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.

An engineered cell line lacking OGG1 and MUTYH glycosylases implicates the accumulation of genomic 8-oxoguanine as the basis for paraquat mutagenicity

“…It has been previously shown that cells deficient in both Ogg1 and Mutyh have a higher burden of 8OG in their genome, which is consistent with the role of Ogg1 and Mutyh in preventing 8OG formation and mutagenesis [3, 9, 10, 45, 46]. The levels of 8OG we found in our model are also comparable with other published data [15, 41, 47]. We expected to see higher levels of 8OG in DKO cells for all concentrations of PQ.…”

“…Our finding extends those of a previous study that showed the co-depleted cells (FEN1-BRCA1 and XRCC1-BRCA1) had lower levels of 8OG when compared to BRCA1/FEN1/XRCC1 single depleted cells [15]. Cells deficient in mechanistically distinct DNA repair pathways are pushed into a high oxidative stress environment as a survival mechanism called an “adaptive response,” which has been seen in cancer cells.…”

“…The levels of 8OG were used as a marker of oxidative stress in DNA repair-proficient cells (AS52 WT) [15]. As expected, our data showed significant differences in the 8OG basal levels between WT and DKO cells.…”

“…Both pathways generate single-strand breaks (SSBs) in DNA as repair intermediates. If the level of lesions is high, or if the repair is happening concurrent with replication, much more lethal double-strand breaks (DSBs) can occur [13–15]. Therefore, when the capacity to repair SSB is exceeded, or is compromised, the survival of the cell depends on its ability to repair DSBs using either homologous recombination (HR) or non-homologous end-joining (NHEJ) [15, 16].…”

Cardiovascular risk of BRCA1/2 mutation carriers: A review

“…As BRCA genes play an important role in DNA damage repair, they may also interfere with the pathophysiology of atherosclerosis. This hypothesis is supported by the finding that BRCA1/2 deficient cells are more sensitive to oxidative stress [19,20]. In addition, BRCA1 may protect endothelial cells against apoptosis not only by DNA damage repair, but also by down regulating ROS production [21,22].…”