Journal Article

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

Kugler, Michael, Jung, Christophe, Cui, Hengjun, Hopfner, Karl-Peter, Kuybu, Filiz, Lammens, Katja, Chen, Jia-Xuan, Fan, Yilan

2025

Overview

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. The MRN complex plays a key role in detecting, signalling, and processing DNA double-strand breaks. This study reports the cryo-EM structures of human MRN bound to DNA, alone and with telomeric protection factor TRF2, revealing MRN’s structural transitions and regulatory mechanisms.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/45/147 / 631/535/1258/1259 / Acid Anhydride Hydrolases - metabolism / Ataxia Telangiectasia Mutated Proteins - metabolism / Cell cycle / Cell Cycle Proteins - chemistry / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell Cycle Proteins - ultrastructure / Cryoelectron Microscopy / Deoxyribonucleic acid / DNA / DNA - metabolism / DNA Breaks, Double-Stranded / DNA damage / DNA Repair Enzymes - chemistry / DNA Repair Enzymes - genetics / DNA Repair Enzymes - metabolism / DNA Repair Enzymes - ultrastructure / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / DNA-Binding Proteins - ultrastructure / Electron microscopy / Humanities and Social Sciences / Humans / Hydrogen bonds / Kinases / MRE11 Homologue Protein - chemistry / MRE11 Homologue Protein - genetics / MRE11 Homologue Protein - metabolism / MRE11 Homologue Protein - ultrastructure / Mre11 nuclease / MRE11 protein / multidisciplinary / Nuclear Proteins - chemistry / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Nuclear Proteins - ultrastructure / Nuclease / Protein Binding / Regulatory mechanisms (biology) / Science / Science (multidisciplinary) / Signal processing / Telomere - metabolism / Telomere-binding protein / Telomeres / Telomeric Repeat Binding Protein 2 - chemistry / Telomeric Repeat Binding Protein 2 - genetics / Telomeric Repeat Binding Protein 2 - metabolism / TRF2 protein / Yeast