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

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

Author information

1
The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, California 92037, USA.
2
Dsb Repair Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.

Abstract

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.

PMID:
28959974
PMCID:
PMC5624508
DOI:
10.1038/nature24023
[Indexed for MEDLINE]
Free PMC Article

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