title: Requirement for Parp-1 and DNA ligases 1 or 3 but not of Xrcc1 in chromosomal translocation formation by backup end joining.
abstract: In mammalian cells, ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) are repaired in all phases of the cell cycle predominantly by classical, DNA-PK-dependent nonhomologous end joining (D-NHEJ). Homologous recombination repair (HRR) is functional during the S- and G2-phases, when a sister chromatid becomes available. An error-prone, alternative form of end joining, operating as backup (B-NHEJ) functions robustly throughout the cell cycle and particularly in the G2-phase and is thought to backup predominantly D-NHEJ. Parp-1, DNA-ligases 1 (Lig1) and 3 (Lig3), and Xrcc1 are implicated in B-NHEJ. Chromosome and chromatid translocations are manifestations of erroneous DSB repair and are crucial culprits in malignant transformation and IR-induced cell lethality. We analyzed shifts in translocation formation deriving from defects in D-NHEJ or HRR in cells irradiated in the G2-phase and identify B-NHEJ as the main DSB repair pathway backing up both of these defects at the cost of a large increase in translocation formation. Our results identify Parp-1 and Lig1 and 3 as factors involved in translocation formation and show that Xrcc1 reinforces the function of Lig3 in the process without being required for it. Finally, we demonstrate intriguing connections between B-NHEJ and DNA end resection in translocation formation and show that, as for D-NHEJ and HRR, the function of B-NHEJ facilitates the recovery from the G2-checkpoint. These observations advance our understanding of chromosome aberration formation and have implications for the mechanism of action of Parp inhibitors.
authors.affiliation: Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, Germany.
authors.forename: Aashish
authors.initials: A
authors.lastname: Soni
authors.affiliation: Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Siemann
authors.affiliation: Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, Germany.
authors.forename: Martha
authors.initials: M
authors.lastname: Grabos
authors.affiliation: Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Murmann
authors.affiliation: Institute of Nuclear Technology and Radiation Protection, National Centre for Scientific Research ''Demokritos,'' Aghia Paraskevi Attikis, 15310 Athens, Greece.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: Pantelias
authors.affiliation: Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, 45122 Essen, Germany Georg.Iliakis@uk-essen.de.
authors.forename: George
authors.initials: G
authors.lastname: Iliakis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D011839:Radiation, Ionizing; D059767:Recombinational DNA Repair; D014178:Translocation, Genetic; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins
chemical_list: D004268:DNA-Binding Proteins; C000607892:LIG1 protein, human; C000607894:Lig1 protein, mouse; D000075223:Poly-ADP-Ribose Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D029867:Xenopus Proteins; C000619352:Xrcc1 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human; C000618818:Lig3 protein, mouse
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