New publication by the Hopfner lab on a structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2
Fan Y, Kuybu F, Cui H, Lammens K, Chen JX, Kugler M, Jung C, Hopfner KP (2025) Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2. Nat Commun, 16(1):8320 Link
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.
Read the full paper here: https://www.nature.com/articles/s41467-025-64082-x
