title: Common and unique genetic interactions of the poly(ADP-ribose) polymerases PARP1 and PARP2 with DNA double-strand break repair pathways.
abstract: In mammalian cells, chromatin poly(ADP-ribos)ylation (PARylation) at sites of DNA Double-Strand Breaks (DSBs) is mediated by two highly related enzymes, PARP1 and PARP2. However, enzyme-specific genetic interactions with other DSB repair factors remain largely undefined. In this context, it was previously shown that mice lacking PARP1 and H2AX, a histone variant that promotes DSB repair throughout the cell cycle, or the core nonhomologous end-joining (NHEJ) factor Ku80 are not viable, while mice lacking PARP1 and the noncore NHEJ factor DNA-PKcs are severely growth retarded and markedly lymphoma-prone. Here, we have examined the requirement for PARP2 in these backgrounds. We find that, like PARP1, PARP2 is essential for viability in mice lacking H2AX. Moreover, treatment of H2AX-deficient primary fibroblasts or B lymphocytes with PARP inhibitors leads to activation of the G2/M checkpoint and accumulation of chromatid-type breaks in a lineage- and gene-dose dependent manner. In marked contrast to PARP1, loss of PARP2 does not result in additional phenotypes in growth, development or tumorigenesis in mice lacking either Ku80 or DNA-PKcs. Altogether these findings highlight specific nonoverlapping functions of PARP1 and PARP2 at H2AX-deficient chromatin during replicative phases of the cell cycle and uncover a unique requirement for PARP1 in NHEJ-deficient cells.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences; Johns Hopkins School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Rajib
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences; Johns Hopkins School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Sanchita
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences; Johns Hopkins School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Johan
authors.initials: J
authors.lastname: Kamyab
authors.affiliation: Biotechnology and Cell Signaling Unit, University of Strasbourg, 67412 Illkirch, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Danzter
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences; Johns Hopkins School of Medicine, Baltimore, MD 21287, United States.
authors.forename: Sonia
authors.initials: S
authors.lastname: Franco
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059565:G2 Phase Cell Cycle Checkpoints; D006657:Histones / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D000072200:Ku Autoantigen / Q000172:deficiency / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics*; D061251:Primary Cell Culture; D013953:Thymus Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D001562:Benzimidazoles; D002843:Chromatin; D004247:DNA; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D006657:Histones; D000072200:Ku Autoantigen; D009687:Nuclear Proteins; D010793:Phthalazines; D010879:Piperazines; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C521013:veliparib; C499321:Parp1 protein, mouse; C459820:Parp2 protein, mouse; C497264:Prkdc protein, mouse; C000606512:Xrcc5 protein, mouse; C531550:olaparib; C475961:gamma-H2AX protein, mouse
keywords: DNA-PKcs; Double-strand breaks; H2AX; Ku80; PARP1; PARP2