Journal
NATURE
Volume 549, Issue 7673, Pages 548-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature24023
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Funding
- Human Frontiers Science Program [LT000284/2013]
- Paul F. Glenn Center for Biology of Aging Research
- Larry Hillblom Foundation
- Wellcome Trust
- Francis Crick Institute (Cancer Research UK)
- UK Medical Research Council [FC0010048]
- Wellcome Trust [FC0010048]
- NIH [R01 GM102491, R01GM087476, R01CA174942]
- NCI Cancer Center [P30 (CA014195)]
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
- Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals
- Salk Institute Cancer Center [P30CA014195]
- Fritz B. Burns Foundation
- Emerald Foundation
- Donald and Darlene Shiley Chair
- Highland Street Foundation
- Cancer Research UK [11581] Funding Source: researchfish
- The Francis Crick Institute [10267, 742437-TelMetab] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10048] Funding Source: researchfish
- Wellcome Trust [104558/Z/14/Z] Funding Source: researchfish
- Wellcome Trust [104558/Z/14/Z] Funding Source: Wellcome Trust
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Classical non-homologous end joining(1) (cNHEJ) and homologous recombination(2) 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.
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