Academic Journal
An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin.
| Τίτλος: | An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin. |
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| Συγγραφείς: | Nie C; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Frontiers Science Center for Cancer Integrative Omics, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, China., Liu W; Department of Laboratory Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China. Electronic address: lwc191@163.com., Zhang L; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Frontiers Science Center for Cancer Integrative Omics, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, China., Ge S; Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China; Department of Rare Tumors and Early-Phase Clinical Research, Peking University Cancer Hospital (Inner Mongolia Campus), Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, China., Ma M; Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China., Wang J; Department of Oncology, Peking University First Hospital, Beijing, China., Xu Z; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Frontiers Science Center for Cancer Integrative Omics, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, China., Qin Y; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Frontiers Science Center for Cancer Integrative Omics, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, China., Zhou XA; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Frontiers Science Center for Cancer Integrative Omics, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, China., Liu Y; Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China., Wang W; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Frontiers Science Center for Cancer Integrative Omics, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, China., Wang J; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Frontiers Science Center for Cancer Integrative Omics, Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing, China; Department of Gastrointestinal Translational Research, Peking University Cancer Hospital, Beijing, China; Department of Urology, Peking University First Hospital, Beijing, China. Electronic address: wangjd@bjmu.edu.cn. |
| Πηγή: | Molecular cell [Mol Cell] 2026 Sep 17; Vol. 86 (18), pp. 3655-3672.e17. Date of Electronic Publication: 2026 Aug 31. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge Ma : Cell Press Original Publication: Cambridge, Mass. : Cell Press, c1997- |
| Ιατρικοί όροι (MeSH): | Interleukin-1 Receptor-Associated Kinases*/metabolism , Interleukin-1 Receptor-Associated Kinases*/genetics , Ataxia Telangiectasia Mutated Proteins*/metabolism , Ataxia Telangiectasia Mutated Proteins*/genetics , Chromatin*/genetics , Chromatin*/metabolism , RNA, Small Nuclear*/genetics , RNA, Small Nuclear*/metabolism , Transcription, Genetic* , Recombinational DNA Repair*, Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/genetics ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics ; DNA-Binding Proteins/metabolism ; DNA-Binding Proteins/genetics ; DNA Repair Enzymes/metabolism ; DNA Repair Enzymes/genetics ; MRE11 Homologue Protein/metabolism ; MRE11 Homologue Protein/genetics ; Spliceosomes/genetics ; Spliceosomes/metabolism ; Humans ; DNA Breaks, Double-Stranded ; Phosphorylation ; Cell Line, Tumor ; Acid Anhydride Hydrolases |
| Περίληψη: | Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin in human cancer cells. Mechanistically, IRAK1 phosphorylates spliceosomal serine/arginine (SR)-rich proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a "transcription repair bridge" to link transcriptional processes to HR repair and ultimately preserves genomic stability. Inhibiting IRAK1 axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer-cell chemosensitivity. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests Jiadong Wang, W.L., and C.N. have a patent registration (CN116019814B) in China related to this work. |
| Contributed Indexing: | Keywords: ATM; DNA damage response; IRAK1; MRE11-RAD50-NBS1 complex; active transcription; homologous recombination repair; snRNA |
| Substance Nomenclature: | EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases) EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) EC 2.7.11.1 (IRAK1 protein, human) EC 2.7.11.1 (ATM protein, human) 0 (Cell Cycle Proteins) 0 (Chromatin) 0 (Nuclear Proteins) 0 (DNA-Binding Proteins) 0 (RNA, Small Nuclear) EC 6.5.1.- (DNA Repair Enzymes) EC 3.1.- (MRE11 Homologue Protein) 0 (MRE11 protein, human) EC 3.6.- (RAD50 protein, human) 0 (NBN protein, human) EC 3.6.- (Acid Anhydride Hydrolases) |
| Entry Date(s): | Date Created: 20260831 Date Completed: 20260917 Latest Revision: 20260917 |
| Update Code: | 20260918 |
| DOI: | 10.1016/j.molcel.2026.08.006 |
| PMID: | 42673958 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1097-4164 |
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| DOI: | 10.1016/j.molcel.2026.08.006 |