BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging1

Abstract

Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.

Antimüllerian hormone levels are lower in BRCA2 mutation carriers

“…Furthermore, low AMH levels were observed among BRCA2 carriers throughout the reproductive lifespan, a finding that challenges the current hypothesis that the reproductive impact of BRCA2 mutations only occurs among women of advanced reproductive age. (31) Interestingly, we also observed lower AMH values in BRCA negative women, but only when the cohort was restricted to young, regularly menstruating women. We did not observe differences in AMH among BRCA1 carriers compared to controls.…”

“…A subgroup analysis was performed in regularly menstruating women less than 40 years old to limit impact of undiagnosed PCOS and because it has been suggested that the impact of BRCA mutations on fertility occurs only among late reproductive age women. (31) We opted to include regularly-menstruating women taking HC in this subgroup analysis because women with diminished ovarian reserve may use HC for cycle control, and exclusion of HC users could potentially result in exclusion of those with the outcome of interest. Additional subgroup analyses were performed for women without a history of infertility, for women whose BRCA mutation was verified, and for women whose body mass index (BMI) was available.…”

Do DNA Double-Strand Breaks Drive Aging?

“…This decreased ATM function was suggested to underlie the observed decline in p53 response to ionizing radiation in old animals (Feng et al, 2007). Also, the increased level of persistent γH2AX foci in ovarian mouse and human primordial follicles mentioned above was found to be accompanied by a reduced expression level of genes involved in DSB processing, including ATM, MRE11, RAD51 and BRCA1, but not BRCA2 (Oktay et al, 2015; Titus et al, 2013), which may account for the decline of oocyte reserves in aging mammals.…”

Chemotherapy-Induced Damage to Ovary: Mechanisms and Clinical Impact

“…We showed in in vitro and human ovarian xenograft models that doxorubicin [8] and cyclophosphamide [16] induce DNA double-stranded DNA breaks in primordial follicles, which trigger the apoptotic process and death in most cases. Interestingly, we have also shown that the ATM-mediated pathway may be activated in response to this damage and may repair and rescue some primordial follicles in the face of chemotherapyinduced genomic insult [17]. Hence research from our laboratory suggests that alkylating agents and those in the topoisomerase inhibitor category (e.g., doxorubicin) are damaging to primordial follicle oocytes and produce permanent damage to ovarian reserve though some follicles may be able to survive due to their ability to repair DNA damage.…”