title: BRCA2 affects the efficiency of DNA double-strand break repair in response to N-nitroso compounds with differing carcinogenic potentials.
abstract: The tumor suppressor gene breast cancer susceptibility gene 2 (BRCA2) is frequently mutated or epigenetically repressed in human cancer and has a significant role in the homologous recombination (HR) of DNA double-strand breaks (DSBs). Although N-nitrosodiethylamine (NDEA), N-nitrosodiethanolamine (NDELA) and N-nitrosodipropylamine (NDPA) have similar chemical structures and are able to induce DNA damage, they have varying carcinogenic risks. We hypothesized that the DNA damage repair pathways that are induced by these N-nitroso compounds (NOCs) may differ and that this may contribute to the genotoxic-carcinogenic effect of the NOCs. The present study aimed to characterize the formation of DSBs by NDEA, NDELA and NDPA and also to investigate whether BRCA2 is involved in the DNA damage response. The NOCs were observed to time-dependently induce DSBs and the expression of γ-H2AX in gastric cancer SGC7901 cells. It was observed that the DNA damage induced by NDEA, the most potent carcinogen, was not repaired as efficiently as that caused by NDELA or NDPA. The expression of BRCA2 and RAD51 was demonstrated to be inhibited by NDEA treatment but upregulated by NDELA or NDPA treatment. Furthermore, the knock down of BRCA2 expression impaired the DNA damage repair induced by NDELA or NDPA. The cells with this knock down exhibited an increased sensitivity to NDELA or NDPA treatment, but not to NDEA. These findings suggest that a BRCA2-mediated pathway contributes to differential DSB repair and sensitivity in response to NOC exposure and that it may be associated with the genotoxic-carcinogenic potential of NOCs.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, Shanghai 200031;
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Zhao
authors.forename: Yu-Tian
authors.initials: YT
authors.lastname: Wang
authors.forename: Zhao-Wei
authors.initials: ZW
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
keywords: BRCA2; DNA damage repair; DNA double strand breaks; N-nitroso compounds