Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN

Nature. 2017 Sep 20;549(7673):548-552. doi: 10.1038/nature24023.


Classical non-homologous end joining (cNHEJ) and homologous recombination compete for the repair of double-stranded DNA breaks during the cell cycle. Homologous recombination is inhibited during the G1 phase of the cell cycle, but both pathways are active in the S and G2 phases. However, it is unclear why cNHEJ does not always outcompete homologous recombination during the S and G2 phases. Here we show that CYREN (cell cycle regulator of NHEJ) is a cell-cycle-specific inhibitor of cNHEJ. Suppression of CYREN allows cNHEJ to occur at telomeres and intrachromosomal breaks during the S and G2 phases, and cells lacking CYREN accumulate chromosomal aberrations upon damage induction, specifically outside the G1 phase. CYREN acts by binding to the Ku70/80 heterodimer and preferentially inhibits cNHEJ at breaks with overhangs by protecting them. We therefore propose that CYREN is a direct cell-cycle-dependent inhibitor of cNHEJ that promotes error-free repair by homologous recombination during cell cycle phases when sister chromatids are present.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromatids / genetics
  • Chromatids / metabolism
  • Chromosome Aberrations
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair / genetics
  • DNA End-Joining Repair / physiology*
  • G1 Phase
  • G2 Phase*
  • Humans
  • Ku Autoantigen / chemistry
  • Ku Autoantigen / metabolism
  • Protein Binding
  • Recombinational DNA Repair / genetics
  • Recombinational DNA Repair / physiology*
  • S Phase*
  • Telomere / genetics
  • Telomere / metabolism


  • Ku Autoantigen