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.

中文翻译：

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BRCA相关的ATM介导的DNA双链断裂修复和卵巢衰老。

背景技术卵母细胞衰老具有重大的临床后果，但是尚无治疗方法来解决与年龄有关的卵母细胞质量下降。在卵母细胞衰老的治疗中缺乏进展是由于以下事实：对潜在的分子机制还没有足够的了解。BRCA1和2参与同源DNA重组，并在共济失调性毛细血管扩张突变（ATM）介导的DNA双链断裂（DSB）修复中起重要作用。在过去的十年中，越来越多的实验室，翻译和临床证据不断涌现，表明BRCA功能和ATM介导的DNA DSB修复在卵巢衰老中的作用。目的和理由尽管有几种相互竞争或互补的理论，但鉴于越来越多的证据表明BRCA功能和ATM介导的DNA DSB修复机制通常与卵巢衰老有关，我们进行了包括基础，翻译和临床工作在内的评估，以评估有关该主题的当前知识状态。对卵母细胞衰老的潜在机制的清晰了解可能会导致靶向治疗，以保留卵巢储备并改善卵母细胞质量。搜索方法我们在PubMed数据库中搜索包含关键词，BRCA，BRCA1，BRCA2，突变，生育力，卵巢储备，不育，卵巢衰老的机制，卵母细胞或卵母细胞DNA修复的已发表文章，直至2019年5月。除了我们自己的摘要以外，我们不包括摘要或会议记录。结果实验室研究提供了有力且可重复的证据，表明BRCA1功能和ATM介导的DNA DSB修复通常随着年龄的增长而减弱，包括人类在内的多种物种的卵母细胞。在具有BRCA突变的女性和BRCA突变的小鼠中，原始卵泡数量均减少，并且卵母细胞中DNA DSB的积累加速。通常，具有BRCA1突变的女性卵巢储备较低，更年期更早。实验室证据还支持BRCA1和其他ATM介导的DNA DSB修复途径成员在减数分裂功能中的关键作用。综合考虑实验室，翻译和临床证据后，BRCA相关的ATM介导的DNA DSB修复功能可能会成为卵巢衰老的调节剂。此外，DNA损伤和修复似乎是化疗诱导的卵巢衰老的关键特征。潜在影响现有数据表明，BRCA相关的ATM介导的DNA修复途径是调节卵母细胞衰老的强有力候选者，年龄相关的衰老途径可能会损害卵母细胞的健康。这些知识可能会提供机会开发针对性的疗法，以逆转或预防生理或化学疗法诱导的卵母细胞衰老。从实际出发，可能需要特别咨询患有BRCA或类似突变的女性以保持生育能力。