Marangos Petros, Stevense Michelle, Niaka Konstantina, Lagoudaki Michaela, Nabti Ibtissem, Jessberger Rolf, Carroll John
Department of Cell and Developmental Biology, Division of Biosciences, UCL, Gower Street, London WC1E 6BT, UK.
Department of Biological Applications and Technology, University of Ioannina, 45110 Ioannina, Greece.
Nat Commun. 2015 Nov 2;6:8706. doi: 10.1038/ncomms9706.
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.
在哺乳动物卵母细胞中，DNA损伤可导致染色体异常，进而可能导致不孕和发育障碍。然而，关于卵母细胞对DNA损伤的反应却知之甚少。在此，我们发现有DNA损伤的卵母细胞会停滞在第一次减数分裂（MI）的中期。MI停滞是由纺锤体组装检查点（SAC）诱导的，因为抑制SAC可克服DNA损伤诱导的MI停滞。此外，老年小鼠卵母细胞中的这种MI检查点存在缺陷。这些数据使我们提出，SAC是防止携带DNA损伤的卵母细胞继续发育的主要守门人。因此，SAC通过阻止异常成熟卵母细胞及后续胚胎的产生，起到整合防止非整倍体和DNA损伤的保护作用。最后，我们认为在母体衰老过程中逃避这种DNA损伤检查点可能是老年母亲的卵母细胞和胚胎中染色体异常增加的原因之一。
