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DNA repair choice defines a common pathway for recruitment of chromatin regulators.

ABSTRACT: DNA double-strand break repair is essential for maintenance of genome stability. Recent work has implicated a host of chromatin regulators in the DNA-damage response, and although several functional roles have been defined, the mechanisms that control their recruitment to DNA lesions remain unclear. Here we find that efficient double-strand break recruitment of the INO80, SWR-C, NuA4, SWI/SNF and RSC enzymes is inhibited by the non-homologous end-joining machinery, and that their recruitment is controlled by early steps of homologous recombination. Strikingly, we find no significant role for H2A.X phosphorylation in the recruitment of chromatin regulators, but rather their recruitment coincides with reduced levels of H2A.X phosphorylation. Our work indicates that cell cycle position has a key role in DNA repair pathway choice and that recruitment of chromatin regulators is tightly coupled to homologous recombination.

SUBMITTER: Bennett G

PROVIDER: S-EPMC3731036 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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DNA repair choice defines a common pathway for recruitment of chromatin regulators.

Bennett Gwendolyn G Papamichos-Chronakis Manolis M Peterson Craig L CL

Nature communications 20130101

DNA double-strand break repair is essential for maintenance of genome stability. Recent work has implicated a host of chromatin regulators in the DNA-damage response, and although several functional roles have been defined, the mechanisms that control their recruitment to DNA lesions remain unclear. Here we find that efficient double-strand break recruitment of the INO80, SWR-C, NuA4, SWI/SNF and RSC enzymes is inhibited by the non-homologous end-joining machinery, and that their recruitment is ...[more]

PMID: 23811932

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Project description:In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1-Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers, dysregulates DSB repair, enhancing efficiency of likely mutagenic repair, and enabling radiation and cisplatin treatment resistance.

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DNA repair choice defines a common pathway for recruitment of chromatin regulators.

Publications

DNA repair choice defines a common pathway for recruitment of chromatin regulators.

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