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

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 alpha/beta domain. The X-KBM occupies an internal pocket formed by an unprecedented large outward rotation of the Ku80 alpha/beta 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.
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https://hal-amu.archives-ouvertes.fr/hal-02143568
Contributor : Ghislain Bidaut <>
Submitted on : Wednesday, May 29, 2019 - 2:48:09 PM
Last modification on : Tuesday, October 20, 2020 - 9:18:19 AM

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Clément Nemoz, Virginie Ropars, Philippe Frit, Amandine Gontier, Pascal Drevet, et al.. XLF and APLF bind Ku80 at two remote sites to ensure DNA repair by non-homologous end joining. Nature Structural and Molecular Biology, Nature Publishing Group, 2018, 25 (10), pp.971+. ⟨10.1038/s41594-018-0133-6⟩. ⟨hal-02143568⟩

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