Academic Journal
MRE11 proximal polyadenylation site-mediated looping impacts transcription and genomic stability.
| Τίτλος: | MRE11 proximal polyadenylation site-mediated looping impacts transcription and genomic stability. |
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| Συγγραφείς: | Huang K; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Brault ME; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Cong K; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Azazmeh N; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Collins S; MCD, Centre de Biologie Intégrative (CBI), CNRS, Université de Toulouse, UT3, Toulouse, France., Lee S; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Lantz GA; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Raskind G; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Legube G; MCD, Centre de Biologie Intégrative (CBI), CNRS, Université de Toulouse, UT3, Toulouse, France., Beroukhim R; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Chowdhury D; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: dipanjan_chowdhury@dfci.harvard.edu. |
| Πηγή: | Molecular cell [Mol Cell] 2026 May 21; Vol. 86 (10), pp. 1931-1944.e9. Date of Electronic Publication: 2026 Apr 16. |
| 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): | MRE11 Homologue Protein*/genetics , MRE11 Homologue Protein*/metabolism , Genomic Instability* , Transcription, Genetic* , Polyadenylation*, Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Acid Anhydride Hydrolases/genetics ; Acid Anhydride Hydrolases/metabolism ; DNA Repair Enzymes/genetics ; DNA Repair Enzymes/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Animals ; Promoter Regions, Genetic ; DNA Replication ; Mice ; DNA Damage |
| Περίληψη: | Alternative polyadenylation (APA) generates transcript isoforms with variable 3' untranslated regions (UTR) lengths, yet its role in DNA damage response (DDR) genes is poorly understood. Here, we demonstrate that the proximal polyadenylation site (pPAS) of MRE11 engages in PAS-promoter looping to facilitate RNA polymerase recycling and sustain high promoter activity-a mechanism not well characterized in mammals. Deletion of the MRE11 pPAS disrupts this looping, reduces MRE11 transcription, impairs MRE11-RAD50-NBS1 (MRN) complex levels, and phenocopies hypomorphic MRE11 mutations. MRE11pPAS-/- cells exhibit ectopic DNA replication and reduced viability under overgrowth conditions. 5-ethynyl-2'-deoxyuridine sequencing (EdU-seq) revealed aberrant DNA synthesis occurring primarily at intronic and intergenic regions, where MRE11 chromatin immunoprecipitation sequencing (ChIP-seq) showed decreased binding correlating with elevated replication. Furthermore, multiple DDR genes with several PASs also form PAS-promoter loops, suggesting a broader regulatory mechanism. Together these findings identify the MRE11 pPAS as a critical noncoding element that maintains genome stability through transcriptional regulation via PAS-promoter looping. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests D.C. is a member of the Advisory Board of Molecular Cell. D.C. is on the SAB of BPGbio, Inc. and Gambit Bio. R.B. consults for and owns equity in Scorpion Therapeutics and receives research support from Novartis. |
| Grant Information: | R01 CA264900 United States CA NCI NIH HHS; P01 CA269021 United States CA NCI NIH HHS; R01 CA284565 United States CA NCI NIH HHS; P01 CA275717 United States CA NCI NIH HHS; R01 CA208244 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: DNA repair; DNA replication; MRE11; RNA Pol II recycling; alternative polyadenylation; chromatin looping; genome stability; promoter-3′ UTR looping; transcription |
| Substance Nomenclature: | EC 3.1.- (MRE11 Homologue Protein) 0 (Mre11a protein, mouse) 0 (Cell Cycle Proteins) EC 3.6.- (Acid Anhydride Hydrolases) EC 6.5.1.- (DNA Repair Enzymes) 0 (Nuclear Proteins) 0 (DNA-Binding Proteins) 0 (Nijmegen breakage syndrome 1 protein, mouse) EC 3.6.- (Rad50 protein, mouse) |
| Entry Date(s): | Date Created: 20260417 Date Completed: 20260715 Latest Revision: 20260715 |
| Update Code: | 20260715 |
| PubMed Central ID: | PMC13120710 |
| DOI: | 10.1016/j.molcel.2026.03.032 |
| PMID: | 41997154 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1097-4164 |
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| DOI: | 10.1016/j.molcel.2026.03.032 |