Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63
Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63
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DOI：
10.1038/s41594-018-0035-7
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发表时间：
2018-03-01
影响因子：
16.8
通讯作者：
Doetsch, Volker
中科院分区：
文献类型：
--
作者：
Tuppi, Marcel;Kehrloesser, Sebastian;Doetsch, Volker
由于更有效的治疗，癌症患者的存活率正在稳步提高。了解化疗引起的卵巢功能不全（P01）的分子机制，可以确定预防P01的靶点。原始卵泡储备的丧失是POI的最重要原因，其中p53家族成员p63负责DNA损伤诱导的静息卵母细胞凋亡。在这里，我们提供了第一个详细的机制洞察到p63的激活，一个过程，需要由启动激酶CHK 2和刽子手激酶CK 1在小鼠原始卵泡磷酸化。我们进一步描述了磷酸化诱导的结构变化，使p63通过其积极的四聚体构象，并证明先前讨论的c-Abl磷酸化不参与这一过程。抑制CK 1可使原代卵母细胞免于阿霉素和顺铂诱导的细胞凋亡，从而为开发生育保护疗法提供了新的靶点。
The survival rate of cancer patients is steadily increasing, owing to more efficient therapies. Understanding the molecular mechanisms of chemotherapy-induced premature ovarian insufficiency (P01) could identify targets for prevention of P01. Loss of the primordial follicle reserve is the most important cause of POI, with the p53 family member p63 being responsible for DNA-damage-induced apoptosis of resting oocytes. Here, we provide the first detailed mechanistic insight into the activation of p63, a process that requires phosphorylation by both the priming kinase CHK2 and the executioner kinase CK1 in mouse primordial follicles. We further describe the structural changes induced by phosphorylation that enable p63 to adopt its active tetrameric conformation and demonstrate that previously discussed phosphorylation by c-Abl is not involved in this process. Inhibition of CK1 rescues primary oocytes from doxorubicin and cisplatin-induced apoptosis, thus uncovering a new target for the development of fertoprotective therapies.