IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080884.125

Oluwasegun T Akinniyi, Aswathy Sebastian, Shardul Kulkarni, Istvan Albert, Joseph C Reese

{"title":"Degradation factor 1, Def1, regulates mRNA translation and decay through Ccr4-Not-dependent ubiquitylation of the ribosome.","authors":"Oluwasegun T Akinniyi, Aswathy Sebastian, Shardul Kulkarni, Istvan Albert, Joseph C Reese","doi":"10.1261/rna.080884.125","DOIUrl":"10.1261/rna.080884.125","url":null,"abstract":"Yeast Def1 is well known for its role in regulating RNA polymerase II elongation and degrading the large subunit of polymerase during transcriptional stress. It is an abundant cytoplasmic protein that undergoes stress-induced processing and is then transported to the nucleus. Previous research from our laboratory has shown that Def1 interacts with various proteins involved in mRNA decay and translation control and that it regulates mRNA half-lives, suggesting an important role in the cytoplasm. In this study, we report that Def1 binds polyribosomes and that its null mutant strain exhibits phenotypes, indicating a role in translation. Ribo-seq analysis revealed that deleting DEF1 altered ribosome footprints on mRNAs and increased the dwell time of ribosomes at nonoptimal codons in the A-site. Additionally, results from a codon-optimality reporter assay suggest that Def1 facilitates the degradation of mRNAs containing nonoptimal codons. The Ccr4-Not complex links codon optimality to mRNA decay, and Def1's binding to ribosomes depends on its ubiquitin-binding domain, as well as the ubiquitylation of eS7a in the small ribosomal subunit by the Ccr4-Not complex. Moreover, the polyglutamine-rich, unstructured C terminus of Def1 is crucial for its interaction with RNA decay and translation factors. This indicates that Def1 functions as a ubiquitin-dependent scaffold that connects translation status to mRNA decay. In summary, we have identified a cytoplasmic function for Def1 in translation and established it as a regulator of gene expression that spans both transcription and translation processes.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"930-944"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147435055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Terminal loop sequences in viral double-stranded RNAs modulate RIG-I signaling. 病毒双链rna末端环序列调控rig - 1信号转导。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080913.125

Matthew Hackbart, Patrick Wang, Victoria Gnazzo, Carolina B López

引用次数: 0

NMD takes two PIN domains to tango. NMD需要两个PIN域才能正常工作。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.081027.126

Oliver Mühlemann, Evangelos D Karousis

引用次数: 0

Stalled translation on transcripts cleaved by RNase L activates signaling important for innate immunity. 被RNase L切割的转录本上的翻译停滞激活了对先天免疫重要的信号。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080699.125

Agnes Karasik, Grant D Jones, Nicholas R Guydosh

{"title":"Stalled translation on transcripts cleaved by RNase L activates signaling important for innate immunity.","authors":"Agnes Karasik, Grant D Jones, Nicholas R Guydosh","doi":"10.1261/rna.080699.125","DOIUrl":"10.1261/rna.080699.125","url":null,"abstract":"RNase L is an endonuclease that responds to infections by cleaving most host- and pathogen-derived single-stranded RNAs. This widespread RNA cleavage can lead to death of the infected cell via the ribotoxic stress response (RSR). An ongoing challenge is to understand how RNase L's endonuclease activity triggers cell death to benefit the host. To address this question, we used nanopore-based long-read sequencing to show that 3' mRNA fragments in the cell were not fully degraded after RNase L activation and that these fragments were translated by ribosomes. We further asked whether ribosomes on mRNA fragments stall when they reach 3' ends created by RNase L. We used ribosome profiling to capture footprints protected by these ribosomes, which can be identified by their short length (15-18 nt). We found that RNase L activation increased the number of stalled ribosomes at RNase L cleavage sites. Loss of the ribosome rescue factor PELO increased the number of short footprints derived from stalled ribosomes and augmented the RSR. Our work therefore establishes a role for fragmented mRNA in causing ribosome stalling that promotes innate immunity via the RSR.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"945-961"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147309125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A comparison of Dictyostelium discoideum 3'-5' RNA polymerases reveals a conserved tRNA^His guanylyltransferase residue that plays a dual role in catalysis. 比较盘状盘基钢菌的3'-5' RNA聚合酶，发现一个保守的tRNAHis guan酰转移酶残基在催化中起双重作用。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080815.125

Grace N Johnecheck, Korey J Kihm, Jane E Jackman

{"title":"A comparison of Dictyostelium discoideum 3'-5' RNA polymerases reveals a conserved tRNAHis guanylyltransferase residue that plays a dual role in catalysis.","authors":"Grace N Johnecheck, Korey J Kihm, Jane E Jackman","doi":"10.1261/rna.080815.125","DOIUrl":"10.1261/rna.080815.125","url":null,"abstract":"The 3'-5' RNA polymerase family consists of eukaryotic tRNAHis guanylyltransferase (Thg1) and Thg1 homologs known as Thg1-like proteins (TLPs) that exist in all three domains of life. Thg1 catalyzes an essential reaction adding a G-1 nucleotide to the 5' end of the tRNAHis, forming an identity element for tRNA aminoacylation. All TLPs studied, except Dictyostelium discoideum (Ddi) TLP2, perform in vitro Watson-Crick (WC) dependent addition of multiple nucleotides to repair truncated tRNA. DdiTLP2 has similar activity to Thg1, adding G-1 to mt-tRNAHis, but shares other biochemical properties with other TLPs, including a restriction to making WC base pairs during this reaction. We identified two regions in DdiTLP2 that lacked residues that are conserved in other Thg1/TLP enzymes. DdiTLP2 variants in both regions abolish enzymatic activity of DdiTLP2, indicating these regions are important for DdiTLP2 catalysis. Changing DdiThg1 D150 to the corresponding arginine found in DdiTLP2 causes an unexpected reversal of this enzyme's specificity, with a loss of its ability to incorporate a non-WC base-paired G-1 to its physiological substrate, while gaining the ability to add WC base-paired G-1 to mt-tRNAHis Biochemical study of other changes to D150, combined with structural models, suggests a previously unknown role for D150 in controlling substrate specificity at the adenylation step by providing a checkpoint for correct setup of a WC base pair in the active site. Thg1 also appears to have adapted the role of the ancestral D150 residue for a second function, promoting non-WC nucleotide addition to its eukaryotic tRNAHis substrate.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"843-857"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Canonical microRNA loss drives tumor development, implicating therapeutic efficacy of enoxacin in angiosarcoma. 典型microRNA缺失驱动肿瘤发展，暗示依诺沙星对血管肉瘤的治疗效果。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080706.125

Bozhi Liu, Ant Murphy, Annaleigh Benton, Lauren Gartenhaus, William Budka, Juliana M Bronzini, Samuel Hartzler, Madison E Yates, Alejandra Romero Alzate, Nimod D Janson, Shyaman Jayasundara, Sagar Utturkar, Nadia A Lanman, Majid Kazemian, Jason A Hanna

{"title":"Canonical microRNA loss drives tumor development, implicating therapeutic efficacy of enoxacin in angiosarcoma.","authors":"Bozhi Liu, Ant Murphy, Annaleigh Benton, Lauren Gartenhaus, William Budka, Juliana M Bronzini, Samuel Hartzler, Madison E Yates, Alejandra Romero Alzate, Nimod D Janson, Shyaman Jayasundara, Sagar Utturkar, Nadia A Lanman, Majid Kazemian, Jason A Hanna","doi":"10.1261/rna.080706.125","DOIUrl":"10.1261/rna.080706.125","url":null,"abstract":"Angiosarcoma (AS) is a rare and aggressive tumor arising within the endothelium, characterized by a high metastatic rate and poor prognosis. Our prior work established that endothelial loss of Dicer1, a key enzyme in microRNA (miRNA) processing, drives AS formation in mice, indicating a tumor suppressive role for miRNAs in tumorigenesis. Here, we corroborated this hypothesis by generating a novel conditional knockout model targeting Dgcr8, a core component of the microprocessor complex required for pri-miRNA processing. Conditional deletion of Dgcr8 phenocopies Dicer1 loss, resulting in spontaneous AS formation and global loss of mature miRNAs. We further demonstrate that treatment with enoxacin (ENX), a repurposed antibiotic known to enhance miRNA processing, reduces viability, migration, and clonogenicity of AS cells. ENX increases the abundance of tumor-suppressive miRNAs and downregulates oncogenic pathways, including pathways related to cell cycle progression, angiogenesis, and cell migration. These results establish the essential role of miRNA biogenesis in suppressing AS and reveal a pharmacologically targetable vulnerability via ENX-mediated enhancement of miRNA expression in tumors.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"812-826"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147309744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

mRNA COVID-19 vaccines: science versus misinformation. mRNA COVID-19疫苗：科学与错误信息。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080944.126

Jeff Coller, Andrew Geall, Roberta Duncan, Clay Alspach, Sean Ryder, Melissa J Moore, Fátima Gebauer

{"title":"mRNA COVID-19 vaccines: science versus misinformation.","authors":"Jeff Coller, Andrew Geall, Roberta Duncan, Clay Alspach, Sean Ryder, Melissa J Moore, Fátima Gebauer","doi":"10.1261/rna.080944.126","DOIUrl":"10.1261/rna.080944.126","url":null,"abstract":"The rapid development of COVID-19 vaccines as a result of Operation Warp Speed represented an extraordinary triumph of scientific innovation, with multiple vaccine platforms demonstrating remarkable efficacy in preventing severe disease, hospitalization, and death-ultimately saving millions of lives. The U.S. government, pharmaceutical companies, research institutions, and health agencies collaborated at an unprecedented scale to develop, test, and distribute vaccines, showcasing what coordinated medical innovation can accomplish. Vaccination programs successfully prevented catastrophic outcomes and enabled people to return to normal life during the crisis. COVID-19 vaccines continue to provide critical protection for vulnerable populations today, and the mRNA platforms developed have opened new possibilities for treating cancers and other diseases. Yet despite rigorous regulatory oversight and extensive clinical trial data, these vaccines have faced substantial misinformation campaigns that spread false claims about their safety and design. To address these misrepresentations and resultant public concerns, this document draws on rigorous scientific evidence to comprehensively examine the misconceptions surrounding mRNA technology, explaining how these vaccines work, their proven safety record, and their demonstrated benefits.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"759-771"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147481684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content. 调节tRNA合成酶抑制显示抛物线诱导应激颗粒的大小和RNA含量有限。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080883.125

Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon

{"title":"Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.","authors":"Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon","doi":"10.1261/rna.080883.125","DOIUrl":"10.1261/rna.080883.125","url":null,"abstract":"Translation elongation defects cause ribosome stalling and activate the integrated stress response (ISR). During the ISR, translation initiation suppression and ribosome runoff drive mRNA condensation into stress granules. However, the effects of partial translation elongation inhibition on stress granules are poorly defined. We demonstrate that intermediate levels of tRNA synthetase inhibitors activate the ISR and cause assembly of stress granules in a parabolic dose-response pattern. These stress granules are limited in size and number due to ribosome association with mRNAs. Assembly of stress granules by intermediate levels of the prolyl-tRNA synthetase inhibitor halofuginone requires the canonical stress granule scaffolding proteins G3BP1/2 and GCN2-mediated ISR activation. We performed a candidate-based comparative analysis of the composition of stress granules induced by intermediate levels of halofuginone or canonical stressors arsenite or thapsigargin. The stress granules induced by halofuginone, arsenite, or thapsigargin harbor polyadenylated RNA and the canonical stress granule proteins PABPC1, G3BP1, and UBAP2L. We observe stress- and transcript-specific differences in the localization of candidate RNA molecules to stress granules. These results demonstrate that partial translation elongation inhibition permits stress granule assembly through the balance of ISR activation and mRNA association with ribosomes, with implications for the stress response associated with amino acid or tRNA deficiency, therapeutic tRNA synthetase inhibition, or diseases associated with tRNA synthetase mutations.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"870-884"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Editing-independent effects of Drosophila Adar on heterochromatin silencing. 果蝇Adar在异染色质沉默中的编辑非依赖性作用。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080873.125

Khadija Hajji, Damiano Amoruso, Barbora Nováková, Nagraj Sambrani, Deying Yang, Anzer Khan, Vojtech Bystry, Alejandro Medaglia-Mata, Domenico Alessandro Silvestris, Ernesto Picardi, Mary A O'Connell, Liam P Keegan

{"title":"Editing-independent effects of Drosophila Adar on heterochromatin silencing.","authors":"Khadija Hajji, Damiano Amoruso, Barbora Nováková, Nagraj Sambrani, Deying Yang, Anzer Khan, Vojtech Bystry, Alejandro Medaglia-Mata, Domenico Alessandro Silvestris, Ernesto Picardi, Mary A O'Connell, Liam P Keegan","doi":"10.1261/rna.080873.125","DOIUrl":"10.1261/rna.080873.125","url":null,"abstract":"ADAR RNA editing enzymes deaminate selected adenosines to inosines in dsRNA. In Drosophila, inosine in dsRNA inhibits cleavage by Dcr2, and some ADAR proteins contribute an additional, editing-independent inhibition. The Drosophila AdarG isoform, in particular, has been proposed to inhibit HP1-mediated heterochromatin silencing of repetitive sequences initiated by specific dsRNAs. To address the functions of AdarG, we overexpressed it from new UAS-Adar lines, under the control of a temperature-regulated Act5Cts-GAL4 driver. Overexpression of the adult AdarG isoform or catalytically inactive AdarE374A led to larval lethality with some escaper pupae that show an ecdysone-related, head eversion defect. This indicates an editing-independent effect of high Adar expression. Pupae show aberrantly elevated innate immune and early ecdysone gene transcript expression, and no flies eclose. RNAi knockdown of ecdysone receptor A (EcRA) or increased expression of the histone H3K9me2,3-associated HP1 protein partially rescues AdarG overexpression defects and normalizes gene expression in rescued progeny flies. In other reports, Drosophila mutants with reduced HP1, or egg (SetDB1), Su(var)3-9 double mutants with reduced histone H3K9me2,3 also produce larvae with ecdysone-related and innate immune defects. We show that overexpressed AdarG inhibits histone H3K9me-mediated epigenetic silencing through an editing-independent effect, most likely at the dsRNA/Dcr2/Ago2 initiation stage.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"962-981"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147435098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel NLP-based method and algorithm to discover RNA-binding protein (RBP) motifs, contexts, binding preferences, and interactions. 一种新的基于nlp的方法和算法来发现rna结合蛋白（RBP）基序、背景、结合偏好和相互作用。

IF 4.3 3区生物学

RNA Pub Date : 2026-05-18 DOI: 10.1261/rna.080892.125

Shaimae I Elhajjajy, Zhiping Weng

{"title":"A novel NLP-based method and algorithm to discover RNA-binding protein (RBP) motifs, contexts, binding preferences, and interactions.","authors":"Shaimae I Elhajjajy, Zhiping Weng","doi":"10.1261/rna.080892.125","DOIUrl":"10.1261/rna.080892.125","url":null,"abstract":"RNA-binding proteins (RBPs) are essential modulators in the regulation of mRNA processing. The binding patterns, interactions, and functions of most RBPs are not well-characterized. Previous studies have shown that motif context is an important contributor to RBP binding specificity, but its precise role remains unclear. Despite recent computational advances to predict RBP binding, existing methods are challenging to interpret and largely lack a categorical focus on RBP motif contexts and RBP-RBP interactions. There remains a need for interpretable predictive models to disambiguate the contextual determinants of RBP binding specificity in vivo. Here, we present a novel and comprehensive pipeline to address these knowledge gaps. We devise a natural language processing-based method to deconstruct sequences into entities comprising a target k-mer and its flanking regions, then use this representation to formulate RBP binding prediction as a weakly supervised multiple instance learning problem. To interpret our predictions, we introduce a deterministic motif discovery algorithm to leverage our data structure, recapitulating the established motifs of numerous RBPs as validation. Importantly, we characterize the binding motifs and binding contexts for 71 RBPs in HepG2 and 74 RBPs in K562, with many of them being novel. Finally, through feature integration, transitive inference, and a new cross-prediction approach, we propose novel cooperative and competitive RBP-RBP interaction partners and hypothesize their potential regulatory functions. In summary, we present a complete framework for investigating the contextual determinants of specific RBP binding, and we demonstrate the significance of our findings in delineating RBP binding patterns, interactions, and functions.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"885-914"},"PeriodicalIF":4.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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