title: Control of alternative end joining by the chromatin remodeler p400 ATPase.
abstract: Repair of DNA double-strand breaks occurs in a chromatin context that needs to be modified and remodeled to allow suitable access to the different DNA repair machineries. Of particular importance for the maintenance of genetic stability is the tight control of error-prone pathways, such as the alternative End Joining pathway. Here, we show that the chromatin remodeler p400 ATPase is a brake to the use of alternative End Joining. Using specific intracellular reporter susbstrates we observed that p400 depletion increases the frequency of alternative End Joining events, and generates large deletions following repair of double-strand breaks. This increase of alternative End Joining events is largely dependent on CtIP-mediated resection, indicating that it is probably related to the role of p400 in late steps of homologous recombination. Moreover, p400 depletion leads to the recruitment of poly(ADP) ribose polymerase (PARP) and DNA ligase 3 at DNA double-strand breaks, driving to selective killing by PARP inhibitors. All together these results show that p400 acts as a brake to prevent alternative End Joining-dependent genetic instability and underline its potential value as a clinical marker.
authors.affiliation: Université de Toulouse, UPS, LBCMCP, F-31062 Toulouse, France CNRS UMR5088, LBCMCP, F-31062 Toulouse, France.
authors.forename: Gemael-Cedrick
authors.initials: GC
authors.lastname: Taty-Taty
authors.affiliation: Université de Toulouse, UPS, LBCMCP, F-31062 Toulouse, France CNRS UMR5088, LBCMCP, F-31062 Toulouse, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chailleux
authors.affiliation: Université de Toulouse, UPS, LBCMCP, F-31062 Toulouse, France CNRS UMR5088, LBCMCP, F-31062 Toulouse, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Quaranta
authors.affiliation: Université Paris Sud, CNRS UMR8200, IGR, Villejuif, France.
authors.forename: Ayeong
authors.initials: A
authors.lastname: So
authors.affiliation: Université Paris Sud, CNRS UMR8200, IGR, Villejuif, France.
authors.forename: Josée
authors.initials: J
authors.lastname: Guirouilh-Barbat
authors.affiliation: Université Paris Sud, CNRS UMR8200, IGR, Villejuif, France.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Lopez
authors.affiliation: CEA DSV, UMR 967 CEA-INSERM-Université Paris Diderot-Université Paris Sud, Fontenay aux roses, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Bertrand
authors.affiliation: Université de Toulouse, UPS, LBCMCP, F-31062 Toulouse, France CNRS UMR5088, LBCMCP, F-31062 Toulouse, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Trouche
authors.affiliation: Université de Toulouse, UPS, LBCMCP, F-31062 Toulouse, France CNRS UMR5088, LBCMCP, F-31062 Toulouse, France yvan.canitrot@univ-tlse3.fr.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Canitrot
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; C498558:EP400 protein, human