Interactome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway

Nat Commun. 2015 Feb 11:6:6233. doi: 10.1038/ncomms7233.

Abstract

Non-homologous end joining (NHEJ) is a major pathway to repair DNA double-strand breaks (DSBs), which can display different types of broken ends. However, it is unclear how NHEJ factors organize to repair diverse types of DNA breaks. Here, through systematic analysis of the human NHEJ factor interactome, we identify PAXX as a direct interactor of Ku. The crystal structure of PAXX is similar to those of XRCC4 and XLF. Importantly, PAXX-deficient cells are sensitive to DSB-causing agents. Moreover, epistasis analysis demonstrates that PAXX functions together with XLF in response to ionizing radiation-induced complex DSBs, whereas they function redundantly in response to Topo2 inhibitor-induced simple DSBs. Consistently, PAXX and XLF coordinately promote the ligation of complex but not simple DNA ends in vitro. Altogether, our data identify PAXX as a new NHEJ factor and provide insight regarding the organization of NHEJ factors responding to diverse types of DSB ends.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Nuclear / metabolism
  • Cell Line
  • Chickens
  • Crystallography, X-Ray
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair*
  • DNA Ligase ATP
  • DNA Ligases / metabolism
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Ku Autoantigen
  • Mass Spectrometry
  • Models, Biological
  • Models, Molecular
  • Protein Binding
  • Protein Interaction Mapping*
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid*
  • Structural Homology, Protein

Substances

  • Antigens, Nuclear
  • DNA-Binding Proteins
  • NHEJ1 protein, human
  • PAXX protein, human
  • XRCC4 protein, human
  • Xrcc6 protein, human
  • Ku Autoantigen
  • DNA Ligases
  • DNA Repair Enzymes
  • DNA Ligase ATP

Associated data

  • PDB/4WJA