title: BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells.
abstract: Arsenic exposure constitutes one of the most widespread environmental carcinogens, and is associated with increased risk of many different types of cancers. Here we report that arsenite (As[III]) can induce both replication-dependent DNA double-strand breaks (DSB) and homologous recombination (HR) at doses as low as 5 microM (0.65 mg/l), which are within the typical doses often found in drinking water in contaminated areas. We show that the production of DSBs is dependent on active replication and is likely to be the result of conversion of a DNA single-strand break (SSB) into a toxic DSB when encountered by a replication fork. We demonstrate that HR is required for the repair of these breaks and show that a functional HR pathway protects against As[III]-induced cytotoxicity. In addition, BRCA2-deficient cells are sensitive to As[III] and we suggest that As[III] could be exploited as a therapy for HR-deficient tumours such as BRCA1 and BRCA2 mutated breast and ovarian cancers.
authors: The Institute for Cancer Studies, University of Sheffield, Sheffield S10 2RX, UK.
authors: Songmin
authors: S
authors: Ying
authors: Katie
authors: K
authors: Myers
authors: Sarah
authors: S
authors: Bottomley
authors: Thomas
authors: T
authors: Helleday
authors: Helen E
authors: HE
authors: Bryant
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D024682:BRCA2 Protein / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004261:DNA Replication; D011995:Recombination, Genetic
chemical_list: D018053:Arsenites; D024682:BRCA2 Protein; D002273:Carcinogens; C015001:arsenite