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

Clément Nemoz; Virginie Ropars; Philippe Frit; Amandine Gontier; Pascal Drevet; Jinchao Yu; Raphaël Guérois; 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

doi:10.1038/s41594-018-0133-6

Journal articles

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

Clément Nemoz ^{1, 2} Virginie Ropars ^{1, 2} Philippe Frit ³ Amandine Gontier ^{1, 2} Pascal Drevet ^{1, 2} Jinchao Yu ^{1, 4} Raphaël Guérois ^{1, 4} Aurelien Pitois Audrey Comte ⁵ Christine Delteil ³ Nadia Barboule ⁶ Pierre Legrand ⁷ Sonia Baconnais ⁸ Yandong Yin Satish Tadi ⁵ Emeline Barbet-Massin ⁹ Imre Berger ¹⁰ Eric Le Cam ⁸ Mauro Modesti ⁵ Eli Rothenberg Patrick Calsou ³ Jean-Baptiste Charbonnier ^{1, 2}

1 I2BC - Institut de Biologie Intégrative de la Cellule

2 INTGEN - Enveloppe Nucléaire, Télomères et Réparation de l’ADN

B3S - Département Biochimie, Biophysique et Biologie Structurale

3 IPBS - Institut de pharmacologie et de biologie structurale

4 AMIG - Assemblage moléculaire et intégrité du génome

B3S - Département Biochimie, Biophysique et Biologie Structurale

5 CRCM - Centre de Recherche en Cancérologie de Marseille

6 LBCMCP - Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération

7 SSOLEIL - Synchrotron SOLEIL

8 UMR8126 - Signalisation, noyaux et innovations en cancérologie

9 Biological Solid-State NMR Methods - Méthodes de RMN à l'état solide en biologie

ISA - Institut des Sciences Analytiques

10 EMBL - European Molecular Biology Laboratory [Grenoble]

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

Life Sciences [q-bio] / Biochemistry, Molecular Biology / Molecular biology

Life Sciences [q-bio] / Biochemistry, Molecular Biology / Structural Biology [q-bio.BM]

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https://hal-amu.archives-ouvertes.fr/hal-02143568
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Submitted on : Wednesday, May 29, 2019 - 2:48:09 PM
Last modification on : Thursday, July 8, 2021 - 3:52:12 AM

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

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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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