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XLF and APLF bind Ku80 at two remote sites to ensure DNA repair by non-homologous end joining

Research output: Contribution to journalArticle

  • Clement Nemoz
  • Virginie Ropars
  • Philippe Frit
  • Amandine Gontier
  • Pascal Drevet
  • Jinchao Yu
  • Raphaël Guerois
  • Aurelien Pitois
  • Audrey Comte
  • Christine Delteil
  • Nadia Barboule
  • Pierre Legrand
  • Sonia Baconnais
  • Yandong Yin
  • Satish Tadi
  • Emeline Barbet-Massin
  • Imre Berger
  • Eric Le Cam
  • Mauro Modesti
  • Eli Rothenberg
  • Patrick Calsou
  • Jean Baptiste Charbonnier
Original languageEnglish
Pages (from-to)971-980
Number of pages10
JournalNature Structural and Molecular Biology
Volume25
Issue number10
DOIs
DateAccepted/In press - 21 Aug 2018
DatePublished (current) - 5 Oct 2018

Abstract

The Ku70–Ku80 (Ku) heterodimer binds rapidly and tightly to the ends of DNA double-strand breaks and recruits factors of the non-homologous end-joining (NHEJ) repair pathway through molecular interactions that remain unclear. We have determined crystal structures of the Ku-binding motifs (KBM) of the NHEJ proteins APLF (A-KBM) and XLF (X-KBM) bound to a Ku–DNA complex. The two KBM motifs bind remote sites of the Ku80 α/β domain. The X-KBM occupies an internal pocket formed by an unprecedented large outward rotation of the Ku80 α/β domain. We observe independent recruitment of the APLF-interacting protein XRCC4 and of XLF to laser-irradiated sites via binding of A- and X-KBMs, respectively, to Ku80. Finally, we show that mutation of the X-KBM and A-KBM binding sites in Ku80 compromises both the efficiency and accuracy of end joining and cellular radiosensitivity. A- and X-KBMs may represent two initial anchor points to build the intricate interaction network required for NHEJ.

    Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

    Research areas

  • Synthetic Biology

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://www.nature.com/articles/s41594-018-0133-6#Abs1. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 5 MB, PDF document

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