Abstract
Extensive damage to maternal DNA during meiosis causes infertility, birth defects and abortions. However, it is unknown if fully grown oocytes have a mechanism to prevent the creation of DNA-damaged embryos. Here we show that DNA damage activates a pathway involving the spindle assembly checkpoint (SAC) in response to chemically induced double strand breaks, UVB and ionizing radiation. DNA damage can occur either before or after nuclear envelope breakdown, and provides an effective block to anaphase-promoting complex activity, and consequently the formation of mature eggs. This contrasts with somatic cells, where DNA damage fails to affect mitotic progression. However, it uncovers a second function for the meiotic SAC, which in the context of detecting microtubule–kinetochore errors has hitherto been labelled as weak or ineffectual in mammalian oocytes. We propose that its essential role in the detection of DNA damage sheds new light on its biological purpose in mammalian female meiosis.
Highlights
Extensive damage to maternal DNA during meiosis causes infertility, birth defects and abortions
This supposition appears incorrect in the face of observations that show a weak G2/M transition DNA damage response (DDR) checkpoint and catenation checkpoint in fully grown oocytes[7,8], both of which are prominent in somatic cells[9,10]
GH2AX staining should decrease as the DNA damage is repaired[36], and it was confirmed that oocytes do have the capacity to do this with respect to one of the DNA-damaging agents, etoposide, in germinal vesicle (GV) oocytes over a period of the 3–10 h (Fig. 1c)
Summary
Extensive damage to maternal DNA during meiosis causes infertility, birth defects and abortions. DNA damage can occur either before or after nuclear envelope breakdown, and provides an effective block to anaphase-promoting complex activity, and the formation of mature eggs This contrasts with somatic cells, where DNA damage fails to affect mitotic progression. Given the high protection placed on oocytes in primordial follicles, one would anticipate a p53-independent mechanism in fully grown oocytes that prevents formation of DNA-damaged embryos This supposition appears incorrect in the face of observations that show a weak G2/M transition DNA damage response (DDR) checkpoint and catenation checkpoint in fully grown oocytes[7,8], both of which are prominent in somatic cells[9,10]. We find that both physical- and chemical-induced DNA damage given to mouse oocytes has the capacity to induce an MI arrest This arrest is associated with a block to APC activity and raised levels of Mad[2] on kinetochores. As such it is proposed that DNA damage has the capacity to help prevent the creation of deleterious eggs by activating a pathway involving SAC proteins
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