sung, Eliza J Ford, Daniel J Foster, Kyler J Fullmer, Cosette Cromwell, Benoit Viollet, David M Thomson.

  Cryotherapy is a commonly used strategy for skeletal muscle recovery, although the efficacy of its use has been controversial. Therefore, more research is needed to understand under what circumstances it should be used. This study aimed to examine the cell-autonomous effects of acute cold exposure on primary mouse myoblasts, focusing on metabolic signaling through the AMPK/mTORC1 pathway. In it, we hypothesized that cold exposure (COLD) would impair myoblast proliferation, differentiation, and protein synthesis in an AMPK-dependent manner. Wild-type (WT) and AMPK double-knockout (dKO) myoblast cultures were treated at 37 °C or 26 °C to evaluate AMPK-dependent effects. As expected, 30 min of cold exposure activated AMPK and decreased mTORC1 activity and protein synthesis; however, mTORC1 and protein synthesis were downregulated independently of AMPK activation. Additionally, cold exposure suppressed proliferation 6 h post-treatment in WT, but not dKO, myoblasts. On the other hand, in differentiated WT and dKO cells, cold treatment did not influence myotube size, although dKO myotubes exhibited decreased fusion index and increased size compared to WT. These findings offer new insights into the cell-autonomous metabolic effects of cryotherapy in skeletal muscle and indicate that while COLD-induced AMPK activation contributes to impaired myoblast proliferation, AMPK is not necessary for the COLD-induced inhibition of the mTORC1 pathway and protein synthesis.

Keywords:  AMPK; cryotherapy; injury recovery; mTORC1; protein synthesis; skeletal muscle

DOI:  https://doi.org/10.3390/cells15010065
Int J Mol Sci. 2026 Jan 01. pii: 462. [Epub ahead of print]27(1):

RNA-Binding Proteins in Dinoflagellates.

Mariia Berdieva, Pavel Safonov, Sergei Skarlato.

  The described features of dinoflagellate gene expression indicate the predominance of post-transcriptional and translational regulation over transcriptional control. These microorganisms also exhibit extensive RNA editing and distinctive splicing characteristics. This regulatory landscape underscores the central role of RNA-binding proteins in dinoflagellate biology. In this review, we summarize current knowledge on major RNA-binding protein groups identified or bioinformatically annotated in dinoflagellates, including RNA recognition motif domain-containing proteins, Sm and Sm-like family, KH domain-containing proteins, zinc-finger proteins, and Pumilio family proteins, S1 domain-containing and cold shock domain-containing proteins, DEAD/DEAH-box RNA helicases, and pentatricopeptide repeat proteins. We focus on the features of their conserved domains, their functions in eukaryotes, and available data on their presence and putative roles in dinoflagellate cells. Integrating genomic, transcriptomic, and proteomic evidence, and where possible experimental data, we highlight both their overall conservation and potential lineage-specific traits. Our aim is to provide a concise synthesis of current knowledge, identify key uncertainties, and outline promising directions for future research into the evolution and cellular roles of RNA-binding proteins in this ecologically and biologically remarkable group.

Keywords:  RNA-binding proteins; conserved domains; dinoflagellate; gene expression; regulation

DOI:  https://doi.org/10.3390/ijms27010462
bioRxiv. 2026 Jan 02. pii: 2026.01.02.697427. [Epub ahead of print]

Direct RNA Sequencing Reveals Stress-Dependent and Pathway-Specific rRNA Modification Reprogramming During 50S Biogenesis.

Luis A Gracia Mazuca, Salvador A Rodarte, Isaac S Weislow, Jonathon E Mohl, Eda Koculi.

Ribosomal RNA (rRNA) modification and processing are essential steps in ribosome assembly. Using Oxford Nanopore direct RNA sequencing, we simultaneously detect and quantify eight classes of 23S rRNA modifications in the mature 50S large subunit (LSU) from Escherichia coli cells expressing either wild-type DbpA or the helicase-inactive R331A DbpA variant, as well as in two LSU assembly intermediates, 35S and 45S, which accumulate along distinct maturation pathways in R331A DbpA expressing cells. In addition, we analyze 3'-end processing of 23S and 5S rRNAs across these particles. Many 23S rRNA modifications are incorporated at similar levels in LSU assembly intermediates and mature 50S subunits from both wild-type and R331A DbpA expressing cells, indicating that these modifications are incorporated prior to intermediate accumulation and are not preferentially reprogrammed under R331A DbpA induced assembly stress. In contrast, a subset of three modifications exhibits altered incorporation patterns. N 2 -methyladenosine 2507 incorporation is reduced in the 50S LSU from R331A DbpA expressing cells compared with the cells expressing wild-type DbpA, whereas pseudouridine (Ψ) 2508 is increased. In addition, Ψ 2608 is reduced in the 50S subunit from R331A DbpA expressing cells compared with the 35S and 45S intermediates from the same cells and the 50S subunit from wild-type cells. Because the 35S and 45S pathways account for only ∼40% of ribosome assembly in R331A DbpA expressing cells, these findings demonstrate that Ψ2608 incorporation is selectively reprogrammed across alternative in vivo assembly routes, revealing an additional regulatory layer in ribosome biogenesis.

DOI: https://doi.org/10.64898/2026.01.02.697427
Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01016-0. [Epub ahead of print]

ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis.

Siyuan Jiang, Jinghan Sun, Ya Gao, Haifeng Zhang, Ying He, Yibi Zhang, Zhiyuan Xu, Shuwen Cheng, Hong Yan, Liqiang Duan, Peng Xu, Qinong Ye, Shan Gao.

  The view of mRNA function as a translational template is being challenged beyond translation. However, how these non-canonical mRNAs function independently of their coding protein remains largely unexplored. Here, we found that intercellular adhesion molecule 1 (ICAM1) depletion via CRISPR-Cas9 protein knockout and shRNA-mediated RNA knockdown produces opposite effects on cell proliferation in human cells, which is validated by overexpression of mutated coding ICAM1 mRNA and ICAM1 coding sequence (CDS). Mechanistically, cis-antisense transcripts of ICAM1/ICAM1-AS form a double-stranded RNA (dsRNA), which entraps the interleukin enhancer binding factor 2 (ILF2)/ILF3 complex to inhibit DNA binding in a length-dependent manner, thus suppressing EIF4E transcription and global protein synthesis. Clinical analysis highlights the coordinated downregulation of ICAM1/ICAM1-AS, independent of highly expressed ICAM1 protein in lung cancer. In conclusion, this study reveals a role for ICAM1 mRNA in regulating cellular transcription via the dsRNA-ILF2/3 axis. Our findings challenge the phenotype explanation of gene silencing between RNA knockdown and protein knockout and underscore independent mRNA functions.

Keywords:  ICAM1; ILF2/ILF3 complex; dsRNA; lncRNAs; non-canonical mRNAs function; translation

DOI:  https://doi.org/10.1016/j.molcel.2025.12.017
Postepy Biochem. 2025 12 19. 71(4): 383-404

The Role of DNA and RNA Methylation in Cancer: Mechanisms and Therapeutic Potential of Epigenetic and Epitranscriptomic Drugs

Julia Pisarek, Marta Koblowska.

Chemical modifications of DNA and RNA play a pivotal role in the regulation of gene expression, enabling precise control of cellular functions and adaptation to changing environmental conditions. The most common modification in human DNA is cytosine methylation at the 5th position (5mC), while in RNA it is adenosine methylation at the N6 position (m⁶A), recognized as the predominant epitranscriptomic modification. Regulation of these modifications relies on the coordinated action of three groups of proteins: methyltransferases, demethylases, and reader proteins, which recognize modified nucleobases and recruit effector protein complexes, thereby translating the pattern of nucleic acid modifications into a specific biological response. Dysfunction of these protein groups leads to aberrant 5mC and m⁶A patterns, which play a crucial role in the pathogenesis and progression of many human diseases, including cancer. Deregulation of DNA and RNA methylation affects, among others, the control of genes involved in proliferation, apoptosis, and genome stability, which may promote tumor progression; moreover, the dynamic and reversible nature of these modifications makes them attractive diagnostic and therapeutic targets in cancer treatment.

DOI: https://doi.org/10.18388/pb.2021_637
Plant Direct. 2026 Jan;10(1): e70122

Membranous Interacting Partners of Phage-Type Plastid RNA Polymerase Have Limited Impact on Plastid Gene Expression During Chloroplast Development.

Yushi Kurotaki, Yuki Hagiwara, Kosei Noto, Atsuo S Nishino, Sho Fujii.

  In vascular plants, genes in the plastid genome are transcribed by two types of RNA polymerases, namely, phage-type nuclear-encoded and bacterial-type plastid-encoded plastid RNA polymerases (NEP and PEP, respectively). Eudicots, including Arabidopsis, carry two isoforms of NEP, RPOTp and RPOTmp. NEPs transcribe multiple plastid-encoded genes including subunits of PEP and translocon and are thus indispensable for the maintenance of plastids. However, regulatory mechanisms of NEPs are largely unknown. RPOTmp transcribes the 16S rRNA gene from a specific promoter in the seeds during vernalization, and its mutation in Arabidopsis retards chloroplast development. As interacting partners of RPOTmp, two NEP-INTERACTING PROTEINs (NIP1 and NIP2) have been identified and suggested to suppress RPOTmp activity by tethering RPOTmp to the thylakoid membrane during chloroplast development in the presence of light, but their precise roles in transcriptional regulation remain to be addressed. From these previous reports, we hypothesize that the functions of RPOTmp would depend on the light conditions and expression of NIPs. To gain insight into how RPOTmp is controlled, we performed a functional analysis of RPOTmp and NIPs using Arabidopsis mutants during germination in the dark and de-etiolation processes under light. We found that RPOTmp-dependent transcription of 16S rRNA is active in imbibed seeds and remains at a basal level throughout the postgermination processes, regardless of light conditions. We also demonstrated a limited impact of NIPs on RPOTmp function during these processes. Our phylogenetic analysis indicates that NIPs have distinct evolutionary profiles compared with RPOTmp, and Arabidopsis is unlikely to have additional NIP-like proteins in plastids. Based on these findings, we propose a modified model of RPOTmp regulation during chloroplast development: RPOTmp activity remains stable throughout the process of chloroplast differentiation and is unaffected by light and NIPs.

Keywords:  Arabidopsis; chloroplast differentiation; nuclear‐encoded plastid RNA polymerase; transcriptional regulation

DOI:  https://doi.org/10.1002/pld3.70122
PLoS Biol. 2026 Jan;24(1): e3003589

Characterization of RNA interference in the cnidarian Nematostella vectensis reveals partial target silencing but lack of small RNA amplification.

Yael Admoni, Magda Lewandowska, Reuven Aharoni, Junchao Shi, Xudong Zhang, Qi Chen, Yehu Moran.

RNA interference (RNAi) is a sequence-specific mRNA degradation mechanism, in which short interfering RNAs (siRNAs) guide Argonaute proteins to complementary targets, resulting in their degradation. In many organisms, RNAi also serves antiviral roles by processing viral double-stranded RNA (dsRNA) into siRNAs that prevent viral replication. Antiviral RNAi is considered an ancestral mechanism which invertebrates rely on for defense against viruses, whereas vertebrates have evolved instead the interferon pathway. Recent studies suggest that sea anemones, members of the basally-branching phylum Cnidaria, might possess an innate immune response with more vertebrate characteristics than previously thought; however, it is unknown whether cnidarians also employ RNAi as an antiviral response similarly to nematodes and insects. Here, we characterize the response of the model cnidarian Nematostella vectensis to simulated viral infection. We injected dsRNA with eGFP sequence into eGFP-expressing transgenic zygotes and show that siRNAs mapping to the eGFP sequence are generated and induce a moderate but significant knockdown of eGFP expression. Interestingly, we detected no evidence for secondary siRNA production, despite their crucial role in the amplification of antiviral response in other organisms. Notably, siRNA pathway components are specifically upregulated upon dsRNA injection, while microRNA pathway components are downregulated. Furthermore, injection of mRNA coding for self-replicating viral gene fused to eGFP, also induced upregulation of siRNA-related genes and a mild decrease in transgene expression. Overall, we propose that N. vectensis possesses an siRNA-mediated response that lacks secondary amplification and likely functions as a short-term antiviral mechanism.

DOI: https://doi.org/10.1371/journal.pbio.3003589
bioRxiv. 2025 Dec 23. pii: 2025.12.21.694897. [Epub ahead of print]

A dietary pan-amino acid dropout screen in vivo reveals a critical role for histidine in T-ALL.

Komal Mandleywala, Simona Ulrich, Victoria da Silva-Diz, Puneet Sharma, Christopher Thai, Oekyung Kim, Maya Aleksandrova, Gwendolyn Chung, Cristian Eggers, Dieter Lütjohann, Tanaya Kulkarni, Amartya Singh, M Elena Díaz-Rubio, Michael Wierer, Sebastian A Leidel, Xiaoyang Su, Eileen P White, Joshua D Rabinowitz, Raphael J Morscher, Daniel Herranz.

Dietary interventions show therapeutic potential in cancer, but systematic comparisons are lacking. We performed a dietary pan-amino acid dropout screen in an orthotopic model of NOTCH1-driven T-cell acute lymphoblastic leukemia and identified histidine depletion as uniquely antileukemic. Histidine-restricted diets extended survival of leukemic mice in a dose-dependent manner, while remaining well-tolerated. Mechanistically, multiomic profiling revealed that histidine deprivation-induced ribosome stalling activates GCN2 to suppress cholesterol biosynthesis pathways critical for leukemic proliferation. Dietary cholesterol supplementation partially reverted the antileukemic effects of histidine restriction in vivo . These findings couple histidine levels and translational control to cholesterol metabolism, which can be therapeutically exploited for cancer treatment. Our results suggest that defined dietary amino acid restrictions may expose broader therapeutic opportunities in diseases beyond cancer.

DOI: https://doi.org/10.64898/2025.12.21.694897
bioRxiv. 2025 Dec 30. pii: 2025.12.30.697025. [Epub ahead of print]

Delamanid and pretomanid have comparable bactericidal activity but pretomanid potently inhibits Mycobacterium tuberculosis ribosomal rRNA synthesis.

Matthew J Reichlen, Emmanuel Musisi, Samuel T Tabor, Holly Nielsen, Ashley M Gerwing, Firat Kaya, Matthew Zimmerman, Martin I Voskuil, Gregory T Robertson, Nicholas D Walter.

Background: The nitroimidazoles delamanid and pretomanid play an important role in contemporary tuberculosis treatment. It is unclear whether delamanid and pretomanid have meaningfully different activity since both reduce Mycobacterium tuberculosis colony forming units (CFU) similarly in animal models. The RS ratio is a pharmacodynamic marker of ongoing rRNA synthesis that has been associated with treatment-shortening ( i . e ., sterilizing) activity.
Methods: Using Mycobacterium tuberculosis Erdman , we conducted dose-ranging studies in aerobic axenic culture and in the conventional BALB/c mouse high-dose aerosol infection model to compare bactericidal and RS ratio activity of delamanid and pretomanid.
Results: In vitro concentration-response curves showed that delamanid and pretomanid had similar RS ratio effect at maximal concentration but pretomanid was more potent, achieving 90% of the maximal effect (RS-EC 90 ) at a lower concentration (390 ng/mL) than delamanid (810 ng/mL). In mice, delamanid and pretomanid had similar effects on CFU. Human-equivalent doses of delamanid (6 mg/kg) and pretomanid (50 mg/kg) resulted in plasma C max concentrations well below (210 ng/mL) and well above (7,825 ng/mL) the RS-EC 90 , respectively. Delamanid displayed no discernable RS ratio response, even at 16-times the human-equivalent dose. Higher pretomanid doses resulted in significantly greater RS ratio effects.
Conclusions: We found that delamanid and pretomanid have similar bactericidal activity but pretomanid has superior RS ratio activity. Meaningful differences between drugs within the same class were not captured by conventional CFU-based pharmacodynamics, supporting the value of measuring orthogonal drug effects such as the RS ratio.
LAY SUMMARY: Antibiotics in the nitroimidazole class are used in treatment of drug-resistant tuberculosis. There are two approved nitroimidazole antibiotics: delamanid and pretomanid. For decades, it has been unclear whether delamanid and pretomanid are interchangeable or whether they affect the bacterium M. tuberculosis differently. Most studies of the effect of antibiotics count the number of bacterial colonies that form on a culture plate. "Colony forming units" tell us about change in bacterial burden but does not give information about bacterial health. A new way of thinking about antibiotic effect is the RS ratio. The RS ratio is a test that measures how much ribosomal RNA synthesis is ongoing. Ribosomal RNA synthesis is a "vital sign" of bacterial health and activity. The key finding of this study is that although the two nitroimdazole antibiotics look the same in terms of their effect on bacterial burden, they have different effects on bacterial health. This information deepens understanding of differences between two clinically important antibiotics. It also shows that antibiotics testing should consider not only bacterial burden but also new tests of bacterial health.

DOI: https://doi.org/10.64898/2025.12.30.697025
Commun Biol. 2026 Jan 03. 9(1): 10

Canine parvovirus infection affects host cell nucleolar organization and ribosome biogenesis.

Moona Huttunen, Satu Hakanen, Vesa Aho, Simon Leclerc, Aynur Soenmez, Sergey Kapishnikov, Alessandro Zannotti, Visa Ruokolainen, Kari Salokas, Markku Varjosalo, Leena Latonen, Colin R Parrish, Kenneth Fahy, Salla Mattola, Denis L J Lafontaine, Maija Vihinen-Ranta.

The nucleolus is a biomolecular condensate essential for ribosome biogenesis and cellular stress response, and it is a key target for many DNA viruses. However, little is known about how autonomous parvovirus infection impacts the nucleolus. Here, we used ten-fold robust expansion microscopy, cryo soft X-ray tomography, interactomics, and biochemical approaches to study nucleolar remodeling during canine parvovirus infection. The nucleolus is organised in nested layers. Infection led to redistribution of nucleolar upstream binding transcription factor 1 (inner core), fibrillarin (middle layer), and Ki-67 (outer rim). In contrast, peripheral nucleolar proteins (nucleolin and nucleophosmin) and precursor ribosomal RNAs remain in spherical structures. High-resolution microscopy revealed profound nucleolar structural changes, including thickened perinucleolar chromatin and enlarged nucleolar low-protein density channels. BioID identified interactions between viral NS2 and nucleolar proteins involved in ribosome biogenesis. Northern blotting demonstrated a slowdown in ribosome biogenesis during infection. Collectively, these findings provide insights into how parvoviruses remodel nucleolar structure and function.

DOI: https://doi.org/10.1038/s42003-025-09385-x
Genome. 2026 Jan 09.

Low complexity (A/C)GG Repeats and m1 A Methylation Sites in 5` UTRs Regulate Gene Expression.

Zachery W Dickson, Megan Bilodeau, Daniel L Ruiz, Geoffrey Brian Golding.

Repetitive and compositionally biased low-complexity (LC) motifs appear in biological sequences where they interact with the machinery controlling the abundance of their host molecules. They can have significant impacts on physiological function, and act as raw material for evolution of regulatory motifs. The extent to which LC motifs affect abundance is not known. Even definitions of LC sequences are not well established, let alone which motifs exists in LC sequences, and which of those are abundance associated. To fill these knowledge gaps for post-transcriptional impacts of LC motifs, we integrated data from the GTEx project, PaxDb, and the IGSR. We establish definitions for LC motifs in both RNA and protein sequences. We observed that the presence of LC motifs in the 5' UTR were positively associated with transcript abundance. We present a method to de novo identify abundance associated motifs and identified trinucleotide repeats of (A/C)GG as most strongly abundance associated. We observed that m1A methylation sites were strongly associated with both LC motifs and abundance, an effect which is amplified as methylation signatures from unspecialized RNA-seq increased. Together, our results demonstrate that LC motifs play important roles in regulating gene expression.

DOI: https://doi.org/10.1139/gen-2025-0071
Cell Death Dis. 2026 Jan 07. 17(1): 4

Emerging roles of tRNA modification-mediated codon-specific translational reprogramming in cancer biology.

Hanwei Wang, Junsi Zhang, Cen Jiang, Sunwang Xu.

Cancer has become a leading cause of mortality worldwide, with alarming increases in incidence and mortality rates. Emerging evidence suggests that tRNA modification enzymes play a crucial role in cancer development by modulating codon-specific translation. In this review, we focus on 18 tRNA modification enzymes and elucidate their mechanisms of action and roles in disease. We highlight the functions and mechanisms of seven tRNA regulators that mediate favorable tRNA translation in tumorigenesis and cancer progression, providing deeper insights into their clinical potential as cancer-related biomarkers and prognostic indicators. These findings emphasize the need for further investigation into the therapeutic potential of tRNA modification enzymes in cancer management and their potential application in personalized cancer therapy and diagnostics.

DOI: https://doi.org/10.1038/s41419-025-08234-3