Academic Journal
Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2.
| Τίτλος: | Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2. |
|---|---|
| Συγγραφείς: | Fan Y; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen Straße 25, 81377, Munich, Germany., Kuybu F; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen Straße 25, 81377, Munich, Germany., Cui H; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen Straße 25, 81377, Munich, Germany., Lammens K; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen Straße 25, 81377, Munich, Germany., Chen JX; Proteomics Core Facility, Institute of Molecular Biology, Mainz, Germany., Kugler M; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen Straße 25, 81377, Munich, Germany., Jung C; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen Straße 25, 81377, Munich, Germany., Hopfner KP; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen Straße 25, 81377, Munich, Germany. karlpeter.hopfner@lmu.de. |
| Πηγή: | Nature communications [Nat Commun] 2025 Sep 18; Vol. 16 (1), pp. 8320. Date of Electronic Publication: 2025 Sep 18. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| Ιατρικοί όροι (MeSH): | MRE11 Homologue Protein*/metabolism , MRE11 Homologue Protein*/chemistry , MRE11 Homologue Protein*/genetics , MRE11 Homologue Protein*/ultrastructure , Telomeric Repeat Binding Protein 2*/metabolism , Telomeric Repeat Binding Protein 2*/chemistry , Telomeric Repeat Binding Protein 2*/genetics , Cell Cycle Proteins*/metabolism , Cell Cycle Proteins*/chemistry , Cell Cycle Proteins*/genetics , Cell Cycle Proteins*/ultrastructure , DNA-Binding Proteins*/metabolism , DNA-Binding Proteins*/chemistry , DNA-Binding Proteins*/genetics , DNA-Binding Proteins*/ultrastructure , Nuclear Proteins*/metabolism , Nuclear Proteins*/chemistry , Nuclear Proteins*/genetics , Nuclear Proteins*/ultrastructure , DNA Repair Enzymes*/metabolism , DNA Repair Enzymes*/chemistry , DNA Repair Enzymes*/genetics , DNA Repair Enzymes*/ultrastructure , DNA Breaks, Double-Stranded*, DNA/metabolism ; Acid Anhydride Hydrolases/metabolism ; Telomere/metabolism ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Humans ; Cryoelectron Microscopy ; Protein Binding |
| Περίληψη: | The MRE11-RAD50-NBS1 (MRN) complex is a central, multifunctional factor in the detection, signaling and nucleolytic processing of DNA double-strand breaks (DSBs). To clarify how human MRN binds generic and telomeric DNA ends and can separate DNA end sensing from nuclease activities, we determined cryo-electron microscopy (cryo-EM) structures of human MRN bound to DNA and to DNA and the telomere protection factor TRF2. MRN senses DSBs through a tight clamp-like sensing state with closed coiled-coil domains, but auto-inhibited MRE11 nuclease. NBS1 wraps around the MRE11 dimer, with NBS1's ATM recruitment motif sequestered by binding to the regulatory RAD50 S site, necessitating a switch in the NBS1 C helix for ATM activation. At telomeric DNA, TRF2 blocks the second S site via the iDDR motif to prevent nuclease and ATM activation. Our results provide a structural framework for DNA sensing via a gating mechanism and separation of sensing, signaling and processing activities of mammalian MRN. (© 2025. The Author(s).) |
| Competing Interests: | Competing interests: The authors declare no competing interests. |
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| Substance Nomenclature: | EC 3.1.- (MRE11 Homologue Protein) EC 3.6.- (RAD50 protein, human) 0 (Telomeric Repeat Binding Protein 2) 0 (NBN protein, human) 0 (MRE11 protein, human) 0 (Cell Cycle Proteins) 0 (DNA-Binding Proteins) 0 (Nuclear Proteins) EC 6.5.1.- (DNA Repair Enzymes) 0 (TERF2 protein, human) 9007-49-2 (DNA) EC 3.6.- (Acid Anhydride Hydrolases) EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) EC 2.7.11.1 (ATM protein, human) |
| Entry Date(s): | Date Created: 20250918 Date Completed: 20250918 Latest Revision: 20250921 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12446458 |
| DOI: | 10.1038/s41467-025-64082-x |
| PMID: | 40968163 |
| Βάση Δεδομένων: | MEDLINE |
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