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

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Nemoz, Clément | Ropars, Virginie | Frit, Philippe | Gontier, Amandine | Drevet, Pascal | Yu, Jinchao | Guérois, Raphaël | Pitois, Aurelien | Comte, Audrey | Delteil, Christine | Barboule, Nadia | Legrand, Pierre | Baconnais, Sonia | Yin, Yandong | Tadi, Satish | Barbet-Massin, Emeline | Berger, Imre | Le Cam, Eric | Modesti, Mauro | Rothenberg, Eli | Calsou, Patrick | Charbonnier, Jean-Baptiste

Edité par CCSD ; Nature Publishing Group -

International audience. 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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