Distinct characteristics of the DNA damage response in mammalian oocytes

Abstract

DNA damage is a critical threat that poses significant challenges to all cells. To address this issue, cells have evolved a sophisticated molecular and cellular process known as the DNA damage response (DDR). Among the various cell types, mammalian oocytes, which remain dormant in the ovary for extended periods, are particularly susceptible to DNA damage. The occurrence of DNA damage in oocytes can result in genetic abnormalities, potentially leading to infertility, birth defects, and even abortion. Therefore, understanding how oocytes detect and repair DNA damage is of paramount importance in maintaining oocyte quality and preserving fertility. Although the fundamental concept of the DDR is conserved across various cell types, an emerging body of evidence reveals striking distinctions in the DDR between mammalian oocytes and somatic cells. In this review, we highlight the distinctive characteristics of the DDR in oocytes and discuss the clinical implications of DNA damage in oocytes.

Fig. 1. DNA damage-induced apoptosis in oocytes.

a TAp63-induced apoptosis in oocytes from primordial and primary follicles. DNA damage triggers the activation of TAp63, which in turn mediates oocyte apoptosis by inducing the transcription of PUMA and NOX and the subsequent inhibition of BAX and BAK. b Decreased apoptosis during follicular development. During the early stages of follicular development, both primordial and primary follicles highly express TAp63, which allows them to respond to DNA damage through apoptosis. However, as follicles progress to the late antral stage, TAp63 expression diminishes. Consequently, fully grown oocytes become less prone to undergo apoptosis after DNA damage.

Fig. 2. DNA damage checkpoints in oocytes.

a Lack of a robust G2/M DNA damage checkpoint. The canonical ATM-CHK1/2-CDC25 pathway is downregulated in fully grown oocytes and is partly influenced by WIP1 activity. Instead, oocytes use a noncanonical G2/M DNA damage checkpoint, which is associated with the regulation of APC/C-Cdh1 activity. DNA damage induces EMI1 degradation and MDC1 dissociation from APC/C-Cdh1, as well as CDC14B activation, which eventually leads to an increase in APC/C-Cdh1 activity. This, in turn, promotes cyclin B1 degradation, subsequently delaying GVBD. b DNA damage-induced SAC arrest. In general, the SAC is activated in the presence of unattached kinetochores, which leads to the inhibition of APC/C and subsequent anaphase onset. However, in oocytes with DNA damage, the SAC is activated independently of unattached kinetochores during meiosis I.

Fig. 3. Distinct roles of NHEJ and HR during meiotic maturation.

Both the HR and NHEJ repair pathways function separately yet together during meiotic maturation. The details of each pathway are illustrated and highlighted in the boxed areas. When NHEJ is inhibited during meiotic maturation, oocytes with DNA damage exhibit increased DNA damage levels and arrest at the MI stage via SAC activation. On the other hand, HR suppression decreases the integrity of the centromere, causing centromere disruption and SAC inactivation. This further damages chromosome structure and causes chromosome fragmentation during chromosome segregation.

Fig. 4. DSB repair during meiosis I.

In response to DNA damage, a series of coordinated events take place in MI oocytes to facilitate DSB repair. DNA damage triggers rapid shrinkage and stabilization of spindle microtubules and concomitant and transient inactivation of PLK1 at spindle poles. This leads to the dephosphorylation of CIP2A in complex with MDC1 and TOPBP1 and the subsequent recruitment of these proteins to chromosomes from the spindle poles. This mechanism ensures the efficient and accurate repair of DNA damage, preserving genomic integrity during oocyte meiosis.