10779/crick.12620429.v1 Nausica Arnoult Nausica Arnoult Adriana Correia Adriana Correia Jiao Ma Jiao Ma Anna Merlo Anna Merlo Sara Garcia-Gomez Sara Garcia-Gomez Marija Maric Marija Maric Marco Tognetti Marco Tognetti Christopher W Benner Christopher W Benner Simon J Boulton Simon J Boulton Alan Saghatelian Alan Saghatelian Jan Karlseder Jan Karlseder Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN The Francis Crick Institute 2020 Cell Line Chromatids Chromosome Aberrations DNA Breaks, Double-Stranded DNA End-Joining Repair G1 Phase G2 Phase Humans Ku Autoantigen Protein Binding Recombinational DNA Repair S Phase Telomere Boulton FC001048 General Science & Technology 2020-07-15 10:56:42 Journal contribution https://crick.figshare.com/articles/journal_contribution/Regulation_of_DNA_repair_pathway_choice_in_S_and_G2_phases_by_the_NHEJ_inhibitor_CYREN/12620429 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.