Requirement for Parp-1 and DNA ligases 1 or 3 but not of Xrcc1 in chromosomal translocation formation by backup end joining

Nucleic Acids Res. 2014 Jun;42(10):6380-92. doi: 10.1093/nar/gku298. Epub 2014 Apr 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cricetinae
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair*
  • DNA Ligase ATP
  • DNA Ligases / physiology*
  • DNA-Binding Proteins / physiology*
  • G2 Phase / genetics
  • G2 Phase / radiation effects
  • G2 Phase Cell Cycle Checkpoints
  • Humans
  • Mice
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / physiology*
  • Poly-ADP-Ribose Binding Proteins
  • Radiation, Ionizing
  • Recombinational DNA Repair
  • Translocation, Genetic*
  • X-ray Repair Cross Complementing Protein 1
  • Xenopus Proteins


  • DNA-Binding Proteins
  • LIG1 protein, human
  • Lig1 protein, mouse
  • Poly-ADP-Ribose Binding Proteins
  • X-ray Repair Cross Complementing Protein 1
  • XRCC1 protein, human
  • Xenopus Proteins
  • Xrcc1 protein, mouse
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • DNA Ligases
  • DNA Ligase ATP
  • DNA ligase III alpha protein, Xenopus
  • LIG3 protein, human
  • Lig3 protein, mouse