Arnoult Nausica, Correia Adriana, Ma Jiao, Merlo Anna, Garcia-Gomez Sara, Maric Marija, Tognetti Marco, Benner Christopher W, Boulton Simon J, Saghatelian Alan, Karlseder Jan
The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, California 92037, USA.
Dsb Repair Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
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.
经典非同源末端连接（cNHEJ）和同源重组在细胞周期中竞争双链DNA断裂的修复。同源重组在细胞周期的G1期受到抑制，但这两种途径在S期和G2期均活跃。然而，尚不清楚为何在S期和G2期cNHEJ并不总是胜过同源重组。在此我们表明，CYREN（非同源末端连接的细胞周期调节因子）是cNHEJ的细胞周期特异性抑制剂。CYREN的抑制使得cNHEJ在S期和G2期能在端粒和染色体内断裂处发生，并且缺乏CYREN的细胞在损伤诱导后会积累染色体畸变，特别是在G1期之外。CYREN通过与Ku70/80异二聚体结合发挥作用，并通过保护有突出端的断裂优先抑制cNHEJ。因此，我们提出CYREN是cNHEJ直接的细胞周期依赖性抑制剂，在有姐妹染色单体存在的细胞周期阶段通过同源重组促进无差错修复。
