bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–04–19
forty-four papers selected by
Cédric Chaveroux, CNRS
  1. Locally synthesized glycyl aminoacyl-tRNA synthetase is important for local translation in neurons.
  2. Single-mRNA imaging and modeling reveal coupled translation initiation and elongation rates.
  3. Reversible Nucleolar Stress and Cell Growth Arrest Triggered by Acidic pH.
  4. mRNA m6A modifications and the RNA-binding protein YTHDF1 affect translational control in both normal and pathological learning.
  5. Hepatitis C Virus 5'UTR Sequences That Bind eIF3 and Ribosomal 40S Subunits Confer Stimulation of Minus-Strand RNA Synthesis.
  6. The integrated stress response in apicomplexan and trypanosomatid parasites: balancing survival and pathogenesis.
  7. The heme-regulated inhibitor eIF2α kinase: a multifaceted sensor and drug target.
  8. Optogenetic Control of the Integrated Stress Response Limits Glioblastoma Invasion.
  9. A Unified Mechanism of +1 Ribosomal Frameshifting.
  10. nc886 noncoding RNA regulates hepatitis B virus replication via PKR-dependent eIF2α phosphorylation.
  11. From Initiation to Elongation: eIF3 as a Dual-Phase Guardian of Mitochondrial Integrity and Protein Homeostasis in Skeletal Muscle.
  12. The m6A Reader YTHDF3 Promotes Glioma Progression by Regulating the m6A Modification of lncRNA-PAR5.
  13. Localized ribosome access and distal tuning via the Listeria prfA RNA thermometer.
  14. Gymnosporangium yamadae Effector GyHRb12 Targets the Host Ribosomal Protein MdRPS20 to Enhance Translation and Suppress Immunity of Apple Leaves.
  15. LENG8: The nuclear sentry guarding against aberrant RNA leakage.
  16. Emerging roles of non-m6A mRNA modifications in plants.
  17. Suppression of upstream ORF translation is not a widespread mechanism of translational stimulation by yeast helicase Ded1.
  18. Proteolytic dissection of eIF4G reveals the closed-loop mRNP as an architecture for translation repression.
  19. Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
  20. tRNA modifications in cancer: from molecular mechanisms to clinical translation.
  21. Mechanistic insights into E. coli recovery from growth arrest.
  22. Both neighboring codon adjacent nucleotides and codon optimality influence mRNA decay rates.
  23. Inactivation of a purine biosynthesis repressor promotes ribosome synthesis to overcome antibiotic stress.
  24. A jumbo cyanophage encodes the most comprehensive ribosomal protein set in the known virosphere.
  25. RACK1: A multifunctional scaffold protein involved in signal transduction, ribosomal regulation, and Cancer pathogenesis.
  26. Translation quality control in Pseudomonas aeruginosa: current knowledge and perspectives.
  27. Ribosome State Distributions Define Escherichia coli Persister Physiology: Links to Formation, Stress Responses, and Resuscitation Dynamics.
  28. tRNA modification landscapes in streptococci: shared losses and clade-specific adaptations.
  29. m6A RNA methylation regulatory gene expression in response to ethanol and acetaldehyde exposure and withdrawal.
  30. Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
  31. RNA Folding Nearest Neighbor Parameters Including the Modification 1-Methyl-Pseudouridine.
  32. 5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.
  33. The ATRXt Protein Represses rDNA Transcription While Mirroring ATRX Interactions and Heterochromatin Localization.
  34. Cancer-associated synonymous mutations reveal stress signal-dependent mRNA folding that selectively modulates protein function.
  35. Suppression of Glucosylceramide Synthase Reverses Drug Resistance in Cancer Cells Harboring Homozygous p53 Mutants.
  36. Aberrant expression of TRIM26 suppresses ferroptosis through regulating GPX4 protein stability in colorectal cancer.
  37. Exploring functional transitions of the 2'-dG riboswitch aptamer.
  38. Structural plasticity of the membrane-bound protein degradation assembly supports bacterial adaptation to stress.
  39. Cytoplasmic localization of pseudouridine synthase 7 facilitates a pseudouridine-dependent enhancement of cellular stress tolerance.
  40. Stress-induced proteome remodeling at the Golgi-endosome interface.
  41. Selective translation of ZNF281 as part of the integrated stress response system has therapeutic relevance for cardio-oncology.
  42. Regulation of PSAT1 and PHGDH by m6A in endocrine-resistant breast cancer cells.
  43. Characterizations of G-Quadruplex RNA-Protein Interactions in Living Cells.
  44. Evidence for strong purifying selection of human 47S ribosomal RNA genes.
  1. Life Sci Alliance. 2026 Jun;pii: e202603630. [Epub ahead of print]9(6):
    Locally synthesized glycyl aminoacyl-tRNA synthetase is important for local translation in neurons.
    Tyler Brent de Leon, Adi Golani-Armon, Bar Cohen, Yoav S Arava.
      Regulation of gene expression is essential for neuronal development and function. A prominent regulatory mechanism involves synthesis of proteins at their activity site. Such local protein synthesis enables neurons to respond rapidly and tightly to stimuli. Key components of the translation machinery, including mRNA and ribosomes, were identified in subcellular regions of neurons. Yet, the role of tRNAs and their charging enzymes, aminoacyl-tRNA synthetases (ARS), in this process remains largely unclear. Here, we demonstrate that glycyl-tRNA synthetase (Gars1) mRNA is abundant in neurites and undergoes local translation, producing GARS1 protein. Notably, Gars1 mRNA colocalizes with mitochondria in a translation-dependent manner, with its coding sequence (CDS) sufficient to direct this association. The localized GARS1 protein is in close proximity to tRNAGly, and disrupting their proximity impairs local protein synthesis in neurites. These findings establish the functional importance of GARS1 and tRNAGly in neuritic translation and highlight mitochondria as hubs for mRNA transport and translation.
    DOI:  https://doi.org/10.26508/lsa.202603630
  2. Elife. 2026 Apr 17. pii: RP107160. [Epub ahead of print]14
    Single-mRNA imaging and modeling reveal coupled translation initiation and elongation rates.
    Irene Lamberti, Jeffrey A Chao, Cédric Gobet, Felix Naef.
      mRNA translation involves multiple regulatory steps, but how translation elongation influences protein output remains unclear. Using SunTag live-cell imaging and mathematical modeling, we quantified translation dynamics in single mRNAs across diverse coding sequences. Our Totally Asymmetric Exclusion Process (TASEP)-based Hidden Markov Model revealed a strong coordination between initiation and elongation rates, resulting in consistently low ribosome density (≤12% occupancy) across all reporters. This coupling persisted under pharmacological inhibition of the elongation factor eIF5A, where proportional decreases in both initiation and elongation rates maintained homeostatic ribosome density. In contrast, eIF5A knockout cells exhibited a significant decrease in ribosome density, suggesting altered coordination. Together, these results highlight a dynamical coupling of initiation and elongation rates at the single-mRNA level, preventing ribosome crowding and maintaining translational homeostasis in mammalian cells.
    Keywords:  SunTag; TASEP; computational biology; eIF5A; human; single-molecule imaging; systems biology; translation elongation
    DOI:  https://doi.org/10.7554/eLife.107160
  3. J Cell Physiol. 2026 Apr;241(4): e70176
    Reversible Nucleolar Stress and Cell Growth Arrest Triggered by Acidic pH.
    Carulina Bueno de Mesquita, Atsushi Kaida, Hitomi Nojima, Masahiko Miura.
      The tumor microenvironment is often characterized by hypoxia and extracellular acidosis, which modulate various tumor cell phenotypes. Ribosome biogenesis is a highly energy-demanding process that is essential for protein synthesis and cell proliferation and is sensitive to cellular stress, resulting in a nucleolar stress response. However, whether extracellular acidosis impairs ribosome biogenesis and induces nucleolar stress remains unclear. In this study, we demonstrated that an acidic pH downregulates ribosome biogenesis in cancer cells. RNA sequencing revealed the downregulation of genes related to ribosome biogenesis and cell cycle progression under acidic conditions. Consistently, acidic pH reduced the pre-rRNA levels and induced nucleolar stress, as evidenced by NPM1 translocation from the nucleolus to the nucleoplasm, which led to G1 phase arrest and growth inhibition. Importantly, these effects were reversed upon restoration of neutral pH, with recovery of pre-rRNA expression, NPM1 localization, and cell proliferation. Further, an acidic pH shifted the intracellular redox balance toward an oxidized state. Treatment with the reductant dithiothreitol partially reversed NPM1 translocation, suggesting that oxidative stress contributes, at least partially, to the nucleolar stress response. Overall, our findings reveal a previously unrecognized link between extracellular acidosis and impaired ribosome biogenesis, leading to nucleolar stress and reversible growth arrest. This acidosis-driven stress response represents a therapeutic vulnerability in solid tumors, offering a novel strategy to overcome treatment resistance associated with the acidic tumor microenvironment.
    Keywords:  acidic pH; cancer; nucleolar stress; redox change; ribosome biogenesis
    DOI:  https://doi.org/10.1002/jcp.70176
  4. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2518250123
    mRNA m6A modifications and the RNA-binding protein YTHDF1 affect translational control in both normal and pathological learning.
    Zhuoyue Shi, Kailong Wen, Wenqin Fu, Zhongyu Zou, Kathryn Guo, Nabilah H Sammudin, Meera J Patel, Xiangbin Ruan, Shivang Sullere, Shuai Wang, Xiaochang Zhang, Gopal Thinakaran, Chuan He, Xiaoxi Zhuang.
      Animals learn and adapt to environmental changes. However, neural plasticity can also become maladaptive, leading to neurological and psychiatric disorders. How do we use known molecular mechanisms to harness the power of neural plasticity to prevent and treat diseases? Consolidating learning is known to require new protein synthesis. We found that mRNA m6A modifications and the RNA-binding protein YTHDF1 are required for molecular, cellular, and behavioral adaptations in response to environmental changes. Deletion of Ythdf1 in dopamine D1- or D2 receptor-expressing neurons selectively impaired D1- or D2-dependent learning, respectively, including both adaptive and maladaptive learning. This highlights YTHDF1 as a potential therapeutic target for preventing pathological plasticity. YTHDF1 recognizes m6A modifications on transcripts and regulates their translation. Elevated cAMP triggered increased protein synthesis in control striatal neurons but not in Ythdf1-deficient neurons. Behaviorally, cell-type-specific Ythdf1 deletion resembled learning phenotypes caused by deletion of the m6A methyltransferase gene Mettl14, suggesting YTHDF1 as the main mediator of m6A-dependent regulation in the striatum.
    Keywords:  RNA methylation; RNA-binding protein; YTHDF1; neural plasticity
    DOI:  https://doi.org/10.1073/pnas.2518250123
  5. Int J Mol Sci. 2026 Apr 02. pii: 3234. [Epub ahead of print]27(7):
    Hepatitis C Virus 5'UTR Sequences That Bind eIF3 and Ribosomal 40S Subunits Confer Stimulation of Minus-Strand RNA Synthesis.
    Attiya Qadoos Malik, Lyudmila Shalamova, Mozhdeh Khajouei, Jonas Budnik, Anna-Lena Hell, Elena Jost, Gesche K Gerresheim, Oliver Rossbach, Michael Niepmann.
      Hepatitis C Virus (HCV) is a plus-strand RNA virus that replicates its genome via a minus-strand intermediate, which in turn is the template for the synthesis of progeny plus-strand genomes. In order to characterize sequence elements in the HCV 5'-untranslated region (5'UTR) that are possibly involved in the regulation of minus-strand RNA synthesis starting at the genome's 3'end, we used a replicon system in which a possible function of these sequences is uncoupled from other functions like translation regulation. For the specific detection by RT-qPCR of minus strands newly synthesized in the cells from the transfected replicon RNAs, we carefully eliminated the contaminating DNA and transfected RNA and avoided self-priming caused by hairpin formation. We found that the absence of any HCV sequences at the 5'end does not allow genome replication. Stem-loop I-II sequences only allow extremely low-level replication, whereas the presence of stem-loops I-III or the complete 5'UTR allows efficient replication. The mutation of sequences required for the binding of translation initiation factor 3 (eIF3) and the ribosomal 40S subunit in the 5'UTR of the plus strand severely impairs minus-strand synthesis. This suggests that eIF3 and the 40S subunit are involved in plus-strand 5'-3'-end communication and the regulation of minus-strand synthesis.
    Keywords:  encapsidation; negative-strand; packaging; plus-strand; positive-strand; replication
    DOI:  https://doi.org/10.3390/ijms27073234
  6. Front Immunol. 2026 ;17 1804980
    The integrated stress response in apicomplexan and trypanosomatid parasites: balancing survival and pathogenesis.
    Ikram Hammi, Dounia Darif, Damien Arnoult.
      Parasites rely on their hosts for survival and replication and therefore face major challenges as they transition between hosts and encounter hostile microenvironments. Over evolution, these organisms have developed complex mechanisms to rapidly adapt to environmental fluctuations and to exploit host cellular machinery for persistence and dissemination. Among the pathways parasites deploy to cope with stress is the Integrated Stress Response (ISR), a conserved mechanism present in both parasites and their hosts, yet built on partially distinct molecular components. This shared but divergent pathway constitutes a critical battleground that reflects host-parasite coevolution, where host-protective responses intersect with parasite adaptive strategies. This review summarizes the current understanding of how protozoan parasites engage their own ISR-like programs to adapt to harsh environments and how they modulate host ISR signaling to establish and maintain successful infections.
    Keywords:  Integrated Stress Response (ISR); apicomplexa; eIF2a; host-parasite interaction; trypanosomatida; unfolded protein response (UPR)
    DOI:  https://doi.org/10.3389/fimmu.2026.1804980
  7. Trends Cell Biol. 2026 Apr 16. pii: S0962-8924(26)00057-7. [Epub ahead of print]
    The heme-regulated inhibitor eIF2α kinase: a multifaceted sensor and drug target.
    Nicholas Burwick, Xi Fang, Michael Chorev, Bertal H Aktas.
      Heme-regulated eukaryotic translation initiation factor 2 alpha kinase (HRI) is highly expressed in red blood cell precursors and plays a critical role in their maturation by coupling globin synthesis to heme availability. HRI plays critical roles in responding to cytoplasmic and mitochondrial unfolded proteins, oxidative stress response, innate immunity, neurobiology, and the suppression of epithelial cancers. HRI activity is regulated by multiple signaling networks, which, in turn, modify cellular homeostatic responses. In this review, we summarize emerging evidence on the role of HRI in normal biology and pathobiology, the molecular underpinnings of HRI's regulation, and discuss chemical modifiers of HRI, which may form the basis of drug development programs for the treatment of human disorders whose pathobiology can be modified by HRI.
    Keywords:  cytoplasmic protein folding; heme-regulated inhibitor; integrated stress response; mitochondrial stress response; translation initiation
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.014
  8. Cell Biochem Funct. 2026 Apr;44(4): e70212
    Optogenetic Control of the Integrated Stress Response Limits Glioblastoma Invasion.
    Lisa K Månsson, Ethan Dickson, Lun Hao, Angela A Pitenis, Maxwell Z Wilson.
      The integrated stress response (ISR) is a highly conserved signaling network, allowing cells to adapt and respond to various stressors. With its aggressive spread and high recurrence rates, glioblastoma multiforme (GBM) is one of the toughest cancers to date, yet the role of the ISR is still to be well understood, whether activation may suppress or promote this disease, and drug-treatment of GBM has thus far shown inconclusive results. In this work, we use an optogenetic tool, opto-PKR, to specifically trigger ISR activation via light-induced oligomerizing PKR-kinases, offering high spatiotemporal and reversible control, while avoiding potential upstream damage or side effects from drugs. Using immunofluorescence and RNA-sequencing, we show that targeted ISR activation reaching levels where both adaptive (ATF4) and terminal responses (CHOP) are activated results in subsequent downregulation of genes associated with the extracellular environment and glial cell migration, further supported by ECM-stain and scratch assays. Next, we show inhibition of aggressive spread for ISR-activated GBM spheroids in collagen 3D culture. Photopatterning of ISR activation in spheroids demonstrates a cell-intrinsic effect at the tissue scale, and recovery studies indicate a tunable, non-ablative intervention space. These findings suggest a route to containment and motivate ISR-activating small molecule screening in GBM models.
    Keywords:  3D Culture; Opto‐PKR; cancer; cell migration; therapeutics
    DOI:  https://doi.org/10.1002/cbf.70212
  9. Cold Spring Harb Perspect Biol. 2026 Apr 13. pii: a041968. [Epub ahead of print]
    A Unified Mechanism of +1 Ribosomal Frameshifting.
    Ivan Sorokin, Andrei A Korostelev.
      Ribosomes decode 3-nucleotide codons and move in 1-codon increments to maintain the messenger RNA (mRNA) frame thereby accurately producing the encoded protein. In special cases, including viral genomes and regulatory cellular proteins, frameshifting occurs to expand the coding repertoire of an mRNA to make more than one protein. How these frameshifting events are induced and regulated is an active area of research. Here, we discuss recent progress in the understanding of +1 frameshifting (+1FS), during which the ribosome shifts by 1 mRNA nucleotide in the 3' direction. Structural and biochemical studies yielded insights into +1FS induced by mRNA slippery sequences and transfer RNA (tRNA) stem-loop expansion or modifications. tRNAs with an additional anticodon nucleotide are explored as a biotechnology tool for expanding the genetic code in an approach termed quadruplet decoding. We revisit the challenges of the quadruplet decoding model, discuss +1FS scenarios in bacteria and eukaryotes, and propose a unifying structural mechanism for +1FS.
    DOI:  https://doi.org/10.1101/cshperspect.a041968
  10. Front Cell Infect Microbiol. 2026 ;16 1742078
    nc886 noncoding RNA regulates hepatitis B virus replication via PKR-dependent eIF2α phosphorylation.
    Zahra Zahid Piracha, Umar Saeed.
       Objectives: Hepatitis B virus (HBV) replication is tightly controlled by host stress and innate immune pathways. The small noncoding RNA nc886 (vtRNA2-1) is a known endogenous inhibitor of protein kinase R (PKR), but its role in HBV biology remains unclear. This study aimed to define the function of the nc886-PKR-eIF2α axis in HBV-replicating hepatoma cells and to determine whether nc886 depletion suppresses HBV replication via PKR-dependent translational control.
    Materials and methods: Huh7 cells and Huh7 cells stably harboring a 1.3-mer HBV replicon were used. Endogenous nc886 and PKR expression was assessed by RT-qPCR and Western blot. Loss-of-function experiments employed two independent siRNAs against nc886 and one siRNA against PKR, alone or in combination, with scramble siRNA as control. PKR activation was induced by Poly(I:C); PKR and integrated stress response (ISR) were pharmacologically modulated using C16 (PKR inhibitor) and ISRIB (eIF2B activator), at non-toxic doses defined by MTT assay. Intracellular HBV DNA was measured by Southern blot, HBV pgRNA and subgenomic RNAs by Northern blot and RT-qPCR, and secreted HBsAg/HBeAg by ELISA. PKR-eIF2α-ATF4 signaling was evaluated by Western blot.
    Results: nc886 and PKR were efficiently and specifically knocked down without affecting cell viability. nc886 silencing in Huh7-HBV cells increased PKR-dependent eIF2α phosphorylation and ATF4, reduced HBV pgRNA and subgenomic RNAs, and decreased intracellular HBV DNA and secreted HBsAg/HBeAg. PKR knockdown alone slightly enhanced HBV readouts and completely rescued nc886-mediated inhibition of HBV replication and ISR activation in dual-knockdown cells. C16 or ISRIB restored HBV DNA, RNA and antigen production in nc886-silenced or Poly(I:C)-treated cells, while having no effect in control cells, indicating that rescue depended on ISR modulation.
    Conclusion: nc886 acts as a critical negative regulator of PKR-dependent ISR signaling during HBV replication in Huh7 cells. Its depletion activates PKR and eIF2α, imposing a translational block that suppresses HBV gene expression. The nc886-PKR-eIF2α module represents a novel host regulatory axis with potential relevance for host-directed HBV therapies.
    Keywords:  Huh7 hepatoma cells; eIF2α phosphorylation; hepatitis B virus (HBV); integrated stress response; nc886; noncoding RNA; protein kinase R (PKR); translational regulation
    DOI:  https://doi.org/10.3389/fcimb.2026.1742078
  11. FASEB J. 2026 Apr 30. 40(8): e71808
    From Initiation to Elongation: eIF3 as a Dual-Phase Guardian of Mitochondrial Integrity and Protein Homeostasis in Skeletal Muscle.
    Jianing Xia, Kexin Liao, Jiahuan Wang, Minghao Lu, Yonghao Mu, Yingying Lin.
      Skeletal muscle is the largest organ by mass in the human body, and its functional capacity depends on the precise coordination of protein synthesis, mitochondrial bioenergetics, and regenerative potential. Eukaryotic translation initiation factor 3 (eIF3), a 13-subunit complex (~800 kDa) best known for its multifaceted roles in cancer, is now emerging as a key translational regulator in skeletal muscle physiology and disease. Here, we present a perspective that synthesizes recent advances into a unifying "dual-phase guardian" model. In the first phase, eIF3f acts at the level of translation initiation as a scaffold bridging mTORC1 and S6K1, integrating anabolic and catabolic signals, particularly the MAFbx/Atrogin-1 ubiquitin-proteasome axis, to govern net protein synthesis and muscle mass. In the second phase, eIF3e remains bound to 80S ribosomes during early translation elongation (codons 1-60) of approximately 2700 mRNAs encoding mitochondrial and membrane-associated proteins, facilitating co-translational quality control through chaperone recruitment (e.g., CCT/TRiC). Haploinsufficiency of eIF3e in mice produces mitochondrial hyperfusion, diminished respiratory complex I activity, sarcomeric degeneration, and progressive loss of grip strength, a phenotype recapitulating features of mitochondrial myopathy. Complementing these findings, eIF3b supports satellite cell-mediated muscle regeneration by resolving RNA G-quadruplex structures in the 5'-UTR of Anp32e mRNA, while eIF3a modulates fibrotic remodeling through TGF-β/Smad3 signaling. We situate these subunit-level findings within the broader landscape of translational regulators in muscle (eIF2α/ISR, eIF5A, eEF2) and critically evaluate the translational potential and therapeutic challenges, including the absence of human clinical data, tissue-selectivity concerns, and species-specific limitations, that must be addressed before these mechanistic insights can inform treatment of sarcopenia, disuse atrophy, and mitochondrial myopathy.
    Keywords:  co‐translational quality control; eIF3; mTORC1; mitochondrial homeostasis; muscle atrophy; protein synthesis; skeletal muscle; translation elongation
    DOI:  https://doi.org/10.1096/fj.202600039R
  12. Anal Cell Pathol (Amst). 2026 ;2026(1): e8467384
    The m6A Reader YTHDF3 Promotes Glioma Progression by Regulating the m6A Modification of lncRNA-PAR5.
    LiuFei Xu, Yuan Xu, YongBin Duan, Bo Wang, YiYu Luo, XiangPeng Wang.
       BACKGROUND: Long non-coding RNA PAR5 (lncRNA-PAR5) is downregulated in glioma and has been confirmed to inhibit glioma progression; however, the specific regulatory mechanism underlying its downregulation remains unclear.
    OBJECTIVE: This study aimed to investigate the key molecular mechanism by which PAR5 inhibits glioma progression, with a focus on the regulatory role of m6A modification.
    METHODS: Potential m6A modification sites in the PAR5 sequence were predicted using the SRAMP online tool. The expression profiles of m6A regulatory genes in glioblastoma were analyzed via the GEPIA database. RNA pull-down, RIP-qPCR, and MeRIP-qPCR were employed to validate the specific binding of YTHDF3 to PAR5 and its effect on the m6A modification level of PAR5. The expression of PAR5 and YTHDF3 was modulated by cell transfection, and cell proliferation, invasion, and migration were assessed using CCK-8, Transwell, and wound healing assays, respectively. Further in vivo functional validation was performed using a subcutaneous xenograft tumor model in nude mice.
    RESULTS: lncRNA-PAR5 significantly inhibited the proliferation, invasion, and migration of glioma cells. Bioinformatics analysis and experimental validation revealed that the m6A reader protein YTHDF3 is highly expressed in glioma, specifically recognizes and binds to PAR5, and promotes PAR5 degradation by enhancing its m6A modification level, thereby negatively regulating PAR5 expression. Functional experiments demonstrated that YTHDF3 plays a pro‑oncogenic role, while knockdown of YTHDF3 suppressed malignant phenotypes of glioma, an effect that could be partially reversed by simultaneous knockdown of PAR5. In vivo experiments further confirmed that YTHDF3 knockdown inhibits tumor growth by upregulating PAR5.
    CONCLUSION: YTHDF3 promotes glioma cell proliferation, invasion, and migration by inhibiting PAR5 expression through enhancing its m6A modification. This study reveals the critical role of the YTHDF3/PAR5 axis in glioma progression and provides a potential novel target for glioma‑targeted therapy.
    Keywords:  YTHDF3; glioma; invasion; lncRNA-PAR5; m6A modification; migration; proliferation
    DOI:  https://doi.org/10.1155/ancp/8467384
  13. bioRxiv. 2026 Apr 09. pii: 2026.04.08.717274. [Epub ahead of print]
    Localized ribosome access and distal tuning via the Listeria prfA RNA thermometer.
    Martin R O'Steen, Jocelyn V Chen, David H Beier, Nils G Walter, Sarah C Keane.
      RNA thermometers (RNATs) are temperature-responsive structures in 5' untranslated regions (UTRs) of bacterial messenger RNA (mRNA) that control translation by modulating ribosome access. The Listeria monocytogenes prfA RNAT represses translation of PrfA (positive regulatory factor A), the master virulence regulator, at ambient temperature and activates it near the human host temperature (∼37 °C) by modulating ribosome binding site (RBS) accessibility. However, the prfA RNAT shares no homology with known RNAT classes, and its unfolding mechanism remains unclear. Here, we used analytical ultracentrifugation and single-molecule kinetic analysis of RNA transient structure (SiM-KARTS) to map prfA RNAT unfolding. SiM-KARTS analysis demonstrates that thermal opening occurs predominantly at the RBS, while the upper helix of the RNAT hairpin remains largely folded at 37 °C. The RBS binding kinetics increases with temperature in parallel with translation output, establishing a quantitative link between structural unfolding and function. Mutations in the upper helix impair thermal regulation, indicating that this region tunes switching even as it stays structured at host temperature. Together, these data reveal a hierarchical unfolding pathway in which initial RBS opening triggers activation, whereas the upper helix remotely tunes temperature sensitivity.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.04.08.717274
  14. Int J Mol Sci. 2026 Mar 25. pii: 2970. [Epub ahead of print]27(7):
    Gymnosporangium yamadae Effector GyHRb12 Targets the Host Ribosomal Protein MdRPS20 to Enhance Translation and Suppress Immunity of Apple Leaves.
    Chuxing Li, Chenxi Shao, Yingmei Liang.
      The apple rust fungus Gymnosporangium yamadae (G. yamadae) secretes effector proteins into host apple leaf cells to facilitate parasitism. Among these, the candidate effector GyHRb12 was found to localize to the nucleus upon transient expression in Nicotiana benthamiana leaf cells, although its functional role remained unclear. Subsequent investigations demonstrated that overexpression of GyHRb12 protein decreases plant cell resistance and attenuates the transcription of multiple antifungal-related genes. Using a yeast two-hybrid screen, MdRPS20, a component of the 30S ribosomal subunit, was identified as an interactor of GyHRb12. Proteomic analysis revealed that GyHRb12 modulates the expression of proteins involved in protein translation processes, which may be mediated by changes in ribosomal abundance. Notably, mutating the 14th amino acid in MdRPS20 disrupted its interaction with GyHRb12, underscoring the critical role of this residue in effector recognition and subsequent suppression of host immunity. Collectively, these findings demonstrate that G. yamadae employs a nuclear-localized effector to target a ribosomal subunit protein, thereby reprogramming host translation activity and suppressing host immunity.
    Keywords:  Malus domestica; effector protein; immune-suppressive factor; ribosomal subunit; rust fungi
    DOI:  https://doi.org/10.3390/ijms27072970
  15. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00202-9. [Epub ahead of print]86(8): 1417-1418
    LENG8: The nuclear sentry guarding against aberrant RNA leakage.
    Cornelia Kilchert, Katja Sträßer.
      In this issue of Molecular Cell, Tian et al.1 identify LENG8 as a conserved modular factor that enforces nuclear RNA quality control by coupling 5' splice site recognition to transcript retention and exosome-mediated degradation.
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.026
  16. Nat Plants. 2026 Apr 15.
    Emerging roles of non-m6A mRNA modifications in plants.
    Zhenfeng Teng, Lisha Shen.
      Internal chemical modifications of mRNA constitute a key epitranscriptomic layer of gene regulation in eukaryotes. Although N6-methyladenosine (m6A) has been the most intensively studied, accumulating evidence reveals important roles of non-m6A mRNA modifications, such as 5-methylcytosine, N4-acetylcytidine and pseudouridine, in plants. These modifications modulate diverse aspects of mRNA metabolism, including alternative splicing, stability, translation and long-distance transport, and thereby shape plant development and environmental adaptation. Here we summarize current advances in understanding non-m6A mRNA modifications in plants, emphasizing their regulatory roles in mRNA metabolism and their effects on plant development and stress resilience. We also review the detection technologies for non-m6A modifications and discuss key challenges and future directions towards elucidating their regulatory functions.
    DOI:  https://doi.org/10.1038/s41477-026-02284-x
  17. bioRxiv. 2026 Apr 11. pii: 2026.04.10.717766. [Epub ahead of print]
    Suppression of upstream ORF translation is not a widespread mechanism of translational stimulation by yeast helicase Ded1.
    Rakesh Kumar, Gemma May, Neelam Dabas Sen, Joel McManus, Alan G Hinnebusch.
      Ded1 is an essential DEAD-box helicase in yeast that broadly stimulates translation initiation and is critical for mRNAs with structured 5'UTRs. We have evaluated the proposal that Ded1 stimulates translation primarily by preventing initiation at upstream ORFs (uORFs) associated with stable secondary structures. By Ribo-Seq analysis under experimental conditions designed to suppress artifactual 5'UTR translation, we found that reduced translation of the main open-reading-frames (mORFs) in native mRNAs is generally not accompanied by increased 5'UTR translation in ded1 mutant cells, and that the presence of translated uORFs in yeast mRNAs generally does not confer heightened dependence on Ded1 for efficient translation of mORFs. Results from a high-throughput reporter assay examining native 5'UTRs reinforce the importance of Ded1 in initiation from structured 5' UTRs and show that impairing Ded1 has minimal effects on translational repression by uORFs. Our results demonstrate that, in cells growing vegetatively in rich medium, translational stimulation by suppression of inhibitory uORFs is restricted to a minority of Ded1 targets, and that unwinding of 5' UTR secondary structures per se is the principal mechanism for Ded1 stimulation of translation initiation.
    DOI:  https://doi.org/10.64898/2026.04.10.717766
  18. bioRxiv. 2026 Apr 07. pii: 2026.04.06.716749. [Epub ahead of print]
    Proteolytic dissection of eIF4G reveals the closed-loop mRNP as an architecture for translation repression.
    Ryan Johnston, Mollie A Brekker, Noelle Khalil, Monty E Goldstein, Anne Aldrich, Autumn O Grimins, Sami Gritli, Assen Marintchev, Michael D Blower, Mohsan Saeed, Shawn M Lyons.
      Formation of a "closed-loop" mRNP, in which the 5' cap and 3' poly(A) tail are bridged by eIF4E-eIF4G-PABP interactions, has long been proposed to drive efficient translation initiation. Direct tests of this model in mammalian cells have remained elusive. Using auxin-inducible degron (AID) technology to acutely deplete eIF4G1, we find that global translation is only partially reduced and recovers without restoration of eIF4G1 levels. We identify eIF4G3 as an underappreciated contributor to basal translation that buffers translational output upon eIF4G1 loss without increased protein expression, explaining the modest defects observed in prior RNAi-based studies. Systematic replacement of eIF4G1 with defined cleavage products and interaction mutants reveals that PABP binding by eIF4G1 is dispensable for bulk translation initiation: the central caspase-3 cleavage fragment of eIF4G1 (casp3-cp M ), which lacks the PABP-interaction domain, fully rescues global protein synthesis, and acute depletion of both major cytoplasmic PABP paralogs primarily destabilizes mRNAs rather than impairing initiation. In contrast, the N-terminal enteroviral 2A cleavage product (2A-cp N ) is a potent, dominant translational repressor that requires simultaneous eIF4E and PABP engagement to form a dead-end closed-loop mRNP that sequesters initiation factors without enabling 43S recruitment. These findings reveal that the eIF4G-PABP closed-loop architecture is not required for productive initiation but can be actively co-opted for translational silencing. This explains why viral eIF4G cleavage, but not factor depletion, produces near-complete translational shutoff. The modular architecture of eIF4G enables diametrically opposing translational outcomes through selective proteolytic processing.
    DOI:  https://doi.org/10.64898/2026.04.06.716749
  19. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00193-0. [Epub ahead of print]86(8): 1511-1528.e12
    Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
    Lvxin Xie, Shuchao Ren, Li Zhang, Ziqing Wang, Tong Wu, Qing Dai, Shikun Xiang, Zhihua Qian, Yufan Xian, Shutong Xu, Xiao-Lin Chen, Chuan He, Yi Liu, Zhipeng Zhou.
      Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), with core structural subunits encoded by mitochondrial DNA (mtDNA) and translated by mitochondrial ribosomes. However, how mitochondrial translation elongation influences OXPHOS biogenesis remains unclear. Here, we show that in Neurospora crassa, the mitochondrial ribosomal RNA (rRNA) methyltransferase 1 (MRM1) promotes OXPHOS biogenesis by repressing translation elongation independently of its catalytic activity. The N-terminal intrinsically disordered region (IDR) of MRM1 binds simultaneously to mitochondrial ribosomes and mRNAs. Disrupting either interaction accelerates elongation and enhances synthesis of mtDNA-encoded OXPHOS subunits but impairs their co-translational folding and membrane insertion. Pharmacological slowing of mitochondrial translation partially alleviates these defects. The MRM1 IDR is conserved in Ascomycete fungi and is essential for plant infection by Magnaporthe oryzae. Together, our findings identify translation elongation control as a mechanism coordinating mitochondrial protein synthesis and folding during OXPHOS biogenesis and MRM1 as a potential target for broad-spectrum antifungal strategies.
    Keywords:  Magnaporthe oryzae; Neurospora crassa; mitochondrial rRNA methyltransferase; mitochondrial translation; oxidative phosphorylation; protein folding; translation elongation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.017
  20. Biomark Res. 2026 Apr 11.
    tRNA modifications in cancer: from molecular mechanisms to clinical translation.
    Cillian H Cheng, Chi Chun Wong.
      tRNA modifications, the most extensively and diversely modified class of RNA across all domains of life, have garnered significant and growing attention in research over the past decade. tRNA modification defects and tRNA fragmentation has been observed within a wide spectrum of cancer types, suggesting their potential as diagnostic and prognostic biomarkers. Mechanistic studies demonstrate that regulatory enzymes for tRNAs and tdRs function as oncogenes or tumor suppressors with vital roles in cancer initiation, progression, metastasis, metabolic rewiring, therapy resistance, and immune evasion, highlighting the therapeutic potential of targeting perturbed tRNA modification machinery in cancer treatment. Herein, we summarize our current understanding of the role of tRNA modifications in cancer, and outline translational and clinical implications for cancer diagnosis and treatment. Emphasis is placed on how tRNA modifications determine the fate of target tRNAs and its influence on protein expression, molecular mechanisms and cell phenotypes. Finally, we discuss the hurdles and potential solutions to translating recent knowledge of tRNA modifications into clinical practice.
    Keywords:  Cancer; Clinical applications; Molecular mechanisms; Transfer RNA (tRNA); tRNA modification; tRNA-derived RNAs (tdRs)
    DOI:  https://doi.org/10.1186/s40364-026-00919-x
  21. Nat Commun. 2026 Apr 11.
    Mechanistic insights into E. coli recovery from growth arrest.
    Ahmed H Hassan, Yuko Nakano, Howard Gamper, Isao Masuda, Ludmila Vesela, Matyas Pinkas, Sathya Narayanan Nagarajan, Jonathan Dworkin, Gregor Blaha, Ya-Ming Hou, Gabriel Demo.
      Bacteria survive hostile conditions by shutting down protein synthesis, but how they restart growth remains poorly understood. Here, we use an E. coli ΔrimM strain, which exhibits a prolonged growth arrest, as a model to investigate how bacteria recover from this state and restore protein synthesis. RimM is a conserved ribosome maturation factor for the 3'-major (head) domain of the 16S rRNA within the bacterial 30S subunit. The loss of RimM causes a longer delay in recovery than other 30S maturation factors, including RbfA. Cryo-EM analysis of ΔrimM ribosomes suggests a delayed recruitment of ribosomal proteins to the 30S head domain and increased occupancy of the initiation factors IF1 and IF3, as well as recruitment of the silencing factor RsfS to the 50S subunit. These coordinated changes provide a safeguarding mechanism to block the assembly of premature 70S ribosomes. Notably, while the delayed 30S assembly in ΔrimM reduces the activity of global protein synthesis during the recovery phase, bacteria attempt to compensate for this deficiency by producing higher levels of the ribosomal machinery, indicating a programmatic change in energy allocation. These findings highlight the importance of the RimM-assisted assembly of the ribosomal head domain for bacterial recovery from growth arrest.
    DOI:  https://doi.org/10.1038/s41467-026-71781-6
  22. RNA. 2026 Apr 13. pii: rna.080900.125. [Epub ahead of print]
    Both neighboring codon adjacent nucleotides and codon optimality influence mRNA decay rates.
    Reed S Sorenson, Leslie E Sieburth.
      Codon optimality-mediated decay (COMD) is a major pathway that determines mRNA decay rates in eukaryotes. Conservation of this pathway in plants has not been demonstrated. To identify codons that might influence cotranslational mRNA decay rates, we compared codon usage bias in Arabidopsis seedling-expressed mRNAs with their mRNA half-lives (t1/2s). Finding differences in codon usage between transcripts with short and long t1/2s led to a model of mRNA decay rate based on codon frequencies. This codon-decay rate model explained 21% of decay rate variance in Arabidopsis and was predictive of decay rates of synonymously recoded genes. In the COMD pathway, NOT3, a component of the CCR4-NOT deadenylation complex, can detect slow ribosome decoding and trigger decay cotranslationally. Because the N-terminal sensor domain of NOT3 is retained in plant genomes, it's likely that plants, yeast and humans use the same mechanism. However, codon optimality in Arabidopsis was not reading-frame dependent, suggesting that additional sequence features also contributed to decay rates. These features were computationally identified as specific adjacent nucleotides of neighboring codons. The influence of adjacent codons appears to be a conserved feature of cotranslational decay, as published datasets from wheat (Triticum aestivum) and fission yeast (Schizosaccharomyces pombe) also showed neighboring codon adjacent nucleotides to impact RNA decay rates. These findings show that codon sequence can influence mRNA decay rates independently of charged tRNA concentrations and suggest a paradigm of selection among synonymous codons that are decoded through wobble base pairing.
    Keywords:  RNA decay; codon context; codon-optimality-mediated decay; synthetic gene; wobble decoding
    DOI:  https://doi.org/10.1261/rna.080900.125
  23. mBio. 2026 Apr 13. e0011826
    Inactivation of a purine biosynthesis repressor promotes ribosome synthesis to overcome antibiotic stress.
    Alexandre Le Scornet, Yongjun Tan, Dapeng Zhang, Jue D Wang, Mee-Ngan F Yap.
      Macrolide, lincosamide, and streptogramin (MLS) antibiotics are structurally distinct molecules that inhibit protein synthesis by binding overlapping sites within the 23S rRNA of bacterial ribosomes. The clinical utility of MLS antibiotics has diminished due to the dissemination of erythromycin resistance rRNA methyltransferase (Erm) genes. Staphylococcus aureus ErmB methylates the universally conserved A2058 nucleotide of the 23S rRNA (m6A2058), resulting in cross-resistance to all MLS antibiotics by reducing drug-binding affinity. The operonic upstream ribosome stalling peptide ErmBL was thought to be the sole regulatory element controlling ErmB synthesis and the extent of MLS resistance. Unexpectedly, our laboratory evolution experiments revealed that numerous loss-of-function mutations outside the bicistronic ermBL-ermB operon amplify ErmB-mediated MLS resistance. Among these are mutations in genes critical for purine de novo biosynthesis and the salvage pathway. Specifically, inactivation of the gene encoding the purine biosynthesis transcriptional repressor (PurR) converts an otherwise moderately resistant ermBL-ermB (ermB+) strain into one exhibiting pronounced hyper-resistance to MLS antibiotics. This cooperative resistance phenotype is not attributable to increased ermB expression or elevated m6A2058 modification. Instead, purR inactivation leads to derepression of purine and pyrimidine biosynthesis, accompanied by increased expression of ribosome components. We find that the elevated ribosome abundance and translational capacity of the ermB+∆purR are directly proportional to its accelerated growth rate, thereby priming S. aureus for survival under high MLS concentrations. These findings support a model in which expanded nucleotide metabolites and a surplus of antibiotic-free ribosomes drive global translation to buffer the inhibitory effects of MLS antibiotics.IMPORTANCEThe Erm rRNA methyltransferase superfamily represents the most prevalent determinant of MLS resistance in nosocomial Gram-negative and Gram-positive bacteria. Previous studies have established that erm expression is primarily governed by upstream ribosome stalling peptide and the 5' untranslated regions. Using the widespread S. aureus ermBL-ermB (ermB+) operon as a model system, we unexpectedly identified second-site mutations in purR that synergistically enhance MLS resistance in an ermB+ background. Loss of purR function derepresses nucleotide biosynthesis and ribosome production, thereby promoting bacterial growth under antibiotic stress. While numerous purR single-nucleotide polymorphisms across multiple species have been associated with antibiotic resistance, no study has directly linked these sequence polymorphisms to their regulatory function. Our results highlight the critical role of ribosome abundance and nucleotide metabolism in shaping antibiotic efficacy.
    Keywords:  PurR; RNA methylation; Staphylococcus aureus; antibiotic resistance; erythromycin; macrolide; nucleotide metabolism; ribosome
    DOI:  https://doi.org/10.1128/mbio.00118-26
  24. ISME J. 2026 Apr 10. pii: wrag084. [Epub ahead of print]
    A jumbo cyanophage encodes the most comprehensive ribosomal protein set in the known virosphere.
    Isaac Meza-Padilla, Sarit Avrani, Kirsten M Müller, Jozef I Nissimov.
      It has been proposed that a defining distinction between viruses and cells lies in the absence or presence of ribosomal genes, respectively. Recent studies revealing that viruses occasionally encode ribosomal proteins (RPs) have challenged this view. However, so far, only viral genomes with up to three RPs have been discovered. Here, we perform a functional genome analysis of the Microcystis jumbo phage PhiMa05 and show that it encodes six RPs, an RP acetyltransferase, and a ribosome biogenesis protein. To our knowledge, this makes PhiMa05 the first cyanophage reported to encode RPs, as well as the virus with the most comprehensive RP-coding set of the known virosphere. Evolutionary analyses suggest that these viral RP-coding genes may have been horizontally transferred from a temperate ancestor of PhiMa05 to certain members of the Vampirovibrionia, a non-photosynthetic basal lineage of Cyanobacteriota, via the integration of the viral genome. We find that four RPs, the RP acetyltransferase, and the ribosome biogenesis protein of the PhiMa05-like prophages are the only copies of those proteins that the near-complete genomes of some Vampirovibrio hosts possess. We hypothesize that such cellular organisms may depend on the PhiMa05-like prophage for protein synthesis, and hence life itself. Collectively, our results provide evidence for the existence of viruses with particularly enriched sets of RP-coding genes and indicate that, in some cases, such viral genes have been transferred to cells, potentially becoming essential for the survival of the host.
    Keywords:   Microcystishorizontal gene transfer; Vampirovibrio ; Ribosome; cyanophage; jumbo phage; paleovirology; prophage; virus ecology; virus evolution
    DOI:  https://doi.org/10.1093/ismejo/wrag084
  25. Cell Signal. 2026 Apr 11. pii: S0898-6568(26)00171-3. [Epub ahead of print]144 112519
    RACK1: A multifunctional scaffold protein involved in signal transduction, ribosomal regulation, and Cancer pathogenesis.
    Jing-Cheng Yang, Ya-Ya Du, Wei-Qiong Zuo, Jing-Yue Yao, Ke Ma, Ying Liang, Ming-Gao Zhao, Zhi-Mei Li.
      RACK1 (receptor for activated C kinase 1) is a highly conserved WD40 repeat family scaffold protein. As a central signaling hub, it regulates cell proliferation, migration, apoptosis, and stress responses by binding key molecules like protein kinase C, Src kinases, and integrin β-subunits. Additionally, RACK1 acts as a ribosomal protein, associating with the 40S subunit to modulate translational stalling and ubiquitination, influencing ribosome function and protein synthesis. RACK1 shows significantly down- or up-regulated in different tumors, highlighting its complex bidirectional signaling role. These effects are mediated through regulation of oncogenic pathways, apoptosis induction, metastasis inhibition, and modulation of metabolic and immune microenvironments. Therefore, the enthusiasm for RACK1-targeted therapeutic strategy is growing and placed RACK1 under the spotlight of oncology. This manuscript, to our knowledge, is the first review to summarize the role of RACK1 in pan-cancers via analysis of comprehensive gene information, and targeted inhibitors. Specifically, we introduce the structure of RACK1 and discuss the current understanding of its mechanism as a central signaling hub that coordinates diverse pathways to regulate cell proliferation, migration, apoptosis, and stress responses. This review outlines the potential therapeutic applications for targeting RACK1 and may contribute to the development of effective RACK1 inhibitors within the strategy of structure-based drug discovery of cancer therapy.
    Keywords:  Cancer pathogenesis; Cancer therapy; RACK1; Ribosomal regulation; Signal transduction
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112519
  26. FEMS Microbiol Rev. 2026 Apr 15. pii: fuag018. [Epub ahead of print]
    Translation quality control in Pseudomonas aeruginosa: current knowledge and perspectives.
    Bastien L'Hermitte, Reynald Gillet, Christine Baysse.
      The fitness and virulence of Pseudomonas aeruginosa rely on its ability to maintain a functional pool of ribosomes, which are essential for protein synthesis. This review explores the intricate ways of ribosome protection, rescue and hibernation, by which P. aeruginosa preserves ribosome functionality under stress. These processes enhance the adaptability and resistance of this pathogen to ribosome-targeting antibiotics and present significant challenges to current therapeutic strategies. By highlighting recent discoveries and identifying promising directions for future research, this review aims to explore potential targets for innovative drug discovery.
    Keywords:   Pseudomonas aeruginosa ; Antibiotic resistance; Ribosome quality control; ribosome hibernation; ribosome protection; ribosome rescue
    DOI:  https://doi.org/10.1093/femsre/fuag018
  27. Microb Biotechnol. 2026 Apr;19(4): e70352
    Ribosome State Distributions Define Escherichia coli Persister Physiology: Links to Formation, Stress Responses, and Resuscitation Dynamics.
    Hyein Kim, Sooyeon Song.
      Persister cells survive antibiotic exposure and contribute to infection relapse, yet the molecular features that distinguish them from actively growing cells remain incompletely defined. Here, we used sucrose gradient-based ribosome sedimentation profiling to characterise ribosome complex distributions in Escherichia coli persister cells and monitored their dynamics during resuscitation. Rifampicin-induced persister cells were characterised by pronounced enrichment of translationally inactive 90-100S ribosome complexes and a concomitant reduction in 70S ribosomes relative to exponentially growing cells. Upon nutrient replenishment, ribosome distributions progressively shifted toward higher 70S and polysome (complexes of multiple ribosomes simultaneously translating a single mRNA) levels, coinciding with growth recovery, indicating that resuscitation involves gradual remodelling of ribosome states rather than abrupt restoration of active translation. Functional analysis of ribosome-associated factors demonstrated that RMF, HPF and RaiA promote 100S ribosome accumulation and enhance persister formation, whereas deletion of rmf severely impaired both 100S formation and persistence. In contrast, loss of HflX did not measurably affect persister formation, consistent with a role downstream of persister establishment. In multiple stress-induced persister models including rifampicin, tetracycline, CCCP and starvation, as well as in a clinically relevant E. coli O157:H7 (EHEC) strain, ribosome distributions consistently exhibited a quantitative reversal of the AUC_70S/AUC_100S ratio (Ratio < 1.0) relative to exponentially growing cells (Ratio > 1.0). Collectively, these findings demonstrate that this shift in the 70S-to-100S balance is a consistent and shared feature of E. coli persister physiology and that ribosome state distributions link persister formation to resuscitation dynamics. These findings provide a quantitative ribosome-state framework that may inform the development of anti-persistence strategies targeting ribosome hibernation factors.
    Keywords:  100S ribosome; antibiotic persistence; bacterial resuscitation; ribosome hibernation; ribosome sedimentation profiling
    DOI:  https://doi.org/10.1111/1751-7915.70352
  28. Open Biol. 2026 Apr 15. pii: 250445. [Epub ahead of print]16(4):
    tRNA modification landscapes in streptococci: shared losses and clade-specific adaptations.
    Ho-Ching Tiffany Tsui, Chi-Kong Chan, Yifeng Yuan, Roba Elias, Jingjing Sun, Virginie Marchand, Marshall Jaroch, Guangxin Sun, Irfan Manzoor, Ana Kutchuashvili, Grazyna Leszczynska, Kinda Seaton, Yuri Motorin, Kelly Rice, Manal Swairjo, Peter C Dedon, Malcolm E Winkler, Valérie de Crécy-Lagard.
      tRNA modifications are central to bacterial translational control. Here, we integrated genetics, mass spectrometry, epitranscriptomics and comparative genomics to map the tRNA modification genes of the Gram-positive pathogens Streptococcus mutans and Streptococcus pneumoniae. Both species show a marked loss of modifications dependent on Fe-S enzymes, consistent with a broader trend of Fe-S enzyme reduction in Streptococcus central metabolism. In addition, the D, m1A, m7G, t6A and i6A modifications were mapped in S. pneumoniae tRNAs, and we confirmed that a unique DusB1 enzyme is responsible for the insertion of all the detectable D modifications. We uncovered differences in queuosine (Q) metabolism: while S. mutans synthesizes Q de novo, S. pneumoniae instead salvages preQ₁ and accumulates the epoxy-Q precursor, a strategy shared with multiple other streptococci as revealed by analysis of Q pathways in 1599 sequenced streptococcal genomes. Comparative essentiality profiling of modification genes revealed notable differences, including the essentiality of the N⁶-threonylcarbamoyladenosine (t⁶A) synthesis enzyme TsaE in S. pneumoniae but not in S. mutans, which was confirmed by genetic studies. We found that suppressor mutations in asnS encoding asparaginyl-tRNA synthetase (AsnRS) restored viability to ∆tsaE mutants, albeit with reduced growth. Our finding highlights the functional importance of modifications in the recognition of tRNAs by aminoacyl-tRNA synthetases.
    Keywords:  TsaE; dihydrouridine; pseudogene; queuosine; t6A; tRNA modification
    DOI:  https://doi.org/10.1098/rsob.250445
  29. Environ Epigenet. 2026 ;12(1): dvag011
    m6A RNA methylation regulatory gene expression in response to ethanol and acetaldehyde exposure and withdrawal.
    Ji Sun Koo, Qiansheng Zhan, Huiping Zhang.
      6-methyladenosine (m6A) RNA methylation, regulated by writer, eraser, and reader proteins, modulates mRNA stability, splicing, and translation, thereby influencing key cellular processes. Environmental stressors, such as alcohol, may disrupt this epitranscriptomic machinery and contribute to disease vulnerability. In this study, we investigated how chronic exposure to ethanol, its toxic metabolite acetaldehyde, and subsequent withdrawal affect the expression of m6A regulatory genes. Neuron-like (SH-SY5Y) and non-neuronal (SW620) cells were exposed for 3 weeks to ethanol (40 mM) or acetaldehyde (30 μM) (concentrations comparable to blood levels after heavy drinking), followed by a 24-h withdrawal period. Gene expression of seven writers (KIAA1429, METTL3, METTL4, METTL14, RBM15, RBM15B, and WTAP), two erasers (ALKBH5, FTO), and nine readers (YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPA2B1) was quantified by RT-qPCR. Concurrently, RNA-seq data from eight reward-related brain regions of 24 individuals of European ancestry (12 with alcohol use disorder [AUD] and 12 controls) were analyzed for AUD-associated expression changes in m6A regulatory genes. In cell models, ethanol broadly suppressed the expression of most m6A regulatory genes, whereas withdrawal largely restored their levels. Acetaldehyde induced subtler gene expression changes, likely reflecting its lower exposure concentration and rapid metabolism. Postmortem brain analysis revealed trends toward altered expression of m6A regulatory genes across multiple brain regions in individuals with AUD. Collectively, these findings suggest that chronic alcohol exposure dysregulates m6A regulatory gene expression and may impact downstream RNA regulatory pathways involved in AUD pathophysiology. Further studies are warranted to elucidate the mechanisms by which alcohol-induced dysregulation of m6A regulators influences AUD risk.
    Keywords:  RNA-seq; RT-qPCR; cellular model; ethanol/acetaldehyde exposure/withdrawal; human postmortem brains; m6A erasers; m6A readers; m6A writers
    DOI:  https://doi.org/10.1093/eep/dvag011
  30. Trends Biochem Sci. 2026 Apr 16. pii: S0968-0004(26)00061-7. [Epub ahead of print]
    Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
    Andrew N Bayne, Jean-François Trempe.
      PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.
    Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control (MQC); mitophagy; stress response; therapeutic development
    DOI:  https://doi.org/10.1016/j.tibs.2026.02.014
  31. bioRxiv. 2026 Apr 11. pii: 2026.04.09.717343. [Epub ahead of print]
    RNA Folding Nearest Neighbor Parameters Including the Modification 1-Methyl-Pseudouridine.
    Elzbieta Kierzek, Thandolwethu S Shabangu, Olivia M Hiltke, Megan Miaro, Sebastian Arteaga, Brent M Znosko, Elizabeth A Jolley, Philip C Bevilacqua, John SantaLucia, Holly A SantaLucia, Haining Lin, Mihir Metkar, Sharon Aviran, Marta Soszynska-Jozwiak, Ryszard Kierzek, David H Mathews.
      Nearest neighbor analysis is commonly used to estimate RNA folding stabilities. In this contribution, we report a set of RNA folding nearest neighbor parameters for estimating free energy change for RNA sequences including 1-methyl-pseudouridine. Development of mRNA vaccines has identified 1-methyl-pseudouridine as a key nucleobase modification for suppressing innate immune responses. However, the contributions of these modifications to RNA folding stability were unclear. Our new parameters provide helical terms for 1-methyl-pseudouridine-adenine and 1-methyl-pseudouridine-guanine base pairs. The parameters also estimate loop stabilities for loops with 1-methyl-pseudouridine or a combination of 1-methyl-pseudouridine and uridine. These parameters are derived using 208 optical melting experiments and tested against an additional 16 optical melting experiments. On average, we find that substitution of uridine with 1-methyl-pseudouridine stabilizes RNA folding, with the extent of stabilization depending on adjacent sequence. The estimation of tRNA folding ensembles for tRNA sequences with 1-methyl-pseudouridine was significantly improved using the new nearest neighbor parameters. The new nearest neighbor parameters are provided as part of the RNAstructure software package. With these parameters, the secondary structures of natural sequences with 1-methyl-pseudouridine and mRNA therapeutics fully substituted with 1-methyl-pseudouridine can be modeled.
    DOI:  https://doi.org/10.64898/2026.04.09.717343
  32. EMBO Rep. 2026 Apr 13.
    5' UTR length shapes alternative N-terminal protein isoforms across cancers and in rare disease.
    Jimmy Ly, Eric M Smith, Matteo Di Bernardo, Yi Fei Tao, Elizabeth M Black, Ekaterina Khalizeva, Iain M Cheeseman.
      The 5' untranslated region (5' UTR) of an mRNA is classically viewed as a regulatory region that controls the amount of protein production, but not the resulting protein sequence. Here, we demonstrate that 5' UTR length plays a direct role in alternative N-terminal protein isoform production by controlling start codon selection. We find that very short 5' UTRs enhance leaky ribosome scanning, thereby promoting the production of truncated alternative N-terminal protein isoforms. We also show that endogenous changes in 5' UTR length due to alternative transcription initiation can tune the relative abundance of alternative N-terminal isoforms from the same gene. In addition, we identify mutations in rare genetic diseases that alter 5' UTR length, including a deletion in the VHL 5' UTR in von Hippel-Lindau disease that shifts translation toward the shorter VHLp19 isoform. Together, our results implicate 5' UTR length as a determinant of alternative N-terminal isoform production and reveal an underappreciated mechanism by which noncoding changes can reshape the proteome.
    DOI:  https://doi.org/10.1038/s44319-026-00776-7
  33. Int J Mol Sci. 2026 Mar 29. pii: 3103. [Epub ahead of print]27(7):
    The ATRXt Protein Represses rDNA Transcription While Mirroring ATRX Interactions and Heterochromatin Localization.
    Mathieu G Levesque, David J Picketts.
      The ATRX gene encodes an SWI/SNF-type chromatin remodeling protein that is critical for proper development of the mammalian central nervous system and musculoskeletal system. While significant progress has been made in understanding the molecular functions of the full-length (FL) ATRX protein, there is still very little known about its conserved alternative spliceoform, ATRXt. ATRXt is a truncated isoform of ATRX which lacks the entire SWI/SNF domain due to the retention of intron 10, which results in the in-frame addition of 61 unique amino acids (exon 10a) at its C-terminus. Here, we demonstrate that ATRXt accounts for 5-20% of total ATRX protein levels, while showing tissue- and differentiation-specific changes in expression levels compared to its full-length counterpart. ATRXt shows enriched localization at H3K9me3-positive heterochromatin but not at PML-nuclear bodies, while physically interacting with the known FL-ATRX protein partners, DAXX and HP1α. Exon 10a can target a GFP-fusion protein to the nucleolus, but removal of exon 10a from ATRXt does not prevent nucleolar localization. Finally, re-introducing ATRXt into the ATRX-negative U2OS cell line reduced rRNA transcription and severely hampered cell growth, similar to previous studies using FL-ATRX. Our study highlights that ATRXt has many of the same properties as FL-ATRX, suggesting that some roles of ATRX do not require remodeling activity, while highlighting the need to distinguish ATRXt's functions from those of the full-length protein.
    Keywords:  alternative splicing; chromatin remodeling; heterochromatin; nucleolus; ribosome biogenesis
    DOI:  https://doi.org/10.3390/ijms27073103
  34. RNA. 2026 Apr 17. pii: rna.080976.126. [Epub ahead of print]
    Cancer-associated synonymous mutations reveal stress signal-dependent mRNA folding that selectively modulates protein function.
    Sivakumar Vadivel Gnanasundram, Lixiao Wang, Sa Chen, Ondrej Bonczek, Borivoj Vojtesek, Robin Fahraeus.
      Recent technical advances have facilitated studies on changes in mRNA structures in response to signaling pathways. However, if mRNA structures can affect the function of the encoded protein remains poorly understood. In-cell RNA structural probing (SHAPE-MaP) demonstrates how two cancer-associated synonymous mutations (CASMs) at proline codon 34 (c.102 C>A and c.102 C>G) prevent DNA damage-induced TP53 mRNA folding, whereas the non-cancer-associated c.102 C>U mutation does not. Transcript and chromatin immunoprecipitation (ChIP) analysis reveal that p53 expressed from CASM34 has reduced promoter binding and reduced induction of p53 downstream target genes PUMA and 14-3-3-σ, but not p21CDKN1A. Transcriptome analysis reveals a CASM34-mediated global attenuation of DNA damageresponsive gene expression. Together, the results demonstrate that CASM34 interferes with signal-induced p53 mRNA folding during DNA damage, leading to selective modulation of p53 protein activity. More broadly, our findings highlight a general concept by which cancer-associated synonymous mutations target signal-induced mRNA structures that influence the encoded protein.
    Keywords:  DNA damage response; RNA structures; p53; synonymous cancer mutation
    DOI:  https://doi.org/10.1261/rna.080976.126
  35. Int J Mol Sci. 2026 Apr 02. pii: 3237. [Epub ahead of print]27(7):
    Suppression of Glucosylceramide Synthase Reverses Drug Resistance in Cancer Cells Harboring Homozygous p53 Mutants.
    Md Saqline Mostaq, Mohammad N Amin, Amanda Raphael, Celine Asbury, Anish Gupta, Xin Gu, Xianlin Han, Davorka Sekulic, Pawel Michalak, Lin Kang, Yong-Yu Liu.
      Glucosylceramide synthase (GCS) catalyzes ceramide glycosylation in response to cell stress that produces glucosylceramide and other glycosphingolipids. GCS overexpression is a cause of drug resistance and enriches cancer stem cells (CSCs) during cancer chemotherapy. Previous studies showed that GCS modulates the expression of p53 mutants and oncogenic gain-of-function (GOF) in heterozygous knock-in cell models (TP53 R273H-/+). However, it is unclear whether GCS can modulate the effects of homozygous p53 mutations, which are common in many cancer cases. We report herewith that inhibition of GCS, via UGCG knockout and using an inhibitor (Genz-161), effectively re-sensitizes drug resistance and diminishes CSCs in colon cancer cells carrying the homozygous p53 R273H mutation. In aggressive WiDr cells carrying TP53 R273H mutation, knockout of UGCG gene using CRISPR/Cas9 editing or inhibition of GCS with Genz-161 sensitized cancer cells to oxaliplatin, irinotecan and paclitaxel. With decreased ceramide glycosylation in lipidomic profiling, both UGCG knockout and Genz-161 treatments substantially decreased wound healing, and diminished CSCs and tumor growth under chemotherapy. Interestingly, inhibition of RNA m6A methylation by neplanocin A markedly increased p53 function and reversed drug resistance. Mechanistic investigation revealed that GCS inhibition downregulated methyltransferase-like 3 (METTL3) expression and decreased RNA-m6A modification on mutant p53 R273H effects. Altogether, our findings demonstrate that ceramide glycosylation promotes METTL3 expression and RNA m6A methylation in response to drug-induced stress, thereby promoting mutant p53 expression and associated GOF. Conversely, inhibition of GCS can diminish CSCs and drug resistance via reduction in m6A modification and advance of p53-assocaited tumor suppressive function. GCS inhibition is an achievable approach for mutant cancer treatment.
    Keywords:  N6-methyladenosine; RNA modification; cancer stem cells; drug resistance; glucosylceramide synthase; missense mutation; p53 tumor suppressor
    DOI:  https://doi.org/10.3390/ijms27073237
  36. Mol Biol Rep. 2026 Apr 16. pii: 620. [Epub ahead of print]53(1):
    Aberrant expression of TRIM26 suppresses ferroptosis through regulating GPX4 protein stability in colorectal cancer.
    Guanghai Wu, Kunming Zheng, Shichao Xu, Juan Wang, Jing Xu.
       BACKGROUND: Ferroptosis is recognized as a critical regulator of tumor growth in colorectal cancer (CRC). The enzyme GPX4 plays a vital role in regulating ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols, thus protecting cells from ferroptosis. However, the mechanisms by which GPX4 mediates ferroptosis in CRC remain largely unexplored.
    METHODS AND RESULTS: A significant increase was observed in both mRNA and protein expression of TRIM26 in CRC tissues compared to healthy colon tissues. TRIM26 regulates the cell proliferation in both HT-26 and HCT116 cells. TRIM26 affects CRC cell proliferation in both apoptotic and ferroptotic independent manners. Ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1, counteract the effects of TRIM26 knockdown, whereas ferroptosis inducers mitigate the effects of TRIM26 overexpression on ferroptosis in cancer cells. In vitro studies demonstrates that aberrant TRIM26 expression positively influences the stability of GPX4. TRIM26 directly interacts with GPX4 and catalyzes the ubiquitination of GPX4, which thus enhances GPX4 protein stability. Furthermore, rescue experiments indicate that the enhancement of ferroptosis caused by sh-TRIM26 is reversed following GPX4 overexpression.
    CONCLUSIONS: Collectively, these findings underscore the significance of aberrant TRIM26 expression in disrupting ferroptosis through the regulation of GPX4 protein stability in CRC. This insight suggests a potential therapeutic strategy targeting TRIM26 to inhibit tumor growth in CRC.
    Keywords:  Colorectal cancer; Ferroptosis; GPX4; TRIM26
    DOI:  https://doi.org/10.1007/s11033-026-11782-2
  37. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2528806123
    Exploring functional transitions of the 2'-dG riboswitch aptamer.
    Erdong Ding, Susmit Narayan Chaudhury, Karissa Y Sanbonmatsu, José N Onuchic.
      Riboswitches are structural elements in the 5' untranslated region of mRNAs that adopt different conformations under different conditions. Transitions between these different states are involved in controlling gene expression and occur on relatively slow timescales. The RNA structure based model is a coarse-grained description developed by combining structural information with electrostatic interactions for RNA molecules. The simplicity of this model allows for the exploration of longer timescales and the entire energy landscape of the riboswitch aptamer which is not possible with physical force fields. Molecular dynamics simulations using this simpler representation are consistent with explicit solvent simulations and SHAPE and NMR experiments. Our simulations reveal a temperature range, which includes room temperature, where the P1 helix is stable in the presence of ligand binding while flexible in the ligand-free state. These simulations suggest a multibasin free energy profile for the aptamer domain of the 2'-dG riboswitch, where the secondary structures are stably formed with a different organization of the tertiary structures, especially in the absence of the ligand. It is also suggested that the Mg2+ ions have a significant stabilizing effect, especially on the tertiary structures and on the regulatory helix P1, creating magnesium-mediated attractive interactions between phosphate groups in some cases. The mechanism proposed by experimentalists for the functional transition requires the breaking of the P1 helix. This process occurs on relatively slow timescales, and therefore necessitates the proposed model which allows direct connection to experimental observations.
    Keywords:  RNA folding; energy landscape; magnesium; riboswitch
    DOI:  https://doi.org/10.1073/pnas.2528806123
  38. Cell Rep. 2026 Apr 10. pii: S2211-1247(26)00309-8. [Epub ahead of print]45(4): 117231
    Structural plasticity of the membrane-bound protein degradation assembly supports bacterial adaptation to stress.
    Naseer Iqbal, Sandro Keller, Alireza Ghanbarpour.
      Protein degradation by ATPases associated with diverse cellular activities) (AAA+) proteases is essential for bacterial adaptation to stress. The membrane-bound protease FtsH forms an inner-membrane complex with the SPFH (stomatin, prohibitin, flotillin, and HflK/C) (SPFH) proteins HflK and HflC that promotes recovery from aminoglycoside antibiotics. Although open and closed HflK/C conformations have been described, their functional relevance has remained unclear. Here, we engineer a disulfide-crosslinked HflK/C variant to stabilize the closed state and determine its structure by high-resolution cryo-electron microscopy (cryo-EM). Cells expressing this variant, or an HflK/C mutant that disrupts FtsH binding, exhibit impaired growth under aminoglycoside stress, demonstrating that conformational dynamics and productive HflK/C-FtsH interactions are required for adaptation. Surprisingly, cryo-EM of the FtsH⋅HflK/C complex from tobramycin-treated cells reveals a distinct conformation with two openings that may facilitate substrate entry during proteotoxic stress. Together, these findings establish HflK/C conformational flexibility as a determinant of stress adaptation and provide a framework for understanding SPFH protein function.
    Keywords:  CP: molecular biology; FtsH AAA protease; HflK/C membrane assembly; SPFH family; aminoglycoside stress; bacterial stress response; cryo-electron microscopy; membrane protein quality control; proteostasis; stress-induced conformation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117231
  39. Nat Commun. 2026 Apr 17.
    Cytoplasmic localization of pseudouridine synthase 7 facilitates a pseudouridine-dependent enhancement of cellular stress tolerance.
    Minli Ruan, Sean M Engels, Matthew R Burroughs, Xiaoyan Li, Rosella Stower, Talia Tzadikario, Connor Powell, Dylan Bloch, Oleksandra Fanari, Stuart Akeson, Daniel E Eyler, Chase A Weidmann, Sara Rouhanifard, Miten Jain, Lydia M Contreras, Kristin S Koutmou.
      Pseudouridine (Ψ) is an abundant post-transcriptional modification found across all classes of RNA. It is widely speculated that Ψ inclusion in messenger RNAs (mRNAs) might provide an avenue for cells to control gene expression post-transcriptionally. Here we demonstrate that one of the principal mRNA pseudouridylating enzymes, pseudouridine synthase 7 (PUS7), exhibits a stress-induced accumulation in the cytoplasm of yeast and human epithelial lung cells. Stress-induced and cytoplasmic localization of PUS7 promotes Ψ-incorporation into hundreds of mRNA targets. In contrast, the modification status of tRNA sites targeted by PUS7 (Ψ13 and Ψ35) is unperturbed. Furthermore, engineered PUS7 cytoplasmic localization increases cellular fitness under reactive oxygen species (ROS) and divalent metal ion stress. Quantitative proteomics reveal a reshaping of the proteome upon PUS7 relocalization under stress. Collectively, our data demonstrate that PUS7 localization alters mRNA pseudouridylation patterns, reshapes the proteome, and influences cellular fitness.
    DOI:  https://doi.org/10.1038/s41467-026-71654-y
  40. J Cell Sci. 2026 Apr 16. pii: jcs.264535. [Epub ahead of print]
    Stress-induced proteome remodeling at the Golgi-endosome interface.
    Gina Simon, Savina Abraham Pol, Melisa Dendusic, Nina Schulze, Simone Stupia, Michelle Koci, Lana Buzuk, Beatrice Thier, Philine Steinbach, Hai Trinh, Jasmin Schillinger, Sabrina Ninck, Farnusch Kaschani, Markus Kaiser, Michael Ehrmann, Annette Paschen, Doris Hellerschmied.
      Cellular stress response pathways support cell survival under stress and are often leveraged by cancer cells to gain advantageous traits. How cells respond to Golgi apparatus (Golgi) stress is incompletely understood, limiting insights into the role of Golgi stress in cancer. Here, we combined small molecule stress models and proteomic analyses to elucidate stress-induced changes at the Golgi. Our data establish the depletion of Golgi transport proteins as a common response to different Golgi stressors, including ionophores and inhibitors of the Oxysterol binding protein (OSBP). Ionophores further induce de novo expression of the stress response protein FAM129A/NIBAN1, which localizes to the remodeled secretory pathway. In a group of melanoma cells, displaying a dedifferentiated epithelial-to-mesenchymal-transition (EMT)-like phenotype, FAM129A is constitutively expressed. In these cells, stress-induced localization of FAM129A to the secretory pathway is achieved by relocalization from the plasma membrane. Collectively, our data highlight the Golgi-endosome interface as a critical hub of the cellular response to Golgi stress and reveal cancer cell specific effects of this response.
    Keywords:  Chemical biology; FAM129A/NIBAN1; Golgi stress; Ionophores; Melanoma
    DOI:  https://doi.org/10.1242/jcs.264535
  41. Sci Transl Med. 2026 Apr 15. 18(845): eadz7727
    Selective translation of ZNF281 as part of the integrated stress response system has therapeutic relevance for cardio-oncology.
    Maria Areli Lorenzana-Carrillo, Saymon Tejay, Guocheng Huang, Joseph Nanoa, Yuan-Yuan Zhao, Cory Wagg, Farah Eaton, Michelle Mendiola Pla, Dawn E Bowles, Adam Kinnaird, Evangelos D Michelakis, Seyed Amirhossein Tabatabaei Dakhili, John R Ussher, Gopinath Sutendra.
      A well-recognized attribute of several common and standard cancer therapeutics is the development of cardiotoxicity. Although many anticancer agents appear to target a relatively select and distinct signaling pathway in the tumor, we hypothesized that several different classes of chemotherapeutics may converge into one central stress-sensing system in terminally differentiated cardiomyocytes. Here, we showed that anticancer intercalating/alkylating agents, tyrosine kinase inhibitors, or receptor inhibitors can converge and increase the selective and preferential translation of the transcription factor ZNF281 in cardiomyocytes. Cardiomyocyte-specific ZNF281-deficient mice were completely resistant to anthracycline-mediated cardiotoxicity (AIC), whereas cardiomyocyte-specific ZNF281-overexpressing mice had clinical features of cardiotoxicity. Inhibition of ZNF281 with ZIM, a first-of-its-kind small-molecule drug, completely prevented AIC, enhanced lung tumor regression, and prevented lung metastasis in a metastatic melanoma model. Induction of ZNF281, along with its downstream signaling cascade, was preserved in myocardial tissues from patients with AIC, indicating the translational potential of ZNF281 inhibition in alleviating cardiotoxicity resulting from chemotherapeutic treatments.
    DOI:  https://doi.org/10.1126/scitranslmed.adz7727
  42. Biochim Biophys Acta Mol Basis Dis. 2026 Apr 15. pii: S0925-4439(26)00129-8. [Epub ahead of print] 168266
    Regulation of PSAT1 and PHGDH by m6A in endocrine-resistant breast cancer cells.
    Kellianne M Piell, Anna Vallarta, Ali E Wilt, Bailey L Avila-Valdes, Mary H Sumlut, Navya Goli, Belinda J Petri, Liqing He, Xiang Zhang, Brian F Clem, Carolyn M Klinge.
      The N-6-methyladenosine (m6A) modification of mRNA regulates transcript abundance in endocrine therapy (ET)-resistant breast cancer (BCa) cells. We reported that m6A reader HNRNPA2B1 decreased miR-145p and miR-424-5p targeting PSAT1 and miR-34b-5p and miR-876-5p targeting PHGDH, thus stimulating the serine synthesis pathway (SSP) in ET-resistant BCa cells. Here we examined m6A regulation of PSAT1 and PHGDH. We report that siMETTL3 increased miR-145-5p, reducing PSAT1, and miR-34b-5p and miR-876-5p, reducing PHGDH, without affecting HNRNPA2B1 or NFkB and decreasing MYC, known to stimulate PSAT1 and PHGDH transcription. In contrast, the METTL3 inhibitor STM2457 increased METTL3, MYC, HNRNPA2B1, NFkB, PSAT1, PHGDH, and serine synthesis, and decreased the miRNAs. These data suggest that reducing METTL3 protein and inhibition of its catalytic activity have different effects on these targets. Selected results were verified in ET-resistant T47D and ZR-75-1 BCa cells. METTL3's stimulation of translation may play a role in these differences. Indeed, siMETTL3 had no effect on MYC, PHGDH, or PSAT1 pre-mRNA whereas STM2457 increased these pre-mRNAs. Overall, our data support a model for m6A regulation of PHGDH and PSAT1 indirectly through miRNAs that target PHGDH and PSAT1.
    Keywords:  Breast cancer; Endocrine resistance; METTL3; PHGDH; STM2457; m6A; miRNA
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168266
  43. Anal Chem. 2026 Apr 17.
    Characterizations of G-Quadruplex RNA-Protein Interactions in Living Cells.
    Feng Tang, Xiaochen Liang, Douglas F Porter, Weili Miao, Kevin Maehlmann, Jun Yuan, Paul A Khavari, Yinsheng Wang.
      RNA guanine quadruplexes (rG4s) are noncanonical nucleic acid structures that contribute to diverse cellular functions and disease mechanisms. Defining the proteins that interact with rG4s (rG4IPs) is essential for elucidating their biological roles. Here, we build on the RNA-protein interaction detection (RaPID) platform to develop G4-RaPID, a tailored chemoproteomic strategy for the unbiased profiling of rG4IPs in living cells. Using G4-RaPID, we identified 105 candidate rG4IPs that were commonly enriched across three distinct rG4 sequences. Biochemical analyses confirmed that recombinant hnRNPA0, CHD4, and IGF2BP1 proteins directly bind rG4 structures in vitro. In addition, CLIP-seq experiments revealed significant enrichment of hnRNPA0 binding at endogenous rG4 loci. Luciferase reporter assays further demonstrated that hnRNPA0 engages the rG4 in the 5' UTR of NRAS mRNA to negatively regulate its translation. Together, these results establish G4-RaPID as a robust approach for mapping rG4-protein interactions in living cells and document hnRNPA0-rG4 recognition as a regulatory mechanism controlling NRAS mRNA translation.
    DOI:  https://doi.org/10.1021/acs.analchem.6c00902
  44. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2529741123
    Evidence for strong purifying selection of human 47S ribosomal RNA genes.
    Xufan Ma, Fiona Chow, Buz Galbraith, Daniel Sultanov, Eli K Behar, Andreas Hochwagen.
      The multicopy 47S ribosomal RNA (rRNA) genes are among the most highly expressed genes in the human genome, yet to-date essentially no disease-causing sequence variants have been identified. This lack of disease association is surprising, as defects in 47S rRNA transcription and changes in ribosomal protein dosage, as well as nucleotide changes in the mitochondrial rRNA, all result in disease. The failure to identify rRNA-associated diseases may thus primarily stem from the experimental challenges associated with analyzing this chromosomally isolated high-copy gene family. Here, we used an evolutionary approach to test whether mutations in the human 47S genes can have phenotypic consequences. By analyzing sequence variants among rRNA genes across >3,000 individuals from the high-coverage 1,000 Genomes Project, we demonstrate highly stratified variant abundance across the 47S rRNA genes. In individual genomes, variants were frequently amplified in the transcribed spacer sequences and the evolutionarily young expansion segments, but rarely across the conserved 18S, 5.8S, and 28S rRNA-encoding sequences. Variant numbers and amplification were lowest in evolutionarily highly constrained nucleotide elements that are identical across >90% of sequenced eukaryotes. These results indicate that strong purifying selection acts to suppress copy number expansion of deleterious variants among the hundreds of 47S rRNA copies and imply that deleterious variants in the 47S rRNA have the potential to cause phenotypic consequences at very low copy numbers. As low-copy variant calls are rarely considered in association studies, this may explain why disease associations with 47S rRNA variants have so far escaped detection.
    Keywords:  conserved nucleotide elements; purifying selection; rDNA; ribosomal RNA genes
    DOI:  https://doi.org/10.1073/pnas.2529741123
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