title: PARP3 affects the relative contribution of homologous recombination and nonhomologous end-joining pathways.
abstract: The repair of toxic double-strand breaks (DSB) is critical for the maintenance of genome integrity. The major mechanisms that cope with DSB are: homologous recombination (HR) and classical or alternative nonhomologous end joining (C-NHEJ versus A-EJ). Because these pathways compete for the repair of DSB, the choice of the appropriate repair pathway is pivotal. Among the mechanisms that influence this choice, deoxyribonucleic acid (DNA) end resection plays a critical role by driving cells to HR, while accurate C-NHEJ is suppressed. Furthermore, end resection promotes error-prone A-EJ. Increasing evidence define Poly(ADP-ribose) polymerase 3 (PARP3, also known as ARTD3) as an important player in cellular response to DSB. In this work, we reveal a specific feature of PARP3 that together with Ku80 limits DNA end resection and thereby helps in making the choice between HR and NHEJ pathways. PARP3 interacts with and PARylates Ku70/Ku80. The depletion of PARP3 impairs the recruitment of YFP-Ku80 to laser-induced DNA damage sites and induces an imbalance between BRCA1 and 53BP1. Both events result in compromised accurate C-NHEJ and a concomitant increase in DNA end resection. Nevertheless, HR is significantly reduced upon PARP3 silencing while the enhanced end resection causes mutagenic deletions during A-EJ. As a result, the absence of PARP3 confers hypersensitivity to anti-tumoral drugs generating DSB.
authors.affiliation: Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, Equipe labellisée Ligue Nationale Contre Le Cancer, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, BP10413, 67412 Illkirch, France francoise.dantzer@unistra.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Beck
authors.affiliation: Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, Equipe labellisée Ligue Nationale Contre Le Cancer, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, BP10413, 67412 Illkirch, France francoise.dantzer@unistra.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Boehler
authors.affiliation: Université Paris Sud, CNRS UMR8200, Institut de Cancérologie Gustave-Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Josée
authors.initials: J
authors.lastname: Guirouilh Barbat
authors.affiliation: Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, Equipe labellisée Ligue Nationale Contre Le Cancer, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, BP10413, 67412 Illkirch, France.
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Bonnet
authors.affiliation: Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, Equipe labellisée Ligue Nationale Contre Le Cancer, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, BP10413, 67412 Illkirch, France.
authors.forename: Giuditta
authors.initials: G
authors.lastname: Illuzzi
authors.affiliation: Laboratoire de biophotonique et pharmacologie, UMR 7213, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Faculté de pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Ronde
authors.affiliation: CEA DSV iRCM SCSR, Laboratoire de radiopathologie, INSERM, U967, 92265 Fontenay-aux-Roses, France.
authors.forename: Laurent R
authors.initials: LR
authors.lastname: Gauthier
authors.affiliation: Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, Equipe labellisée Ligue Nationale Contre Le Cancer, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, BP10413, 67412 Illkirch, France.
authors.forename: Najat
authors.initials: N
authors.lastname: Magroun
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Anbazhagan
authors.initials: A
authors.lastname: Rajendran
authors.affiliation: Université Paris Sud, CNRS UMR8200, Institut de Cancérologie Gustave-Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Lopez
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
authors.affiliation: CEA DSV iRCM SCSR, Laboratoire de radiopathologie, INSERM, U967, 92265 Fontenay-aux-Roses, France.
authors.forename: François D
authors.initials: FD
authors.lastname: Boussin
authors.affiliation: Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, Equipe labellisée Ligue Nationale Contre Le Cancer, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, BP10413, 67412 Illkirch, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Schreiber
authors.affiliation: Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire d'Excellence Medalis, Equipe labellisée Ligue Nationale Contre Le Cancer, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, 300 bld. S. Brant, BP10413, 67412 Illkirch, France francoise.dantzer@unistra.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dantzer
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072200:Ku Autoantigen; D009687:Nuclear Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059767:Recombinational DNA Repair; D051716:Replication Protein A / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D051716:Replication Protein A; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D005047:Etoposide; C480979:PARP3 protein, human; D011065:Poly(ADP-ribose) Polymerases; C516794:RPA2 protein, human; D004265:DNA Helicases; C103532:RAD54L protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen