Regulation of DNA Repair pathway choice in S/G2 by the NHEJ inhibitor CYREN

Classical non-homologous end joining 1 (cNHEJ) and homologous recombination 2 (HR) compete for the repair of double stranded breaks of DNA during the cell cycle. HR is inhibited in G1 phase of the cell cycle, but both pathways are active in S and G2 phases. Why cNHEJ does not always outcompete HR in S and G2 phases has been unclear. Here we show that CYREN is a cell cycle specific inhibitor of cNHEJ. CYREN suppression allows cNHEJ at telomeres and intrachromosomal breaks during S and G2 phases, while cells lacking CYREN accumulate chromosomal aberrations upon damage induction, specifically outside 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 inhibitor of cNHEJ, thereby promoting error free repair by HR in cell cycle phases where sister chromatids are present.