An increasing trend to postpone parenthood over the last three decades has intensified the incidence of age-related infertility in the developed world. In women, fertility begins to decline from 30 years of age and subsequently leads to increased risk of miscarriages and birth defects from 35 years onwards. This decline in female fertility is primarily due to depletion of the ovarian reserve of follicles and deterioration of oocyte quality with ageing. Mammalian oocytes remain arrested at dictyate stage of prophase I post-recombination for the entire reproductive life span of a female (lasting up to 50 years in women). This protracted arrest makes oocytes particularly vulnerable to DNA damage by several exogenous and endogenous chemicals that compromise genomic integrity and developmental competence. Cells have evolved several DNA damage response (DDR) and DNA repair mechanisms that function to ensure genomic integrity is maintained throughout their lifespan.Nucleic acid binding proteins (NABPs) form part of a complex molecular signalling network and undergo specific modifications to identify and elicit an apt response that activates cell cycle checkpoints or repair mechanisms. Notably, age-related decline in expression or spontaneous mutations of these genes are associated with several conditions including neurodegenerative diseases and infertility. In this thesis, I study the physiological roles of two such NABPs – Ssb1,2 and Setx in the context of female fertility.In chapter 3, I investigated the roles of single stranded-DNA binding proteins (Ssb1/Nabp2 and Ssb2/Nabp1) using an oocyte-specific knockout mice model. Ssb1 and Ssb2 are known to regulate multiple DNA metabolic processes including transcription, replication and the DDR. While lack of Ssb1 impairs fertility in males, its role in oocyte development and female fertility remains unknown.Here, I found that oocyte-specific deletion of Ssb1 and Ssb2 (Ssb1,2 DKO) causes female infertility in mice. Interestingly, the infertility was not due to widespread elimination of oocytes, but due to defective follicle development and severe impairment of oocyte developmental competence. Specifically, the numbers of dominant pre-ovulatory follicles in Ssb1,2 DKO ovaries were dramatically reduced, with all earlier stages of follicle development remaining intact. Moreover, the majority of oocytes obtained from Ssb1,2 DKO mice were significantly smaller in size, devoid of cumulus cover and were transcriptionally active. Notably, oocyte-secreted factors bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), known to be responsible for cumulus expansion and ovulation, were severely downregulated both at mRNA transcript as well as protein levels, indicating upstream regulatory control by Ssb1,2.Taken together, these findings establish the importance of Ssb1,2 for the acquisition of oocyte developmental competence and in the maintenance of female fertility in mammalian system by regulating the final phases of oocyte growth and antral follicle development.Next, I investigated the role of Senataxin (SETX) in female fertility. SETX is a putative DNA/RNA helicase that protects genomic integrity against oxidative DNA damage. The absence of Setx causes male infertility due to persistence of DNA double strand breaks (DSBs) produced during meiotic recombination, highlighting its important role in DNA repair. Chapter 4 provides a comprehensive analysis of the role of Setx in protecting oocyte genomic integrity during development and ageing using Setx-knockout mice.I found that both the ovarian reserve and oocyte yield were intact in young (2-4 months old) mice. In striking contrast, oocyte yield and ovarian reserve were dramatically reduced in older (6-8 months old) females. This showed that loss of Setx did not have any impact on female fertility whilst young, but subsequently leads to severe depletion of the ovarian reserve with ageing. The declines in ovarian reserve and oocyte yield were accompanied by a significant increase in DSBs in oocytes both at the growing stage in ovarian follicles and at full growth. Further, I found that the increased DSBs in Setx-mutant oocytes was due to an inability to repair DNA damage induced by increasing levels of reactive oxygen species (ROS) brought about by ageing. Early ovarian failure and other observations made in the Setx mouse model reflect clinical manifestations reported in patients diagnosed with premature ovarian insufficiency (POI, previously known as premature ovarian failure), an idiopathic condition that affects 1% of women worldwide. Significantly, POI has been reported in patients suffering from ataxia oculomotor apraxia type 2, a neurodegenerative disorder caused by mutations in SETX gene. Investigation carried out using Setx mouse model not only uncovered SETX as a genetic factor but also provided an insight into the pathogenesis of POI.Increased DNA damage caused severe inhibition of germinal vesicle breakdown (GVBD) in older Setx-mutant oocytes, indicating the presence of a G2/M DDR checkpoint. This was significant because previous studies investigating the G2/M DDR in fully-grown oocytes have almost always used an in vitro model involving treatment with chemotherapeutic drugs. In these previous studies, DNA-intact oocytes isolated from antral follicles were subjected to severe short-lived treatment (1-3 h) with genotoxic agents. Despite incurring severe DNA damage, these oocytes enter M-phase with minimal disruption, showing that fully-grown oocytes are unable to mount an immediate G2/M DDR checkpoint. In vitro studies focusing on the immediate G2/M DDR checkpoint primarily investigated the activation of the canonical phosphorylation pathway mediated by the master kinases ataxia-telangiectasia mutated (ATM)/ ataxia-telangiectasia and Rad 3 related (ATR). However, in chapter 5, using Setx-mutant oocytes and a commonly used chemotherapeutic drug, etoposide, I found that fully-grown oocytes could respond to DNA damage which has been present for several hours. I also identified that this DDR that took longer to evolve, involved anaphase promoting complex (APC)-Cdh1 (APC-Cdh1) mediated proteolysis of cyclin B1, a co-activator of the master M-phase kinase cyclin-dependent kinase 1 (Cdk1). This shows that fully-grown oocytes can mount a strong non-canonical DDR checkpoint at the G2/M boundary in response to persistent damage. Overall, the outcomes of this thesis have demonstrated novel roles of NABPs in regulating gene expression and genomic integrity that contribute to oocyte development and maintenance of female fertility. Persistent DNA damage observed in the Setx-/- model also aided in the identification of a novel G2/M DDR mechanism. This is significant because oocytes that ovulate in middle-aged women are prone to increased DNA damage that may have accumulated over the span of ~3-4 decades. Hence this model of persistent DNA damage better reflects the physiological scenario and deepens our understanding of how oocytes marshal threats to their genomic integrity.