BRCA1 and BRCA2 protect against oxidative DNA damage converted into double-strand breaks during DNA replication Journal Article


Authors: Fridlich, R.; Annamalai, D.; Roy, R.; Bernheim, G.; Powell, S. N.
Article 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. © 2015 .
Keywords: controlled study; human cell; dna replication; dna damage; homologous recombination; cell cycle s phase; breast cancer; cell growth; brca1 protein; brca2 protein; chromosomal instability; double stranded dna break; hydrogen peroxide; oxidative stress; chromosome aberrations; brca; cell metabolism; rad51 protein; cancer; human; female; priority journal; article; interstitial chromosome deletion
Journal Title: DNA Repair
Volume: 30
ISSN: 1568-7864
Publisher: Elsevier Inc.  
Date Published: 2015-06-01
Start Page: 11
End Page: 20
Language: English
DOI: 10.1016/j.dnarep.2015.03.002
PROVIDER: scopus
PUBMED: 25836596
PMCID: PMC4442488
DOI/URL:
Notes: Export Date: 4 May 2015 -- Source: Scopus
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  1. Simon Nicholas Powell
    332 Powell
  2. Rohini Roy
    4 Roy