Xrcc5/KU80 is not required for the survival or activation of prophase-arrested oocytes in primordial follicles

Frontiers in Endocrinology

Endocrinology

Jessica M. Stringer¹  Natasha D. Ratnayaka-Gamage¹  Lauren R. Alesi¹  Karla J. Hutt¹  Nadeen Zerafa¹ 

[1] Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia;

关键词: DNA repair;    DNA damage;    oocytes;    non-homologous end joining;    fertility;   

DOI  :  10.3389/fendo.2023.1268009

 received in 2023-07-27, accepted in 2023-09-18,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThe non-growing, meiotically-arrested oocytes housed within primordial follicles are exquisitely sensitive to genotoxic insults from endogenous and exogenous sources. Even a single DNA double-strand break (DSB) can trigger oocyte apoptosis, which can lead to accelerated depletion of the ovarian reserve, early loss of fertility and menopause. Therefore, repair of DNA damage is important for preserving the quality of oocytes to sustain fertility across the reproductive lifespan. This study aimed to evaluate the role of KU80 (encoded by the XRCC5 gene) – an essential component of the non-homologous end joining (NHEJ) pathway – in the repair of oocyte DNA DSBs during reproductive ageing, and following insult caused by the DNA-damaging chemotherapies cyclophosphamide and cisplatin.MethodsTo investigate the importance of KU80 following endogenous and exogenous DNA damage, ovaries from conditional oocyte-specific Xrcc5 knockout (Xrcc5 cKO) and wildtype (WT) mice that were aged or exposed to DNA damage-inducing chemotherapy were compared. Ovarian follicles and oocytes were quantified, morphologically assessed and analysed viaimmunohistochemistry for markers of DNA damage and apoptosis. In addition, chemotherapy exposed mice were superovulated, and the numbers and quality of mature metaphase- II (MII) oocytes were assessed.ResultsThe number of healthy follicles, atretic (dying) follicles, and corpora lutea were similar in Xrcc5 cKO and WT mice at PN50, PN200 and PN300. Additionally, primordial follicle number and ovulation rates were similar in young adult Xrcc5 cKO and WT mice following treatment with cyclophosphamide (75mg/kg), cisplatin (4mg/kg), or vehicle control (saline). Furthermore, KU80 was not essential for the repair of exogenously induced DNA damage in primordial follicle oocytes.DiscussionThese data indicate that KU80 is not required for maintenance of the ovarian reserve, follicle development, or ovulation during maternal ageing. Similarly, this study also indicates that KU80 is not required for the repair of exogenously induced DSBs in the prophase-arrested oocytes of primordial follicles.

【 授权许可】

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Copyright © 2023 Ratnayaka-Gamage, Alesi, Zerafa, Stringer and Hutt