Structural Biology
Next chapter in the MRN chronicles
19.09.2025
Karl-Peter Hopfner’s team uncovers the structural basis of DNA break sensing by MRE11-RAD50-NBS1 complex and its regulation by telomeric factor TRF2
The MRE11-RAD50-NBS1 (MRN) complex plays a central role in the detection, signalling and nucleolytic processing of DNA double-strand breaks (DSBs). Yilan Fan, Filiz Kuybu and Hengjun Cui in Karl-Peter’s team resolved the cryo-EM structures of MRN bound to DNA and telomeric protection factor TRF2, revealing a tight clamp-like sensing state coupled with auto-inhibited nuclease conformation. The NBS1 motif for recruiting downstream kinase ATM is sequestered by binding to the regulatory RAD50 S site. At telomeric DNA, TRF2 blocks the second S site to prevent MRN nuclease function and ATM activation. These findings provide a structural framework for the topological sensing of DNA ends by MRN and its functional segregation of sensing, signalling, and processing activities.
Original Publication:
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.
Nat Commun. 2025 Sep 18;16(1):8320. doi: 10.1038/s41467-025-64082-x.