DNA damage in the oocytes SACs

KEYWORDS:

• DNA damage response
• oocyte
• meiosis
• checkpoint

This article refers to:

DNA damage response during mouse oocyte maturation

Current work from 3 laboratories, including one published in this journal has tackled this question. It appears that induction of DNA damage in fully grown oocytes does not activate the checkpoint and allows progression to meiosis I.¹ This resembles the situation in somatic cells where the G2 checkpoint could be efficiently activated only before the onset of prophase and excessive DNA damage during mitosis activates the spindle assembly checkpoint (SAC).² Similarly, oocytes exposed to high doses of DNA damaging agents (including etoposide, doxorubicin, UVB or ionizing radiation) did not extrude the first polar body and failed to complete meiosis.^3,4 Such DNA damage-induced arrest in meiosis I (MI) was fully dependent on inhibition of the anaphase-promoting complex and could be overcome by inhibition of MpsI kinase or by depletion of Mad2, both essential components of SAC. Induction of double-stranded DNA breaks (DSBs) increased the level of Mad2 and Bub1 at kinetochores, most probably due to the presence of pericentromeric DNA damage that disrupts kinetochore-microtubule attachments.^4,5 Although SAC has been previously implicated in timing of meiosis I in oocytes, its activity was thought to be much lower compared to mitotic cells: whereas a single unattached kinetochore can prevent anaphase onset in mitotic cells, a critical mass of attached kinetochores in oocytes is sufficient to trigger activation of anaphase-promoting complex. Therefore involvement of SAC in response to DNA damage in oocytes comes as a surprise. Since the capacity of SAC is decreasing with age, it has been postulated that DNA damage-induced chromosomal aberrations may contribute to the age-related infertility.³ In addition, collateral DNA damage in ovaries may cause infertility and therefore better knowledge of DNA damage response during gametogenesis may help to preserve the fertility in female cancer survivors.

On the other hand the vast majority of DNA damage occurring during physiological conditions is likely to be located far apart from the centromeric regions or below the threshold recognized by the relatively weak SAC in oocytes. Indeed, Mayer and colleagues performed a careful titration of the radiomimetic drug neocarzinostatin (NCS) and demonstrated that meiosis is completed with normal timing in the presence of low number of DSBs.⁶ In addition, oocytes treated with a low dose of NCS removed EGFP-securin with the same dynamics as control oocytes suggesting no SAC activity. However, treatment with a low dose of NCS significantly increased inter-kinetochore distance between homologous chromosomes in metaphase I, increased the number of lagging chromosomes in anaphase I and caused free diffusion of the chromosomal fragments in metaphase II.⁶ Interestingly, these severe segregation errors occurred in about one third of oocytes whereas the larger part of oocytes did not show any major defects suggesting that DNA repair can fix most of the lesions before segregation of the homologous chromosomes. This possibility is supported by the decreased number of γH2AX foci (established marker of DSBs) present in metaphase II.⁶ In addition, inhibition of the exonuclease activity of Mre11 by mirin decreased the level of NCS-induced γH2AX signal in MI oocytes and caused mis-segregation of chromosomes suggesting that resection of DNA ends may be needed for efficient phosphorylation of H2AX and efficient DNA repair during oocyte maturation. Whereas DNA repair is largely suppressed in somatic cells during mitosis, it appears that oocytes can efficiently repair DNA during meiotic division.⁷ Nevertheless, more research is still needed to disclose the molecular mechanisms of DNA repair in mammalian meiosis.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.