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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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    1. Jacob Falck & Julia Coates & Stephen P. Jackson, 2005. "Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage," Nature, Nature, vol. 434(7033), pages 605-611, March.
    2. Florian Roisné-Hamelin & Sabrina Pobiega & Kévin Jézéquel & Simona Miron & Jordane Dépagne & Xavier Veaute & Didier Busso & Marie-Hélène Le Du & Isabelle Callebaut & Jean-Baptiste Charbonnier & Philip, 2021. "Mechanism of MRX inhibition by Rif2 at telomeres," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Dominic Johnson & Margaret Crawford & Tim Cooper & Corentin Claeys Bouuaert & Scott Keeney & Bertrand Llorente & Valerie Garcia & Matthew J. Neale, 2021. "Concerted cutting by Spo11 illuminates meiotic DNA break mechanics," Nature, Nature, vol. 594(7864), pages 572-576, June.
    4. Elda Cannavo & Petr Cejka, 2014. "Sae2 promotes dsDNA endonuclease activity within Mre11–Rad50–Xrs2 to resect DNA breaks," Nature, Nature, vol. 514(7520), pages 122-125, October.
    5. Eleni P. Mimitou & Lorraine S. Symington, 2008. "Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing," Nature, Nature, vol. 455(7214), pages 770-774, October.
    6. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Addendum: Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 636(8042), pages 4-4, December.
    7. Marcel Hohl & You Yu & Vitaly Kuryavyi & Dinshaw J. Patel & John Petrini, 2025. "Structure guided functional analysis of the S. cerevisiae Mre11 complex," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    8. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 630(8016), pages 493-500, June.
    9. Christophe Jung & Peter Bandilla & Marc von Reutern & Max Schnepf & Susanne Rieder & Ulrich Unnerstall & Ulrike Gaul, 2018. "True equilibrium measurement of transcription factor-DNA binding affinities using automated polarization microscopy," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    10. Tristan Bepler & Kotaro Kelley & Alex J. Noble & Bonnie Berger, 2020. "Topaz-Denoise: general deep denoising models for cryoEM and cryoET," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    11. Freddy Khayat & Elda Cannavo & Majedh Alshmery & William R. Foster & Charly Chahwan & Martino Maddalena & Christopher Smith & Antony W. Oliver & Adam T. Watson & Antony M. Carr & Petr Cejka & Alessand, 2021. "Inhibition of MRN activity by a telomere protein motif," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    12. Fernando Moreno-Herrero & Martijn de Jager & Nynke H. Dekker & Roland Kanaar & Claire Wyman & Cees Dekker, 2005. "Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA," Nature, Nature, vol. 437(7057), pages 440-443, September.
    13. Vera M. Kissling & Giordano Reginato & Eliana Bianco & Kristina Kasaciunaite & Janny Tilma & Gea Cereghetti & Natalie Schindler & Sung Sik Lee & Raphaël Guérois & Brian Luke & Ralf Seidel & Petr Cejka, 2022. "Mre11-Rad50 oligomerization promotes DNA double-strand break repair," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    14. Travis H. Stracker & Monica Morales & Suzana S. Couto & Hussein Hussein & John H. J. Petrini, 2007. "The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex," Nature, Nature, vol. 447(7141), pages 218-221, May.
    Full references (including those not matched with items on IDEAS)

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