Journal
ONCOGENE
Volume 31, Issue 30, Pages 3495-3504Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.516
Keywords
DNA double-strand breaks; DNA repair; homologous recombination; genomic stability; ISceI
Funding
- AFHU
- United States Binational Science Foundation [2009286]
- Israel Cancer Association
- Israel Science Foundation [943/09]
- Israel Cancer Research Foundation
- Israel Ministry of Health [6007]
- European Union [IRG-206872, 238176]
- HU
- Israel Psychobiology Institute
- Lady Davies Fellowship program
- Edmond J Safra Foundation
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [2009286] Funding Source: National Science Foundation
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DNA double-strand breaks (DSBs), the most hazardous DNA lesions, may result in genomic instability, a hallmark of cancer cells. The main DSB repair pathways are non-homologous end joining (NHEJ) and homologous recombination (HR). In mammalian cells, NHEJ, which can lead to inaccurate repair, predominates. HR repair (HRR) is considered accurate and is restricted to S, G2 and M phases of the cell cycle. Despite its importance, many aspects regarding HRR remain unknown. Here, we developed a novel inducible on/off switch cell system that enables, for the first time, to induce a DSB in a rapid and reversible manner in human cells. By limiting the duration of DSB induction, we found that non-persistent endonuclease-induced DSBs are rarely repaired by HR, whereas persistent DSBs result in the published HRR frequencies (non-significant HR frequency versus frequency of similar to 10%, respectively). We demonstrate that these DSBs are repaired by an accurate repair mechanism, which is distinguished from HRR (most likely, error-free NHEJ). Notably, our data reveal that HRR frequencies of endonuclease-induced DSBs in human cells are >10-fold lower than what was previously estimated by prevailing methods, which resulted in recurrent DSB formation. Our findings suggest a role for HRR mainly in repairing challenging DSBs, in contrast to uncomplicated lesions that are frequently repaired by NHEJ. Preventing HR from repairing DSBs in the complex and repetitive human genome probably has an essential role in maintaining genomic stability. Oncogene (2012) 31, 3495-3504; doi:10.1038/onc.2011.516; published online 21 November 2011
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