bims-spribo Biomed News
on Specialized ribosomes
Issue of 2026–10–25
nineteen papers selected by
Maxim Bouvet, Università di Torino
  1. Ribo-seq rRNA reads reveal co-predicted signatures of ribosome heterogeneity and collisions.
  2. mRNA Structure Regulates Translation at Every Step.
  3. Ribosome biogenesis and selective translational control as oncogenic vulnerabilities in hematologic malignancies.
  4. Structural basis for start codon selection by eIF5-mimic proteins.
  5. Structural features of ZAK kinase regulation at the ribosome.
  6. From ribosomal stress to clonal adaptation: Del(5q) MDS as a paradigmatic acquired ribosomopathy.
  7. ALKBH8 promotes acute myeloid leukemia progression by coupling codon-dependent translation elongation to mRNA stability.
  8. Molecular drivers of cotranslational protein assembly in bacteria.
  9. Programmable Enhancement of IRES-Mediated Translation via RNA-Guided eIF4G Recruitment.
  10. Purification of Nascent, Chromatin-Associated RNA Enriched for RNA Modifications.
  11. The PAXT connection is a modifier of rare codon-enriched protein expression.
  12. A methylation-dependent reader couples arginine methylation to S6K2 signaling in vivo.
  13. Structure of Blm10:13S proteasome intermediate reveals parallel assembly pathways for the proteasome core particle.
  14. A role for eIF5A in translational control of stress-inducible proteins in multiple myeloma cell lines.
  15. Genetic code expansion enables plant-directed control of bacterial activity.
  16. Proteome-wide C-degron activity profiling connects conditional regulation of the CTLH E3 ligase complex to ribosome biogenesis.
  17. Engineered human Argonaute 2 for targeted C-to-U RNA base editing.
  18. SnoRNA Evolution, Genomic Context and Mobility: The Role of Function and Host Gene Association.
  19. Profiling Nascent RNA Transcription with TT-Seq.
  1. Brief Bioinform. 2026 Sep 01. pii: bbag575. [Epub ahead of print]27(5):
    Ribo-seq rRNA reads reveal co-predicted signatures of ribosome heterogeneity and collisions.
    Edwin S Kyei-Baffour, William J Faller, Ferhat Alkan.
      Ribosome heterogeneity is increasingly recognized as a key factor in various biological contexts, including development, cancer, and immune responses. To enable systematic exploration of this diversity, we previously developed a bioinformatics method that utilized rRNA reads from Ribo-seq data, detecting changes in ribosomal protein composition (dripARF) and ribosome collisions (dricARF) between conditions simply and efficiently. The method works by projecting differences in rRNA read abundance onto the 3D-structure of the ribosome, following which we perform enrichment tests on predefined heterogeneity-specific rRNA position sets. In this study, we apply this tool to publicly available Ribo-seq datasets to understand the impact of experimental protocol variations and to identify shared biological signals across studies. Our analyses show that the rRNA regions assigned to our prediction sets are consistently enriched in rRNA reads, supporting the core assumptions of our approach. We further examine how various protocol factors influence rRNA read distribution and implement a single-sample rRNA position set enrichment analysis-based weight to limit false positives. Finally, we highlight consistent ribosomal changes across these studies, including prominent co-predictors such as ribosome collisions, eS25, and uS19.
    Keywords:  Ribo-seq; rRNA reads; ribosome collisions; ribosome heterogeneity
    DOI:  https://doi.org/10.1093/bib/bbag575
  2. Biochemistry. 2026 Oct 20. 65(20): 3144-3150
    mRNA Structure Regulates Translation at Every Step.
    Alexandra Khitun, Kevin M Weeks.
      Precise, context-sensitive control of protein synthesis is critical in eukaryotic cells, and mRNA structure has emerged as a central mechanism for achieving this control. mRNA structures influence every stage of translation. During initiation, structures within 5' untranslated regions modulate ribosome association with mRNA and the balance between translation of the main open reading frame and use of upstream or alternative start sites. During elongation, structures in the coding sequence govern ribosome pausing in ways that can either protect mRNA stability or trigger decay. During termination, structures downstream of primary stop codons promote readthrough to generate protein isoforms in a tissue-specific manner. mRNA structures are remodeled by helicase expression, post-transcriptional modifications, and translational programming to provide additional layers of regulation. We review recent advances illuminating diverse mechanisms by which RNA structure modulates translation.
    DOI:  https://doi.org/10.1021/acs.biochem.6c00561
  3. Mol Cancer. 2026 Jul 23. pii: 249. [Epub ahead of print]25(1):
    Ribosome biogenesis and selective translational control as oncogenic vulnerabilities in hematologic malignancies.
    Juan Luiz Coelho-Silva, João Agostinho Machado-Neto.
      The translation of the transcriptome into a functional proteome is not a passive readout of mRNA abundance but a primary regulatory layer that actively shapes the oncogenic landscape. In hematologic malignancies, convergent oncogenic signaling pathways, including MYC, PI3K/AKT/mTOR, and tyrosine kinase fusions, directly reprogram the translational apparatus, driving a qualitative shift toward the selective synthesis of pro-survival, proliferative, and stemness-associated proteins. This deregulated program is orchestrated through multiple interconnected axes: the accelerated biogenesis of ribosomes within the nucleolus, the assembly of the eIF4F initiation complex, the activation of stress-adaptive programs like the integrated stress response (ISR), and a sophisticated layer of epitranscriptomic, tRNA, and RNA-binding protein-mediated regulation. Hematologic cancers provide a uniquely informative framework for deconstructing these processes, illustrated by inherited ribosomopathies, such as Diamond-Blackfan anemia syndrome and Shwachman-Diamond syndrome, which resolve the paradox of how ribosomal insufficiency can evolutionarily transition into malignant transformation. Beyond pathogenesis, the translational machinery represents a rich landscape of actionable vulnerabilities. Pharmacological targeting of RNA Polymerase I, eIF4A, and the ISR has demonstrated selective antitumor activity and synergistic potential with established therapies, including BCL-2 inhibition. This review synthesizes mechanistic and clinical evidence to position the ribosome as an active regulatory node rather than a passive decoding machine. We further examine the challenges facing the field, including translational plasticity under therapeutic pressure, the lack of validated companion biomarkers, and the emerging role of translational control in modulating anti-tumor immunity. Ultimately, we argue that defining the disease-specific translational states of leukemia and lymphoma is essential for the next generation of precision oncology, moving beyond genomic landscapes toward a proteomic-centered understanding of malignancy.
    Keywords:  Hematopoiesis; Ribosome biogenesis; Translational control
    DOI:  https://doi.org/10.1186/s12943-026-02749-9
  4. Sci Adv. 2026 Oct 23. 12(43): eaeg5840
    Structural basis for start codon selection by eIF5-mimic proteins.
    Ximena Zottig, Chun-Ying Huang, Zahra Seraj, Nikolaus Grigorieff, Andrei A Korostelev.
      Start codon selection extensively regulates the cellular proteome and is implicated in cancer and other diseases. The eIF5-mimic proteins (5MPs: 5MP1/BZW2 and 5MP2/BZW2) restrict non-AUG start codon usage and thereby reprogram proteoform expression from mRNAs with alternative start sites, such as the oncogenic c-Myc. Here, using in extracto cryo-electron microscopy (cryo-EM) and biochemical assays, we report how 5MP represses translation dependent on the sequence context at start codons. Cryo-EM structures of 48S preinitiation complexes (PICs) reveal 5MP1 bound at the A site of the small ribosomal subunit. 5MPs act as initiation factors that stabilize an open PIC conformation, promoting mRNA scanning and inhibiting initiation at suboptimal start codons. We propose to designate 5MP as eIF1S (eukaryotic initiation factor 1 scanning). These findings reveal the structural basis for proteome modulation by 5MPs and may help correct dysregulated translation in disease.
    DOI:  https://doi.org/10.1126/sciadv.aeg5840
  5. FEBS J. 2026 Oct 21.
    Structural features of ZAK kinase regulation at the ribosome.
    Shuangshuang Niu, Vienna L Huso, Roland Beckmann, Rachel Green.
      ZAKα is a MAP3K that interacts with ribosomes and autophosphorylates upon widespread ribosome collisions mediating the ribotoxic stress response pathway. While activation of ZAKα determines downstream cell fate outcomes such as cell cycle arrest and apoptosis, the exact nature of ribosome binding and the mechanism of activation have not been fully understood. Our recent cryo-EM structures contribute to bridging this gap by visualizing ZAKα bound to ribosomes in various states (hibernating, translating, and colliding) providing a clear molecular blueprint for ZAKα kinase regulation at the ribosome.
    Keywords:  RACK1; ZAK; cryo‐EM; expansion segments; phosphorylation; ribosome collision; signaling
    DOI:  https://doi.org/10.1111/febs.70766
  6. Semin Hematol. 2026 Sep 30. pii: S0037-1963(26)00096-X. [Epub ahead of print]
    From ribosomal stress to clonal adaptation: Del(5q) MDS as a paradigmatic acquired ribosomopathy.
    Juliette E Pearce, Stephani Schmitz, Rebekka K Schneider.
      Ribosomopathies reveal how defects in ribosome biogenesis generate lineage-specific hematopoietic phenotypes and create selection pressure that shapes clonal evolution. Using the germline ribosomopathies Diamond-Blackfan anemia and Shwachman-Diamond syndrome to inform a conceptual framework, we examine del(5q) myelodysplastic neoplasm as a paradigmatic acquired ribosomopathy. We propose that disease trajectory is governed not only by the initiating ribosomal defect, but by adaptive responses to persistent ribosomal stress, including compensatory rescue mutations, p53 checkpoint bypass, and internalization of ribosomal stress. This framework links lineage-specific failure, inflammatory niche remodeling, and p53-driven progression to therapeutic vulnerabilities, offering a rationale for risk stratification and targeted treatment in ribosome-stressed myeloid neoplasms.
    Keywords:  Acute myeloid leukemia; Clonal hematopoiesis; Del(5q) Myelodysplastic neoplasms; Erythroid Differentiation; Ribosomal stress; Ribosomopathy
    DOI:  https://doi.org/10.1053/j.seminhematol.2026.09.006
  7. Cell Rep. 2026 Oct 22. pii: S2211-1247(26)01272-6. [Epub ahead of print]45(11): 118193
    ALKBH8 promotes acute myeloid leukemia progression by coupling codon-dependent translation elongation to mRNA stability.
    Songyu Li, Yunguang Hong, Songze Deng, Xiang Wu, Zhirong Jia, Yan Liu, Ya Liu, Guocai Wu, Yinhui Chen, Aibing Wu, Xiangwei Gao, Zhanghui Chen.
      Dysregulated mRNA translation is a critical driver of acute myeloid leukemia (AML) progression. While translation initiation is extensively studied, mechanisms governing translation elongation in AML remain unclear. Here, we show that the RNA methyltransferase ALKBH8 is overexpressed in patients with AML and correlates with poor prognosis. ALKBH8 is required for the proliferation and leukemogenic capacity of human and murine AML cells in vitro and in vivo. Mechanistically, ALKBH8 promotes translation-coupled mRNA stabilization via its methyltransferase domain. Loss of ALKBH8 induces ribosome pausing and preferentially destabilizes transcripts enriched in adenine-ending codons. Specifically, ALKBH8 regulates the expression of the DNA repair gene BRCA1 in a codon-dependent manner, supporting homologous recombination and cell survival. Moreover, ALKBH8 depletion sensitizes AML cells to the PARP inhibitor olaparib. Collectively, our study reveals a codon-specific mechanism of ALKBH8-mediated translation, highlighting the ALKBH8-BRCA1 axis as a potential target for therapeutic intervention.
    Keywords:  ALKBH8; AML; BRCA1; CP: cancer; CP: molecular biology; tRNA modification; translation elongation
    DOI:  https://doi.org/10.1016/j.celrep.2026.118193
  8. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2608997123
    Molecular drivers of cotranslational protein assembly in bacteria.
    Jaro L Schmitt, Josef J Auburger, Florian Wruck, Jiří Koubek, Sander J Tans, Bernd Bukau, Günter Kramer.
      Protein complexes are pivotal to all major cellular processes. Translation-coupled complex assembly is ubiquitous in eukaryotes, but its molecular basis and prevalence in bacteria remain poorly understood. Here, we combine ribosome profiling and single-molecule optical tweezers to establish principles governing cotranslational assembly of four structurally diverse complexes in Escherichia coli. We reveal how heterotetramers form cotranslationally via hierarchical assembly pathways, with initial heterodimer formation priming the assembly of higher-order oligomers through a topology-dependent organization of homomeric and heteromeric interfaces. Co-post assembly, defined as interaction between nascent and fully synthesized subunits, initiates when dimerization domains are completely exposed at the ribosome. The assembly order is predominantly unidirectional and matches the operon gene order, with upstream-encoded subunits being synthesized first, and then engaging downstream nascent partner subunits. The co-post assembly efficiency depends both on the native operon structure and the ribosome-associated chaperone trigger factor, which binds emerging oligomerization domains and whose dissociation marks the onset of partner subunit engagement. The handover from chaperone engagement to cotranslational assembly is mediated by nascent chain folding. Finally, we show that co-post assembly provides a fitness advantage. Together, these findings reveal how genome organization and chaperone-assisted folding coordinate cotranslational assembly to promote efficient complex biogenesis and cellular fitness in bacteria.
    Keywords:  cotranslational protein assembly; molecular chaperones; nascent chain folding; operon structure; trigger factor
    DOI:  https://doi.org/10.1073/pnas.2608997123
  9. Biochemistry. 2026 Sep 15. 65(18): 2905-2915
    Programmable Enhancement of IRES-Mediated Translation via RNA-Guided eIF4G Recruitment.
    Binbin Ying, Feiyang Zheng, Yoshinori Kawabe, Masamichi Kamihira.
      Internal ribosome entry sites (IRESs) enable cap-independent translation but often exhibit low and variable efficiency, limiting their use in synthetic gene circuits. Here, we present a programmable strategy to enhance IRES-dependent translation by recruiting a truncated eIF4G scaffold via engineered RNA-binding protein fusions. A λN-eIF4G fusion selectively increased EMCV IRES-mediated translation without affecting cap-dependent expression, achieving up to 7.7-fold enhancement. Translation output was tunable over a broad dynamic range through effector dosage and linker design, revealing key design parameters for controlling activity. The system functioned across multiple mammalian cell lines and in tricistronic constructs, enabling coordinated regulation of polycistronic expression. Computational modeling was consistent with preferential interaction between λN and the EMCV IRES. These results establish a modular framework for the programmable control of translation, define design principles for RNA-guided translational control, and expand the synthetic biology toolkit for post-transcriptional gene regulation.
    DOI:  https://doi.org/10.1021/acs.biochem.6c00420
  10. Methods Mol Biol. 2027 ;3091 77-87
    Purification of Nascent, Chromatin-Associated RNA Enriched for RNA Modifications.
    Pavel Kudrin, Ulf Andersson Vang Ørom.
      RNAs that are being synthesized and remain tethered to chromatin during transcription are key participants in co-transcriptional gene regulation. They contribute to essential processes such as splicing, transcription elongation, and chromatin structure shaping. Co- and post-transcriptional RNA modifications have emerged as critical regulators of RNA metabolism and may modulate the function of chromatin-associated RNAs, including their interactions with chromatin. Here, we describe a method to isolate nascent, chromatin-associated RNA enriched for specific RNA modifications, using a combination of metabolic labeling, cell fractionation, and immunoprecipitation. This approach involves labeling of newly transcribed RNA with nucleotide analogs, followed by subcellular fractionation to enrich for chromatin-bound RNA species. Subsequently, immunoprecipitation with RNA modification-specific antibodies is used to selectively purify RNA bearing specific epitranscriptomic marks. We detail each component of the protocol, which can be adapted to various mammalian cell types and experimental conditions. The nature of this workflow enables investigation of RNA modifications on nascent, chromatin-associated transcripts under physiological or perturbed conditions, including various stimuli, genetic mutants, or disease-relevant cell lines.
    Keywords:  Chromatin; Nascent RNA; RNA modifications
    DOI:  https://doi.org/10.1007/978-1-0716-5627-3_3
  11. Nat Commun. 2026 09 17. pii: 10928. [Epub ahead of print]17(1):
    The PAXT connection is a modifier of rare codon-enriched protein expression.
    Taylor Niehoff, Jackson Peterson, Siqi Li, Sijin Chen, Christopher V Nicchitta, Alain Laederach, Christopher M Counter.
      Synonymous codons occur at unequal rates in the coding genome, with those represented least often termed 'rare.' Rare codon-enriched genes typically exhibit poor expression due to reduced transcription, mRNA stability, export, and translation. However, there are an increasing number of examples whereby rare codon-enriched genes are paradoxically highly expressed, suggestive of mechanisms to overcome the poor expression imposed by rare codons. To identify codon-dependent modifiers, we screen a targeted sgRNA library for genes that, when inactivated, increase the expression of rare versus common codon-enriched fluorescent reporters. This identifies the PAXT connection, a nuclear complex that targets transcripts to the exosome for degradation. Targeted loss of a PAXT component leads to a small but preferential increase in mRNA levels and stability and a more pronounced increase in protein expression of rare compared to common codon-enriched reporters. Transcriptomics coupled to proteomics further reveals that this leads to a preferential increase in the expression of endogenous proteins encoded by poorly expressed and long mRNAs specifically enriched in rare codons. Thus, we identify the PAXT connection as a genetic suppressor of poorly expressed genes enriched in rare codons.
    DOI:  https://doi.org/10.1038/s41467-026-77792-7
  12. Sci Adv. 2026 Oct 23. 12(43): eaei1547
    A methylation-dependent reader couples arginine methylation to S6K2 signaling in vivo.
    Yalong Wang, Bin Liu, Rongjie Fu, Wei He, Daniel J McGrail, Han Xu, Mark T Bedford.
      Arginine methylation regulates diverse cellular processes, yet how methyl-arginine reader proteins couple this modification to kinase signaling in vivo remains poorly defined. Here, we identify staphylococcal nuclease and Tudor domain containing 1 (SND1) as a pancreas-enriched effector that links symmetric dimethylarginine (SDMA) recognition to S6 kinase 2 (S6K2) activation. Disruption of SDMA-mediated binding by a point mutation in the SND1 Tudor domain markedly diminishes ribosomal protein S6 (S6) phosphorylation in the pancreas. Mechanistically, SND1 engages SDMA-modified arginines within the carboxyl-terminal glycine-arginine-rich (GAR) motif of S6K2 and promotes S6K2-dependent S6 phosphorylation. Mice harboring lysine substitutions at these GAR arginines (S6k2 RK) phenocopy Snd1 Tudor-mutant (Snd1 knock-in) animals, exhibiting impaired pancreatic S6 phosphorylation. Transcriptomic analyses reveal extensive overlap in dysregulated pathways between Snd1 and S6k2 mutant pancreata, supporting a shared signaling cascade. Together, these findings establish a methylation-dependent reader-kinase axis that links protein arginine methyltransferase 5-catalyzed arginine methylation to tissue-specific control of ribosome signaling and cellular stress adaptation.
    DOI:  https://doi.org/10.1126/sciadv.aei1547
  13. Nat Commun. 2026 09 21. pii: 10993. [Epub ahead of print]17(1):
    Structure of Blm10:13S proteasome intermediate reveals parallel assembly pathways for the proteasome core particle.
    Mandeep Kaur, Xiang Chen, Stella Y Lee, Tyler M Weaver, Bret D Freudenthal, Kylie J Walters, Jeroen Roelofs.
      The proteasome core particle (CP) can be capped by Blm10/PA200, which promotes ATP-independent degradation of disordered proteins and contributes to attenuating antigenic diversity and impacts immunotherapy upon upregulation. The assembly process that leads to Blm10-CP proteasomes remains unresolved and Blm10 is present not only at mature proteasomes but also bound to assembly intermediates. We identified and solved structures of five CP intermediate complexes by cryo-electron microscopy, two of which include Blm10. We find that CP intermediates interactions with Blm10 and Pba1/Pba2 chaperone complex are mutually exclusive and both leads to mature CP production. We further find no synergy between Pba1/Pba2 and Blm10 for CP assembly. These data suggest a parallel assembly pathway exists for Blm10 proteasomes that does not require sequential activity with Pba1/Pba2. Whereas CP affinity for Pba1/Pba2 is reduced during maturation to promote its release, no such affinity switch occurs for Blm10, further suggesting a parallel Blm10-assembly pathway for production of mature Blm10-bound CPs. Altogether, our findings reveal a functionally distinct CP assembly pathway for the production of mature Blm10-CP proteasomes.
    DOI:  https://doi.org/10.1038/s41467-026-77943-w
  14. Mol Oncol. 2026 Oct 21.
    A role for eIF5A in translational control of stress-inducible proteins in multiple myeloma cell lines.
    Demi Both, Ingrid A M Derks, Raphaël Vanleyssem, Marine Leclercq, Najla El Hachem, Pierre Close, Eric Eldering, Marco Vincent Haselager.
      Impaired protein folding in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR), which can induce apoptosis during prolonged ER stress. ER stress is therapeutically targeted in plasma cell malignancies, such as multiple myeloma (MM), but these treatments remain noncurative, and UPR signaling in B-cell malignancies is incompletely understood. A targeted CRISPR-Cas9 screen in RPMI-8226 cells exposed to thapsigargin identified known ER stress regulators (XBP1, IRE1, and calreticulin) and the translation factor eIF5A (eukaryotic translation initiation factor 5A), whose role in ER stress remains unclear. Competition assays showed that eIF5A depletion is detrimental under basal conditions but confers a proliferation advantage during thapsigargin treatment. Inducible EIF5A knockouts confirmed reduced sensitivity specifically to thapsigargin, loss of eIF5A had no or sensitizing effects on cell death induced by other ER stress drugs. Polysome profiling revealed that not general translation, but the translation of specific mRNA transcripts coding for UPR components and apoptotic proteins was affected by eIF5A depletion. Correspondingly, EIF5A KO cells showed reduced thapsigargin-induced UPR activation. In conclusion, these findings indicate that loss of eIF5A alters the stress response in MM cells.
    Keywords:  ER stress; UPR; apoptosis; eIF5A; multiple myeloma; translation
    DOI:  https://doi.org/10.1002/1878-0261.70328
  15. Nat Biotechnol. 2026 Oct 20.
    Genetic code expansion enables plant-directed control of bacterial activity.
    Vivian Zhong, Michaela A Jones, Avaniek Cabales, Alice Gevorgyan, René Inckemann, Anna A Johnson, Sumudu S Karunadasa, Amanda M Forti, Shou-Ling Xu, Aditya M Kunjapur, Jennifer A N Brophy.
      Microorganisms have the potential to deliver growth-promoting benefits to plants and crops; however, to be useful in a field setting, their gene expression should be programmable and restricted to specific plant hosts and conditions. Here, using O-methyl-L-tyrosine (OMY) as a model compound, we establish noncanonical amino acids (ncAAs) as a tool for plant-based control of associated microbial activity. We use genetic code expansion to engineer OMY-dependent control of protein synthesis in the soil bacterium Bacillus subtilis. Engineered B. subtilis strains express an orthogonal aminoacyl-tRNA synthetase and tRNA pair that, upon provision of OMY, results in suppression of in-frame amber stop codons in target transcripts. We engineer Arabidopsis, tomato and poplar to biosynthesize OMY, showing that plant-derived OMY can stimulate gene expression in both model and wild soil bacteria. This demonstrates that inducible and tissue-specific expression of a single biosynthetic enzyme by the plant enables on-demand control over microbial activity, establishing ncAAs as a tool for programming plant-microorganism partnerships.
    DOI:  https://doi.org/10.1038/s41587-026-03360-5
  16. Mol Cell. 2026 Oct 20. pii: S1097-2765(26)00679-9. [Epub ahead of print]
    Proteome-wide C-degron activity profiling connects conditional regulation of the CTLH E3 ligase complex to ribosome biogenesis.
    Drew W Grant, Shengjiang Tan, Dylan E Ramage, Mamie Z Li, Ying Di, Iva A Tchasovnikarova, Michael P Weekes, Stephen J Elledge, Alan J Warren, Richard T Timms.
      Many E3 ubiquitin ligases recognize degrons located at protein termini, but the paucity of bona fide substrates of N-degron and C-degron pathways hampers our understanding of their physiological significance. Devising an expression screening strategy to assess the effect of C-terminal "capping" on the stability of thousands of human proteins, we systematically identify substrates harboring C-degrons. Interrogating one leading candidate, ZMYND19, we characterize a C-degron pathway governed via the C-terminal to LisH (CTLH) E3 ligase complex subunit Muskelin. Cell-to-cell variability in ZMYND19 stability uncovered conditional regulation, with CTLH-mediated degradation impaired by TNF-α stimulation but enhanced by mTOR inhibition. Parallel genetic and proteomic screens identified angio-associated migratory protein (AAMP) and apoptosis-enhancing nuclease (AEN) as additional substrates of the CTLHMuskelin C-degron pathway, leading us to define an essential role for AAMP in ribosome maturation through chaperone activity toward uL16. Altogether, these data define a C-degron pathway connecting conditional regulation of the CTLH E3 ligase complex to ribosome biogenesis.
    Keywords:  AAMP; AEN; C-degron; CTLH E3 ligase complex; RPL10; ZMYND19; protein degradation; ribosome biogenesis; uL16; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.036
  17. Nat Biotechnol. 2026 Oct 20.
    Engineered human Argonaute 2 for targeted C-to-U RNA base editing.
    Robert F Lusi, Salvador Moncayo von Hase, Corey Model, Steven M Banik.
      Tools for manipulating RNA that rely on nonhuman proteins, such as ISC-based and Cas-based scaffolds, can lead to unintended and little-understood effects on human cells and present challenges in therapeutic translation. Replacing them with human proteins engineered for expanded, programmable functions could bypass the limitations of these foreign proteins. Here we demonstrate that human Argonaute 2 (AGO2) can be repurposed as a modular RNA targeting domain. AGO2 fused to a C-to-U deaminase enables AGO-led targeted editing of RNA (ALTER). Using guide RNAs that remodel target RNA structure for selective editing and reduced nuclease activity, we show that ALTER achieves, on average, 1.9-fold higher C-to-U editing on mRNA targets in HEK293T cells compared with Cas13 editors CURE and RESCUE. Transcriptome-wide RNA-seq revealed similar or lower levels of off-target editing compared to the same Cas13-based editors. Machine learning models predict that far fewer immunogenic peptides will result from ALTER and we show that ALTER is amenable to a validated workflow for artificial intelligence-directed deimmunization.
    DOI:  https://doi.org/10.1038/s41587-026-03359-y
  18. Genome Biol Evol. 2026 Oct 24. pii: evag269. [Epub ahead of print]
    SnoRNA Evolution, Genomic Context and Mobility: The Role of Function and Host Gene Association.
    Samuel Coderre, Alphonse Birane Thiaw, Michelle S Scott.
      Small nucleolar RNAs (snoRNAs) are best known for guiding chemical modifications of ribosomal and spliceosomal RNAs. Most vertebrate snoRNAs are encoded within introns of host genes and therefore depend on the production and processing of host precursor RNAs for their biogenesis. Despite this close genomic association, how host-gene context is associated with snoRNA abundance and evolution remains poorly understood. Here, we combined human snoRNA annotations from snoDB, Ensembl gene annotations, snoRNA-sensitive abundance data across multiple tissues, and vertebrate orthology analyses to systematically characterize snoRNA-host-gene relationships. Host genes were grouped into functional classes to compare snoRNA genomic organization, abundance, and conservation across host contexts. We confirmed that snoRNAs are enriched in ribosome-related and lncRNA host genes. SnoRNAs embedded in ribosome-related host genes, particularly ribosomal protein genes, showed the highest abundance and were predominantly broadly detected across tissues, whereas snoRNAs in other host classes were generally less abundant and more tissue-restricted. Across vertebrates, snoRNA sequences were often widely conserved, but the exact host-gene association was less stable, showing that sequence conservation can persist despite changes in genomic embedding. Ribosome-related host classes nevertheless emerged as comparatively stable environments. Together, these results show that snoRNA-host-gene relationships vary across host contexts and evolutionary histories and are consistent with a conceptual continuum from functionally concordant associations to more independent passenger relationships.
    Keywords:  gene mobility; host gene; noncoding RNA; small nucleolar RNA (snoRNA); vertebrate evolution
    DOI:  https://doi.org/10.1093/gbe/evag269
  19. Methods Mol Biol. 2027 ;3091 89-102
    Profiling Nascent RNA Transcription with TT-Seq.
    Yichun Wang, Liangqi Sun, Wenbo Li.
      Nascent RNA production is a dynamic activity in eukaryotic cells that faithfully reflects the transcriptional activities of a cell population at a specific time point. To capture and quantify dynamic transcriptional activity at high temporal resolution, several methods have been developed, including global or precision run-on sequencing (GRO/PRO-seq) and transient transcriptome sequencing (TT-seq). TT-seq uses in-cell metabolic labeling of RNAs with 4-thiouridine (4sU) to specifically enrich newly synthesized, nascent RNAs. This strategy enables real-time measurement of transcriptional dynamics, including initiation, elongation, and termination, across the entire genome. It also enables the sensitive detection of various noncoding, nascent RNAs produced from regulatory elements, such as promoters and enhancers. By combining short pulse labeling with high-throughput sequencing, TT-seq can provide insights into RNA synthesis/decay rates, enhancer activity, and the kinetics of transcriptional regulation in response to various stimuli. The method has become a valuable tool for studying transcriptional control and gene regulation. Here, we describe the entire TT-seq workflow. Our protocol was based on the original TT-seq protocol, but we made several changes that streamlined the workflow.
    Keywords:  4-Thiouridine (4sU); Enhancer RNA (eRNA); Nascent RNA; Transient transcriptome sequencing (TT-seq)
    DOI:  https://doi.org/10.1007/978-1-0716-5627-3_4
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