The capacity of oocytes for DNA repair

Abstract

Female fertility and offspring health are critically dependent on the maintenance of an adequate supply of high-quality oocytes. Like somatic cells, oocytes are subject to a variety of different types of DNA damage arising from endogenous cellular processes and exposure to exogenous genotoxic stressors. While the repair of intentionally induced DNA double strand breaks in gametes during meiotic recombination is well characterised, less is known about the ability of oocytes to repair pathological DNA damage and the relative contribution of DNA repair to oocyte quality is not well defined. This review will discuss emerging data suggesting that oocytes are in fact capable of efficient DNA repair and that DNA repair may be an important mechanism for ensuring female fertility, as well as the transmission of high-quality genetic material to subsequent generations.

Keywords: Base excision repair; Detection and response; Folliculogenesis; Homologous recombination; Mismatch repair; Non-homologous end joining; Nucleotide excision repair; Ovary; Primordial follicles.

Fig. 1

Schematic representation of folliculogenesis in the mammalian ovary. a Follicles form the functional unit of the ovary and are comprised of the central germ cell (oocyte), surrounded by specialized somatic granulosa cells, as well as a theca cell layer, surrounding mature growing follicles only. A finite supply of non-growing, meiotically arrested primordial follicle oocytes form the ovarian reserve and once lost from the follicle pool, these cells cannot be replenished. From birth onwards, a limited number of primordial follicles are periodically activated to undergo folliculogenesis; a process in which primordial follicles mature through primary, secondary, and antral stages under the influence of follicle-stimulating hormone (FSH) which is produced at puberty. From the growing follicle pool in women, one dominant follicle is ovulated under the influence of luteinizing hormone (LH), leaving behind remnants to form the corpus luteum, required to hormonally support a potential conceptus. The remaining growing follicles undergo atresia, a hormonally regulated apoptotic process, and this is the fate of the majority of follicles. This cyclical pattern continues until the pool of primordial follicles drops below a critical threshold and menopause ensues. b Schematic representation of different oocyte developmental stages. Primordial follicle oocytes are the most abundant form of oocyte in the ovary and are meiotically arrested at diplotene. They are non-dividing, so they can remain arrested in the ovary for months in mice, or decades in humans. They are distinguished morphologically by a surrounding single layer of squamous granulosa cells. Primordial follicle oocytes contain four chromatids (c) and are diploid (2n). Germinal vesicle (GV) oocytes remain meiotically arrested at diplotene, however, represent a fully grown oocyte. GV oocytes are 4c, 2n. Germinal vesicle breakdown indicates that meiosis has resumed and the extrusion of the first polar body represents completion of meiosis I in humans. The oocyte is then arrested at metaphase II (MII), at which stage it is developmentally competent and haploid (2c, n), but will only complete meiosis if fertilization occurs

Fig. 2

Types of DNA damage and repair mechanisms. Alkylating agents can transfer alkyl carbon groups (CH₃) onto DNA and can lead to base-mismatched pairing. Some alkylated bases can be repaired by direct lesion reversal using dioxygenase enzymes e.g., MGMT. Other agents can cause more complex abducts such as reactive oxygen species (ROS) which causes 8-oxoguanine DNA lesions. The base excision repair pathway, via DNA glycosylases (e.g., OGG1), are responsible for replacing a single damaged nucleotide that cannot be repaired by direct reversal. Spontaneous DNA alterations can arise during DNA replication due to dNTP misincorporation, which are primarily repaired by the mismatch repair (MMR) pathway (e.g., MSH2–MSH6 complex initiates the repair of small nucleotide mismatches). DNA interstrand crosslinks are very toxic covalent links within the double helix that prevent DNA unwinding and affect both strands of DNA. The Fanconi anaemia pathway works to coordinate several distinct repair activities belonging to different classic repair pathways. Complex (CPLX) 1 is formed in response to DNA damage recruits FANCD2 which, via interactions with FANCD1, promotes loading of complex 2 that includes components from other repair pathways. When DNA is severely damaged (e.g., UV radiation) and large sections of DNA need to be replaced the nucleotide excision repair pathway is activated, XPC recognizes and binds the helix-distorting lesion and then recruits endonucleases XPG and ERCC1–XPF to excise the damaged DNA fragment and allow polymerase to resynthesis the strand. DNA double strand breaks are caused following exposure to exogenous stressors (e.g., ionizing radiation). Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two main pathways responsible for DNA DSB repair. KU70/KU80 and MRN complex and are involved in the detection of double strand breaks and recruitment of various repair factors (e.g., RAD51 is essential for HR repair and DNA-PKcs is essential for NHEJ repair