bims-mirnam Biomed News
on Mitochondrial RNA metabolism
Issue of 2026–08–30
six papers selected by
Hana Antonicka, McGill University
  1. RNA modifications and RNA-binding proteins: interactions, regulation, and new avenues for therapeutic modulation.
  2. Mutant p53 gains RNA-binding activity to reprogram translation and mitochondrial function.
  3. dsRNAscan maps human dsRNAome, revealing conservation, intermolecular dsRNA, and correlates of ADAR dependency.
  4. Massively parallel characterization of RNA G-quadruplex stability and molecular recognition.
  5. Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity.
  6. Genetic studies with a uracil DNA glycosylase biosensor support a role for mitochondrial UNG1 in nuclear uracil repair.
  1. RSC Chem Biol. 2026 Aug 20.
    RNA modifications and RNA-binding proteins: interactions, regulation, and new avenues for therapeutic modulation.
    Gabriela Vega-Hernández, Amanda L Garner.
      RNA-binding proteins (RBPs) are central regulators of post-transcriptional gene expression, recognizing RNAs through sequence, structure, and chemical modifications. Post-transcriptional RNA modifications, including m6A, m1A, m5C, m7G, and pseudouridine (Ψ), form the epitranscriptome, a dynamic regulatory layer that modulates RNA stability, localization, and translation. These modifications are interpreted by specialized "reader" RBPs that translate epitranscriptomic marks into functional outcomes. Dysregulation of RNA modifications or their associated reader RBPs has been increasingly linked to the development of cancers, neurological disorders, and other diseases, highlighting their potential for therapeutic manipulation. This review summarizes key RNA modifications and regulating RBPs with a specific emphasis on how dysregulation can lead to cancers. We further discuss current approaches for investigating and manipulating reader RBP-RNA interactions, highlighting how these methods enable new opportunities for therapeutic discovery.
    DOI:  https://doi.org/10.1039/d6cb00136j
  2. Cell Rep. 2026 Aug 18. pii: S2211-1247(26)00934-4. [Epub ahead of print]45(8): 117856
    Mutant p53 gains RNA-binding activity to reprogram translation and mitochondrial function.
    Wuyue Zhou, Alice Long, Cameron J Douglas, Dalila Gallegos, James M Burke, David W C MacMillan, Ezgi Hacisuleyman, Ciaran P Seath.
      Tumor suppressor p53 is a transcription factor mutated in ∼50% of cancers. Somatic mutations in the DNA-binding domain abolish tumor suppression and thus lead to a loss-of-function activity, while a small subset of recurrent "hotspot" mutants have been shown to confer gain-of-function activities. Using an intein-based μMap photoproximity labeling approach, we map the interactomes of five hotspot mutants and find that mutant p53 (mut p53) acquires interactions with RNA-binding proteins, shifts toward the cytoplasm, and shows increased proximity to structured RNA and RNA-binding proteins. CLIP (Cross-linking and immunoprecipitation) experiments show that mut p53 possesses an RNA-binding motif and is enriched at 3'UTRs, promoting ribosomal localization and localization at the mitochondrial surface. Using ribosome profiling, we further show that mut p53 alters translation and promotes changes in miRNA processing and mitochondrial function, providing a mechanistic rationale for historically reported but poorly understood phenotypes.
    Keywords:  CLIP-seq; CP: cancer; CP: molecular biology; RNA binding; cancer; gain-of-function; mitochondria; mutant p53; proximity labeling; ribosome profiling; translation; μMap
    DOI:  https://doi.org/10.1016/j.celrep.2026.117856
  3. Mol Cell. 2026 Aug 28. pii: S1097-2765(26)00548-4. [Epub ahead of print]
    dsRNAscan maps human dsRNAome, revealing conservation, intermolecular dsRNA, and correlates of ADAR dependency.
    Ryan J Andrews, Brenda L Bass.
      The human transcriptome contains millions of A-to-I editing sites arising from an unclear number of poorly characterized dsRNAs. Editing sites reveal the presence of dsRNA, but this method is limited by transcription levels, read depth, and ADAR expression and cannot identify unedited dsRNA. To address these limitations, we developed dsRNAscan. Applying dsRNAscan to the human genome predicted 5 million dsRNAs, mostly in repetitive and intergenic regions. Machine learning models trained on A-to-I editing and RNA structure-probing data identified ∼2.4 million high-confidence predictions, which were enriched at dsRNA-binding protein binding sites. Additionally, we predicted hundreds of dsRNAs conserved across vertebrates and observed thousands of editing-enriched regions suspected to arise from intermolecular dsRNAs formed with sense-antisense transcripts. Quantifying expression of intramolecular and intermolecular dsRNAs accessible to cytoplasmic immune sensors revealed that their ratio correlated with ADAR dependency across cancer cell lines. The human dsRNAome is available as a resource at https://dsrna.chpc.utah.edu/.
    Keywords:  A-to-I RNA editing; ADAR; ADAR dependency; Alu elements; DepMap; MDA5; PKR; double-stranded RNA; innate immunity; inverted repeats
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.001
  4. Nucleic Acids Res. 2026 Aug 24. pii: gkag821. [Epub ahead of print]54(16):
    Massively parallel characterization of RNA G-quadruplex stability and molecular recognition.
    Justin G Martyr, Bryan B Guzmán, Alli Jimenez, Rebekah L Rothacher, Francisco F Cavazos, Yue Hu, Rhese D Thompson, Anthony M Mustoe, Maria M Aleman, Daniel Dominguez.
      RNA G-quadruplexes (rG4s) have been implicated as important regulators of RNA metabolism and are promising targets for RNA-targeted therapeutics. rG4s typically require a canonical (G≥2N1-7)4 motif, but the sequence features that affect rG4 stability and recognition by RNA-binding proteins (RBPs) and rG4-binding ligands are not fully understood. To interrogate sequence-level drivers of rG4 folding, we applied a reverse-transcriptase stop sequencing strategy to a library of ∼3000 synthetic rG4s with varied G-tract lengths, loop lengths, and loop compositions, permitting massively parallel quantification of rG4 stability. Our data confirm known sequence-level features and characterize novel combinatorial impacts of these features. We also assessed systematically mutagenized natural rG4s, revealing unexpected mutations that significantly affect rG4 stability, including contributions from flanking sequences outside of the rG4. We further used our strategy to assess rG4 recognition preferences of the model rG4 ligand pyridostatin, revealing a preferential stabilization of rG4s containing mixed-length G-tracts. We additionally demonstrated the potential for large-scale protein-binding assays with our library to reveal rG4 features recognized by RBPs, specifically G3BP1 and FMRP. Our approach and data provide a generalizable framework to study sequence-level drivers of rG4 stability, binding by RBPs, and ligand interactions, defining basic principles of rG4 formation and downstream biology.
    DOI:  https://doi.org/10.1093/nar/gkag821
  5. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2534325123
    Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity.
    Alejandro Arco-Hierves, Konstantina Pamboukas, Linda Bilonda Mutala, Lukasz S Borowski, Celine Mayet, Paul Mazet, Sacha E Silva-Saffar, Dory Vergallo, Anna Paszek, Marta M Dilling, Laurie Askenatzis, Juliette Pascaud, Philippe Labrot, Charlene Lasgi, Johannes N Spelbrink, Albertas Navickas, Thibaut Naninck, Nabila Seddiki, Arnaud Tete, Roman J Szczesny, Gaetane Nocturne, Xavier Mariette, Rami Bechara.
      Chronic interferon (IFN) activation is a hallmark of autoimmune diseases such as systemic lupus erythematosus and Sjögren's disease (SjD), where epithelial cells are key contributors. Although viral and retroelement triggers have been proposed as triggers, direct evidence in patient tissues is limited, and endogenous mechanisms of epithelial IFN dysregulation remain unclear. Mitochondrial double-stranded RNA (mt-dsRNA) is a potent type I IFN (IFN-I) inducer, but its regulation in epithelial cells is poorly understood. We identify a mechanism in which the RNA methyltransferase METTL3 stabilizes REXO2 mRNA in primary salivary gland epithelial cells through N6-methyladenosine (m6A) modification. REXO2 encodes a mitochondrial exonuclease that controls mt-dsRNA. METTL3 inhibition reduces REXO2, causing mt-dsRNA accumulation and IFN-I signaling amplification and inflammation. Single-cell and bulk transcriptomic analyses, together with immunofluorescence of salivary gland tissues from SjD patients and controls, reveal reduced REXO2 expression and elevated IFN-I signatures in SjD. Rexo2 is likewise downregulated in epithelial cells of a spontaneous SjD mouse model. REXO2 loss amplifies IFN-I responses and inflammation across several epithelial contexts, while methyl donors restore REXO2 and dampen IFN activation, highlighting a targetable regulatory checkpoint in IFN-driven autoimmune diseases, alongside potential parallel stress pathways.
    Keywords:  RNA methylation; Sjögren’s disease; autoimmunity; interferon; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2534325123
  6. Nucleic Acids Res. 2026 Aug 24. pii: gkag852. [Epub ahead of print]54(16):
    Genetic studies with a uracil DNA glycosylase biosensor support a role for mitochondrial UNG1 in nuclear uracil repair.
    Yu-Hsiu T Lin, Analisa M Lott, Xingyu Liu, Layla Abdulbaki, Yanjun Chen, Michael A Carpenter, Reuben S Harris.
      The universally conserved enzyme uracil-DNA N-glycosylase (UNG) plays a central role in maintaining genome stability. It functions as the initiating factor in uracil base excision repair (UBER) by catalyzing the removal of uracil lesions in genomic DNA, a necessary first step in restoring genome integrity after hydrolytic deamination of cytosine to uracil or misincorporation of deoxyuridine monophosphate during replication. Although methods have been developed to study UBER in vitro and in cellulo, none provide a quantitative readout of UNG activity on the chromosomal DNA of living cells. To address this gap, we created an UNG biosensor (U-report) that utilizes a modified cytosine base editor to generate a targeted genomic uracil lesion in a fluorescent reporter for C-to-U editing activity. UNG activity ablation through uracil DNA glycosylase inhibition (Ugi) or UNG-knockout results in elevated reporter fluorescence. Isoform-specific knockouts show that mitochondrial UNG1 also contributes to UBER of nuclear DNA. Our studies establish a real-time biosensor for quantification of chromosomal DNA uracil excision activity in living cells and, in support of prior studies, indicate that both UNG isoforms should be addressed in small molecule inhibitor development programs.
    DOI:  https://doi.org/10.1093/nar/gkag852
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