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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Vydáno v:	Nature structural & molecular biology Ročník 25; číslo 10; s. 971 - 980
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Nature Publishing Group 01.10.2018
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1545-9993 1545-9985 1545-9985
DOI:	10.1038/s41594-018-0133-6