BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging

Abstract

Background: Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated (ATM)-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and ATM-mediated DNA DSB repair in ovarian aging.

Objective and rationale: Although there are several competing or complementary theories, given the growing evidence tying BRCA function and ATM-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality.

Search methods: We searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own.

Outcomes: Laboratory studies provided robust and reproducible evidence that BRCA1 function and ATM-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other ATM-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related ATM-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging.

Wider implications: The existing data suggest that the BRCA-related ATM-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.

Keywords: BRCA; BRCA1/2; DNA repair; anti-Mullerian hormone; chemotherapy; mutations; oocyte; ovarian aging; ovarian reserve; ovarian response.

Figure 1

Flow chart of study selection.

Figure 2

ATM-mediated DNA DSB repair pathway. DNA damage is sensed by the MRN complex (sensor of DSBs, consisting of MRE11, RAD50 and NBS1) and 53BP1 (sensor of changes in chromatin structure) which consequently activate ATM (red arrows). MDC1 binds to γH2AX via BRCA1 and is involved in the retention of the MRN complex to chromatin and accumulation of ATM, as well as mediation of the interaction between ATM and γH2AX. ATM phosphorylates γH2AX and activates downstream pathways leading to cell cycle arrest via CHK2 and inhibition of CDC2 (at the G2/M checkpoint, as applicable to oocyte), DNA repair (via activation of DNA strand resection which leads to homologous recombination) and/or apoptosis (via c-abl and TAp63α). DNA strand resection is necessary to invade in the homologous DNA strand. The resulting single-strand (ss) DNA is coated with RPA which in turn activates ATR and leads to cell cycle arrest (via CHK1). In germ cells, RPA is eventually replaced by Rad51 and DMC1 (the latter being germ-cell-specific) through a BRCA2-mediated process, which results in the initiation of homologous recombination. DSB sensor proteins are shown in blue, effectors are shown in green and transducers are shown in red. Molecules also involved in meiotic recombination are denoted with asterisk.

Figure 3

A proposed mechanism of chemotherapy-induced ovarian reserve loss through DNA damage. Primordial follicles have varying abilities to repair DNA double-strand breaks (DSBs) induced by gonadotoxic chemotherapy. When a primordial follicle suffers sufficient DNA damage which cannot be repaired by the ATM-mediated DNA DSB repair pathway, apoptotic pathways will be activated, resulting in follicle death. When on the other hand, DNA DSB repair is successful, the follicle will survive. This mechanism explains why not all follicles suffer the same fate after chemotherapy exposure, in most cases. Recent studies provided strong support for this hypothesis.

Figure 4

Explanation of the limitations in detecting BRCA mutation-related decline in ovarian reserve and fertility. RRSO: risk-reducing salpingo-oophorectomy.

Figure 5

Impact of BRCA mutations on ovarian aging. In women with BRCA mutations, (A) primordial follicle density is lower and declines faster with age compared to controls, and (B) a higher fraction of primordial follicles accumulate DNA DSBs with age (as indicated by γH2AX expression). Both processes are accelerated after age 30.

Figure 6

DNA repair theory of oocyte aging. The DNA DSB repair function declines with age, and this decline is accelerated after age 37. As a result, on the one hand an increasing fraction of primordial follicles accumulate severe DNA double-strand DNA breaks, which results in accelerated apoptotic loss of follicles and ovarian reserve diminishment. In parallel, since ATM-mediated DNA DSB repair and BRCA function are important in meiotic function and chromosome cohesion, aneuploidy risk increases with age, again in an accelerated fashion. If proven, this theory may explain age-related decline in oocyte reserve and quality and its acceleration after about age 37.