title: BRCA1 and BRCA2 protect against oxidative DNA damage converted into double-strand breaks during DNA replication.
abstract: BRCA1 and BRCA2 mutation carriers are predisposed to develop breast and ovarian cancers, but the reasons for this tissue specificity are unknown. Breast epithelial cells are known to contain elevated levels of oxidative DNA damage, triggered by hormonally driven growth and its effect on cell metabolism. BRCA1- or BRCA2-deficient cells were found to be more sensitive to oxidative stress, modeled by treatment with patho-physiologic concentrations of hydrogen peroxide. Hydrogen peroxide exposure leads to oxidative DNA damage induced DNA double strand breaks (DSB) in BRCA-deficient cells causing them to accumulate in S-phase. In addition, after hydrogen peroxide treatment, BRCA deficient cells showed impaired Rad51 foci which are dependent on an intact BRCA1-BRCA2 pathway. These DSB resulted in an increase in chromatid-type aberrations, which are characteristic for BRCA1 and BRCA2-deficient cells. The most common result of oxidative DNA damage induced processing of S-phase DSB is an interstitial chromatid deletion, but insertions and exchanges were also seen in BRCA deficient cells. Thus, BRCA1 and BRCA2 are essential for the repair of oxidative DNA damage repair intermediates that persist into S-phase and produce DSB. The implication is that oxidative stress plays a role in the etiology of hereditary breast cancer.
authors.affiliation: Department of Radiation Oncology and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Ram
authors.initials: R
authors.lastname: Fridlich
authors.affiliation: Department of Radiation Oncology and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Devi
authors.initials: D
authors.lastname: Annamalai
authors.affiliation: Department of Radiation Oncology and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Rohini
authors.initials: R
authors.lastname: Roy
authors.affiliation: Department of Radiation Oncology and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Giana
authors.initials: G
authors.lastname: Bernheim
authors.affiliation: Department of Radiation Oncology and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States. Electronic address: powells@mskcc.org.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002869:Chromosome Aberrations; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004261:DNA Replication; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D061986:MCF-7 Cells; D009154:Mutation; D018384:Oxidative Stress; D051135:Rad51 Recombinase / Q000378:metabolism; D016196:S Phase
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D006861:Hydrogen Peroxide; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: BRCA; Cancer; Chromosome aberrations; Homologous recombination; Oxidative stress
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