Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level
Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level
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DOI：
10.7554/elife.13909
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发表时间：
2016-03-14
期刊：
影响因子：
7.7
通讯作者：
Doetsch, Volker
中科院分区：
文献类型：
--
作者：
Coutandin, Daniel;Osterburg, Christian;Doetsch, Volker
哺乳动物卵母细胞在减数分裂前期I的网状体阶段被长时间阻滞，在此期间，高浓度的p53家族成员TAp63 α使它们对DNA损伤诱导的细胞凋亡敏感。TAp63 α保持在无活性和排他的二聚体状态，但在检测到DNA损伤时经历快速磷酸化诱导的四聚体和伴随的活化。在这里，我们表明，TAp63 α二聚体是一个动力学捕获状态。激活遵循弹簧加载机制，不需要卵母细胞中其他细胞因子的进一步翻译，并且与阻断四聚化界面的抑制性结构的解折叠相关。使用生物物理学方法以及细胞和卵巢培养实验的组合，我们解释了TAp63 α如何在没有DNA损伤的情况下保持无活性，但在响应一些DNA双链断裂时引起快速的卵母细胞消除，从而作为母体繁殖的关键质量控制因素。
Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63 alpha sensitizes them to DNA damage-induced apoptosis. TAp63 alpha is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63 alpha dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63 alpha is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.