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

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 th...

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Bibliographic Details
Published in:Nature structural & molecular biology Vol. 25; no. 10; pp. 971 - 980
Main Authors: Nemoz, Clement, Ropars, Virginie, Frit, Philippe, Gontier, Amandine, Drevet, Pascal, Yu, Jinchao, Guerois, 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
Format: Journal Article
Language:English
Published: United States Nature Publishing Group 01.10.2018
Subjects:
Binding sites
Conserved Sequence
Crystal structure
Crystallography, X-Ray
Deoxyribonucleic acid
DNA
DNA damage
DNA End-Joining Repair
DNA repair
DNA Repair Enzymes - chemistry
DNA Repair Enzymes - metabolism
DNA Repair Enzymes - physiology
DNA-(Apurinic or Apyrimidinic Site) Lyase - chemistry
DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism
DNA-(Apurinic or Apyrimidinic Site) Lyase - physiology
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - metabolism
DNA-Binding Proteins - physiology
Homology
Humans
Ku Autoantigen - chemistry
Ku Autoantigen - metabolism
Ku Autoantigen - physiology
Models, Molecular
Molecular interactions
Mutation
Non-homologous end joining
Poly-ADP-Ribose Binding Proteins - chemistry
Poly-ADP-Ribose Binding Proteins - metabolism
Poly-ADP-Ribose Binding Proteins - physiology
Protein Domains
Proteins
Radiosensitivity
Repair
ISSN:1545-9993, 1545-9985, 1545-9985
Online Access:Get full text
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Summary: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.
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ISSN:1545-9993
1545-9985
1545-9985
DOI:10.1038/s41594-018-0133-6