BRCA2 affects the efficiency of DNA double‑strand break repair in response to N‑nitroso compounds with differing carcinogenic potentials

Zhao,Wen‑Ting; Wang,Yu‑Tian; Huang,Zhao‑Wei; Fang,Jing

doi:10.3892/ol.2013.1269

BRCA2 affects the efficiency of DNA double‑strand break repair in response to N‑nitroso compounds with differing carcinogenic potentials

Authors:
- Wen‑Ting Zhao
- Yu‑Tian Wang
- Zhao‑Wei Huang
- Jing Fang
View Affiliations

Affiliations: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, Shanghai 200031, P.R. China, Department of Gastroenterology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
Published online on: March 22, 2013 https://doi.org/10.3892/ol.2013.1269
Pages: 1948-1954

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Wooster R, Bignell G, Lancaster J, et al: Identification of the breast cancer susceptibility gene BRCA2. Nature. 378:789–792. 1995. View Article : Google Scholar : PubMed/NCBI
2	Tavtigian SV, Simard J, Rommens J, et al: The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 12:333–337. 1996. View Article : Google Scholar : PubMed/NCBI
3	Jakubowska A, Nej K, Huzarski T, Scott RJ and Lubiński J: BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br J Cancer. 87:888–891. 2002. View Article : Google Scholar : PubMed/NCBI
4	Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 108:171–182. 2002. View Article : Google Scholar : PubMed/NCBI
5	Liede A, Karlan BY and Narod SA: Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 22:735–742. 2004. View Article : Google Scholar : PubMed/NCBI
6	Patel KJ, Yu VP, Lee H, et al: Involvement of Brca2 in DNA repair. Mol Cell. 1:347–357. 1998. View Article : Google Scholar : PubMed/NCBI
7	Moynahan ME, Pierce AJ and Jasin M: BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 7:263–272. 2001. View Article : Google Scholar : PubMed/NCBI
8	O’Donovan PJ and Livingston DM: BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis. 31:961–967. 2010.PubMed/NCBI
9	Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 434:913–917. 2005. View Article : Google Scholar : PubMed/NCBI
10	Wang W and Figg WD: Secondary BRCA1 and BRCA2 alterations and acquired chemoresistance. Cancer Biol Ther. 7:1004–1005. 2008. View Article : Google Scholar : PubMed/NCBI
11	Thompson LH and Schild D: Homologous recombinational repair of DNA ensures mammalian chromosome stability. Mutat Res. 477:131–153. 2001. View Article : Google Scholar : PubMed/NCBI
12	Pellegrini L and Venkitaraman A: Emerging functions of BRCA2 in DNA recombination. Trends Biochem Sci. 29:310–316. 2004. View Article : Google Scholar : PubMed/NCBI
13	Shivji MK and Venkitaraman AR: DNA recombination, chromosomal stability and carcinogenesis: insights into the role of BRCA2. DNA Repair (Amst). 3:835–843. 2004. View Article : Google Scholar : PubMed/NCBI
14	Ohnishi T, Mori E and Takahashi A: DNA double-strand breaks: their production, recognition, and repair in eukaryotes. Mutat Res. 669:8–12. 2009. View Article : Google Scholar : PubMed/NCBI
15	Davies AA, Masson JY, McIlwraith MJ, et al: Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 7:273–282. 2001. View Article : Google Scholar : PubMed/NCBI
16	Foster ER and Downs JA: Histone H2A phosphorylation in DNA double-strand break repair. FEBS J. 272:3231–3240. 2005. View Article : Google Scholar : PubMed/NCBI
17	Esashi F, Galkin VE, Yu X, et al: Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nat Struct Mol Biol. 14:468–474. 2007. View Article : Google Scholar : PubMed/NCBI
18	Rogakou EP, Pilch DR, Orr AH, Ivanova VS and Bonner WM: DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 273:5858–5868. 1998. View Article : Google Scholar : PubMed/NCBI
19	van Attikum H, Fritsch O, Hohn B and Gasser SM: Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair. Cell. 119:777–788. 2004.PubMed/NCBI
20	Pellegrini L, Yu DS, Lo T, et al: Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature. 420:287–293. 2002. View Article : Google Scholar : PubMed/NCBI
21	Powell SN and Kachnic LA: Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. 22:5784–5791. 2003. View Article : Google Scholar : PubMed/NCBI
22	Filho PJ, Rios A, Valcárcel M and Caramao EB: Development of a new method for the determination of nitrosamines by micellar electrokinetic capillary chromatography. Water Res. 37:3837–3842. 2003. View Article : Google Scholar : PubMed/NCBI
23	Brambilla G and Martelli A: Genotoxic and carcinogenic risk to humans of drug-nitrite interaction products. Mutat Res. 635:17–52. 2007. View Article : Google Scholar : PubMed/NCBI
24	Hecht SS: Approaches to cancer prevention based on an understanding of N-nitrosamine carcinogenesis. Proc Soc Exp Biol Med. 216:181–191. 1997. View Article : Google Scholar : PubMed/NCBI
25	Williams GM, Iatropoulos MJ, Jeffrey AM, Luo FQ, Wang CX and Pittman B: Diethylnitrosamine exposure-responses for DNA ethylation, hepatocellular proliferation, and initiation of carcino-genesis in rat liver display non-linearities and thresholds. Arch Toxicol. 73:394–402. 1999. View Article : Google Scholar
26	Pinto LF, Moraes E, Albano R, et al: Rat oesophageal cytochrome P450 (CYP) monooxygenase system: comparison to the liver and relevance in N-nitrosodiethylamine carcinogenesis. Carcinogenesis. 22:1877–1883. 2001. View Article : Google Scholar
27	Visoni S, Lang M and Ribeiro Pinto LF: Hamster exhibits major differences in organ-specific metabolism of the esophageal carcinogen N-nitrosodiethylamine. Toxicol Lett. 183:90–94. 2008.PubMed/NCBI
28	International Agency for Research on Cancer (IARC): Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum. Suppl 7:1–440. 1987.PubMed/NCBI
29	International Agency for Research on Cancer (IARC): Some N-Nitroso Compounds. IARC Monogr Eval Carcinog Risks Hum. 17:1–365. 1978.
30	International Agency for Research on Cancer (IARC): Tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamines. IARC Working Group Lyon, 23–30 October 1984. IARC Monogr Eval Carcinog Risk Chem Hum. 37:1–268. 1985.PubMed/NCBI
31	Bradley MO, Dysart G, Fitzsimmons K, Harbach P, Lewin J and Wolf G: Measurements by filter elution of DNA single- and double-strand breaks in rat hepatocytes: effects of nitrosamines and gamma-irradiation. Cancer Res. 42:2592–2597. 1982.PubMed/NCBI
32	Loeppky RN, Ye Q, Goelzer P and Chen Y: DNA adducts from N-nitrosodiethanolamine and related beta-oxidized nitrosamines in vivo: (32)P-postlabeling methods for glyoxal- and O(6)-hydroxyethyldeoxyguanosine adducts. Chem Res Toxicol. 15:470–482. 2002. View Article : Google Scholar
33	Wiltshire T, Senft J, Wang Y, et al: BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven. Mol Pharmacol. 71:1051–1060. 2007. View Article : Google Scholar : PubMed/NCBI
34	Wang Y, Wiltshire T, Senft J, et al: Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven. Mol Cancer Ther. 5:3153–3161. 2006. View Article : Google Scholar : PubMed/NCBI
35	Fillingham J, Keogh MC and Krogan NJ: GammaH2AX and its role in DNA double-strand break repair. Biochem Cell Biol. 84:568–577. 2006.PubMed/NCBI
36	Dickey JS, Redon CE, Nakamura AJ, et al: H2AX: functional roles and potential applications. Chromosoma. 118:683–692. 2009. View Article : Google Scholar : PubMed/NCBI
37	Phillips ER and McKinnon PJ: DNA double-strand break repair and development. Oncogene. 26:7799–7808. 2007. View Article : Google Scholar : PubMed/NCBI
38	Hefferin ML and Tomkinson AE: Mechanism of DNA double-strand break repair by non-homologous end joining. DNA Repair (Amst). 4:639–648. 2005. View Article : Google Scholar : PubMed/NCBI
39	Schoenfeld AR, Apgar S, Dolios G, Wang R and Aaronson SA: BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol Cell Biol. 24:7444–7455. 2004. View Article : Google Scholar : PubMed/NCBI
40	Philip S, Swaminathan S, Kuznetsov SG, et al: Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. Cancer Res. 68:9973–9981. 2008. View Article : Google Scholar : PubMed/NCBI