Abstract
In mammalian oocytes DNA damage can cause chromosomal abnormalities that potentially lead to infertility and developmental disorders. However, there is little known about the response of oocytes to DNA damage. Here we find that oocytes with DNA damage arrest at metaphase of the first meiosis (MI). The MI arrest is induced by the spindle assembly checkpoint (SAC) because inhibiting the SAC overrides the DNA damage-induced MI arrest. Furthermore, this MI checkpoint is compromised in oocytes from aged mice. These data lead us to propose that the SAC is a major gatekeeper preventing the progression of oocytes harbouring DNA damage. The SAC therefore acts to integrate protection against both aneuploidy and DNA damage by preventing production of abnormal mature oocytes and subsequent embryos. Finally, we suggest escaping this DNA damage checkpoint in maternal ageing may be one of the causes of increased chromosome anomalies in oocytes and embryos from older mothers.
Highlights
In mammalian oocytes DNA damage can cause chromosomal abnormalities that potentially lead to infertility and developmental disorders
DNA damage in oocytes leads to MI arrest
Our data show that o20% of oocytes treated with Etoposide, Phleomycin or Doxorubicin progress through meiosis I and extrude a first polar body (Pb1), compared with more than 80% of control oocytes (Fig. 1a,b)
Summary
In mammalian oocytes DNA damage can cause chromosomal abnormalities that potentially lead to infertility and developmental disorders. To investigate the target of DNA damage in causing MI arrest we analysed the spindle and chromosome configuration in Etoposide-treated oocytes. To examine if the SAC is responsible for DNA damage-induced MI arrest, we used immunofluorescence to determine whether Mad[2] and Bub[1] remain on the kinetochores.
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