Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, South Korea.
Mol Cell Biol. 2014 Apr;34(8):1460-73. doi: 10.1128/MCB.01223-13. Epub 2014 Feb 10.
The dichotomy in DNA damage sensitivity of developing mouse oocytes during female germ line development is striking. Embryonic oocytes withstand hundreds of programmed DNA double-strand breaks (DSBs) required for meiotic recombination. Postnatal immature oocytes fail to tolerate even a few DSBs induced by gamma radiation treatment. TAp63α, a p53 family member, undergoes phosphorylation and mediates postnatal immature oocyte death following gamma radiation treatment, which is thought important for germ line quality maintenance. Whether prenatal meiotic oocytes tolerate DNA DSBs simply because they lack TAp63α expression is not clear. We found a significant number of oocytes in newborn mice initiate TAp63α expression and simultaneously carry meiotic DNA DSBs. However, the risk of premature death appears unlikely, because newborn oocytes strongly abate TAp63α phosphorylation induction and resist normally lethal doses of ionizing radiation damage. A calyculin A-sensitive Ser/Thr phosphatase activity downregulates TAp63α phosphorylation and ATM kinase mediates phosphorylation. Possible alterations in the relative balance of these counteracting activities during development may first temper TAp63α phosphorylation and death induction during meiotic DNA DSB repair and recombination, and afterward, implement germ line quality control in later stages. Insights into inherent DNA DSB resistance mechanisms in newborn oocytes may help prevent infertility in women in need of radiation or chemotherapy.
在雌性生殖细胞发育过程中，发育中的小鼠卵母细胞的 DNA 损伤敏感性存在二分法，这一点非常明显。胚胎卵母细胞能够承受减数分裂重组所需的数百个程序性 DNA 双链断裂 (DSB)。而出生后未成熟的卵母细胞甚至无法耐受伽马辐射处理引起的少数几个 DSB。TAp63α 是 p53 家族的一员，在受到伽马辐射处理后，它会发生磷酸化，并介导出生后未成熟卵母细胞的死亡，这被认为对生殖细胞质量的维持很重要。然而，是否由于产前减数分裂卵母细胞缺乏 TAp63α 表达，它们就能够耐受 DNA DSB，目前尚不清楚。我们发现，大量处于新生期的小鼠卵母细胞开始表达 TAp63α，同时携带减数分裂 DNA DSB。然而，它们似乎不太可能过早死亡，因为新生卵母细胞强烈抑制 TAp63α 磷酸化诱导，并抵抗通常可导致致死剂量的电离辐射损伤。一种 calyculin A 敏感的丝氨酸/苏氨酸磷酸酶活性下调 TAp63α 的磷酸化，而 ATM 激酶介导磷酸化。在发育过程中，这些拮抗活性的相对平衡可能会首先调节 TAp63α 的磷酸化和死亡诱导，以修复和重组减数分裂 DNA DSB，然后在后期实施生殖细胞质量控制。深入了解新生卵母细胞中固有的 DNA DSB 抵抗机制，可能有助于预防需要接受辐射或化疗的女性不孕。
