Oocytes Progress beyond Prophase in the Presence of DNA Damage

In the female germline, DNA damage has the potential to induce infertility and even to lead to genetic abnormalities that may be propagated to the resulting embryo [1, 2]. The protracted arrest in meiotic prophase makes oocytes particularly susceptible to the accumulation of environmental insults, including DNA damage. Despite this significant potential to harm reproductive capacity, surprisingly little is known about the DNA damage response in oocytes. We show that double-strand breaks in meiotically competent G2/prophase-arrested mouse oocytes do not prevent entry into M phase, unless levels of damage are severe. This lack of an efficient DNA damage checkpoint is because oocytes fail to effectively activate the master regulator of the DNA damage response pathway, ATM (ataxia telangiectasia mutated) kinase. In addition, instead of inhibiting cyclin B-CDK1 through destruction of Cdc25A phosphatase, oocytes utilize an inhibitory phosphorylation of Cdc25B. We conclude that oocytes are the only nontransformed cells that fail to launch a robust G2 phase DNA damage check-point and that this renders them sensitive to genomic instability.