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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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  • Yilan Fan

    (Ludwig-Maximilians-Universität München)

  • Filiz Kuybu

    (Ludwig-Maximilians-Universität München)

  • Hengjun Cui

    (Ludwig-Maximilians-Universität München)

  • Katja Lammens

    (Ludwig-Maximilians-Universität München)

  • Jia-Xuan Chen

    (Institute of Molecular Biology)

  • Michael Kugler

    (Ludwig-Maximilians-Universität München)

  • Christophe Jung

    (Ludwig-Maximilians-Universität München)

  • Karl-Peter Hopfner

    (Ludwig-Maximilians-Universität München)

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.

Suggested Citation

  • Yilan Fan & Filiz Kuybu & Hengjun Cui & Katja Lammens & Jia-Xuan Chen & Michael Kugler & Christophe Jung & Karl-Peter Hopfner, 2025. "Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64082-x
    DOI: 10.1038/s41467-025-64082-x
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