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Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2.

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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
Περιγραφή
ISSN:2041-1723
DOI:10.1038/s41467-025-64082-x