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The Importance of DNA Repair for Maintaining Oocyte Quality In Human Reproduction Update, Vol.24, No.2 pp. 119–134, 2018 Advanced Access publication on January 25, 2018 doi:10.1093/humupd/dmy002 The importance of DNA repair for maintaining oocyte quality in response to anti-cancer treatments, Downloaded from https://academic.oup.com/humupd/article-abstract/24/2/119/4825064 by Biomedical Library user on 24 January 2020 environmental toxins and maternal ageing † † Amy L. Winship , Jessica M. Stringer , Seng H. Liew, and Karla J. Hutt * Ovarian Biology Laboratory, Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC 3800, Australia *Correspondence address. Ovarian Biology Laboratory, Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC 3800, Australia. E-mail: [email protected] orcid.org/0000-0002-5111-8389 Submitted on August 1, 2017; resubmitted on December 5, 2017; editorial decision on January 2, 2018; accepted on January 14, 2018 .............................TABLE OF CONTENTS.............................................................................................. • Introduction • Methods • DNA double-strand breaks • Homologous recombination and non-homologous end-joining • DNA DSB repair in meiotic oocytes Meiosis The induction and repair of meiotic DSBs • DNA DSB repair in primordial follicle oocytes Evidence for efficient repair of DSBs in primordial follicle oocytes Ionizing radiation Chemotherapy Reproductive ageing Environmental toxicants • Evidence for DNA damage response in mature oocytes • Future directions: augmenting DNA repair to protect oocytes during ageing or cancer treatment • Conclusions BACKGROUND: Within the ovary, oocytes are stored in long-lived structures called primordial follicles, each comprising a meiotically arrested oocyte, surrounded by somatic granulosa cells. It is essential that their genetic integrity is maintained throughout life to ensure that high quality oocytes are available for ovulation. Of all the possible types of DNA damage, DNA double-strand breaks (DSBs) are con- sidered to be the most severe. Recent studies have shown that DNA DSBs can accumulate in oocytes in primordial follicles during repro- ductive ageing, and are readily induced by exogenous factors such as γ-irradiation, chemotherapy and environmental toxicants. DSBs can induce oocyte death or, alternatively, activate a program of DNA repair in order to restore genetic integrity and promote survival. The † These authors contributed equally. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected] 120 Winship et al. repair of DSBs has been intensively studied in the context of meiotic recombination, and in recent years more detail is becoming available regarding the repair capabilities of primordial follicle oocytes. OBJECTIVE AND RATIONALE: This review discusses the induction and repair of DNA DSBs in primordial follicle oocytes. SEARCH METHODS: PubMed (Medline) and Google Scholar searches were performed using the key words: primordial follicle oocyte, DNA repair, double-strand break, DNA damage, chemotherapy, radiotherapy, ageing, environmental toxicant. The literature was restricted to papers in the English language and limited to reports in animals and humans dated from 1964 until 2017. The references within these articles were also manually searched. Downloaded from https://academic.oup.com/humupd/article-abstract/24/2/119/4825064 by Biomedical Library user on 24 January 2020 OUTCOMES: Recent experiments in animal models and humans have provided compelling evidence that primordial follicle oocytes can efficiently repair DNA DSBs arising from diverse origins, but this capacity may decline with increasing age. WIDER IMPLICATIONS: Primordial follicle oocytes are vulnerable to DNA DSBs emanating from endogenous and exogenous sources. The ability to repair this damage is essential for female fertility. In the long term, augmenting DNA repair in primordial follicle oocytes has implications for the development of novel fertility preservation agents for female cancer patients and for the management of maternal age- ing. However, further work is required to fully characterize the specific proteins involved and to develop strategies to bolster their activity. Key words: oocyte / DNA repair / primordial follicle / radiotherapy / chemotherapy / ageing Introduction exogenous factors, such as γ-irradiation (Kerr et al., 2012c), chemo- therapy (Kujjo et al., 2010; Titus et al., 2013) and environmental toxi- Within the ovary, oocytes are stored in long-lived structures called cants (Susiarjo et al., 2007; Hunt et al., 2012; Zhang et al., 2012) also primordial follicles. Each primordial follicle comprises a non-growing, results in DSB formation in primordial follicle oocytes. In each of meiotically arrested oocyte, surrounded by a single layer of squamous these contexts, DNA DSBs readily induce primordial follicle oocyte granulosa cells. Primordial follicles are the storage unit of the female death (Suh et al., 2006; Kerr et al., 2012c; Carroll and Marangos, germline and following their activation to enter folliculogenesis, they 2013; Hutt et al., 2013; Rinaldi et al., 2017; Bolcun-Filas et al., 2014). give rise to fully grown, mature, developmentally competent oocytes. The accelerated depletion of the pool of primordial follicles that While some studies have raised the possibility that germline stem ensues can lead to premature ovarian failure (POF), infertility and cells may exist in the adult ovary, their contribution to ovarian func- early menopause, the latter of which is associated with increased risk tion and fertility is controversial (Johnson et al., 2004; Zou et al., of adverse health outcomes for women such as cardiovascular dis- 2009). Consequently, it remains widely accepted that new primordial ease and osteoporosis (Green et al., 2009). follicles cannot be produced after birth even if the supply becomes Alternatively, recent studies in animals and humans have provided prematurely depleted (Kerr et al., 2012a). Thus, it is essential that evidence that primordial follicle oocytes are capable of executing an the genetic integrity of primordial follicle oocytes is maintained to efficient repair program when faced with DNA DSBs, in order to ensure that only those of the highest quality are available for ovula- protect fertility and the genomic integrity of future generations tion, fertilization and subsequent embryonic development. (Oktem and Oktay, 2007; Soleimani et al., 2011; Kerr et al., 2012c). To protect genome integrity, cells have evolved a network of path- Indeed, transcript profiling indicates that oocytes at all stages of ways called the DNA damage response, which is responsible for development have the capacity to repair damaged DNA (Wang detecting DNA damage, activating checkpoints leading to cell cycle et al., 2004; Zeng et al., 2004; Pan et al., 2005; Yoon et al., 2006; Cui arrest and coordinating the repair process. While there are many et al., 2007; Gasca et al., 2007; Menezo et al., 2007; Su et al., 2007; types of DNA lesions (Sancar et al., 2004), double-strand breaks Jaroudi et al., 2009; Zheng et al., 2005). (DSBs) are considered to be the most severe form. Under most cir- For the purpose of this review, we have focused on the oocyte, cumstances, DNA DSBs are highly detrimental to chromosome integ- but it is clear that follicles, the functional unit of the ovary, require rity, cellular function and viability. However, DNA DSBs are co-operation between the oocyte and granulosa cells, as well as the deliberately induced and efficiently repaired in oocytes during meiotic ovarian stroma and vasculature, all of which could be damaged by recombination. Indeed, meiotic DNA DSB formation, processing and exogenous agents, or ageing. Indeed, the factors required for oocyte repair are strictly regulated, both spatially and temporally, to ensure DNA DSB repair also play important roles in DNA stability and that apoptosis is only initiated in the event that repair does not occur DNA damage repair in somatic cells, which are beyond the scope of (Longhese et al., 2009; Baudat et al., 2013; Carroll and Marangos, the current review. In this review, the main pathways that cells 2013; Collins and Jones, 2016). employ for repairing DNA DSBs will be briefly described. The DNA In addition to the requirement for oocytes to repair physiologically repair response that occurs in the context of meiosis may inform us induced DSBs during meiotic recombination, the oocytes maintained of the potential mechanisms of DNA repair induced in the response in primordial follicles must also have the capacity to repair breaks in of oocytes to exogenous damage and will therefore briefly be dis- their DNA during their prolonged meiotic arrest. Recent evidence cussed. We will primarily focus our review on the evidence for DNA suggests that DNA DSBs accumulate in primordial follicle oocytes DSB repair in primordial follicle oocytes in response to exogenous during maternal ageing, likely as a consequence of cellular metabolism genotoxic stress or ageing, touching on recent novel findings in and elevated oxidative stress (Titus et al., 2013). Exposure to mature oocytes, where relevant. DNA repair in oocytes 121 Methods sister-chromatid template, which allows for accurate DNA synthesis and repair. Key proteins involved in HR include,
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