9Q9J

Cryo-EM structure of human Mre11-Rad50-Nbs1 (MRN) complex bound to DNA and telomeric factor TRF2 fragment (438-542)

Summary for 9Q9J

• Entry DOI: 10.2210/pdb9q9j/pdb
• EMDB information: 52961
• Descriptor: Telomeric repeat-binding factor 2, MANGANESE (II) ION, DNA (64-MER), ... (11 entities in total)
• Functional Keywords: mre11-rad50-nbs1 complex, double-strand dna break repair protein, nuclease, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 615048.19

Authors

Cui, H.J.,Lammens, K.,Hopfner, K.P.,Fan, Y.L.,Kuybu, F. (deposition date: 2025-02-26, release date: 2025-10-01)

Primary citation

Fan, Y.,Kuybu, F.,Cui, H.,Lammens, K.,Chen, J.X.,Kugler, M.,Jung, C.,Hopfner, K.P.
Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2.
Nat Commun, 16:8320-8320, 2025

PubMed Abstract: 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.

PubMed: 40968163
DOI: 10.1038/s41467-025-64082-x

Experimental method

ELECTRON MICROSCOPY (2.71 Å)