PIKK在早发性卵巢功能不全中的研究进展

Research Progress of PIKK in Premature Ovarian Insufficiency

摘要: 早发性卵巢功能不全(POI)指女性40岁之前出现卵巢功能明显减退或丧失，现为导致女性生育能力降低以及不孕不育的重要病因。POI病因复杂，具有高度的遗传异质性。近年来随着全基因组测序技术和全外显子组测序技术的快速发展，推动了POI遗传学病因的深入研究，目前DNA损伤修复异常被认为是其最主要致病机制之一，现已发现的重要致病基因(ATM、HFM1、MSH4和ERCC6等)大都富集在与DNA损伤修复密切相关的信号通路中。磷脂酰肌醇3-激酶相关激酶蛋白家族的三个成员：DNA-PK，ATM和ATR，是DNA损伤反应中起主导作用的三种激酶，其突变与POI的发生密切相关。近年来，多项研究揭示了DNA-PK、ATM和ATR抑制剂在生殖系统保护中的潜在价值，为POI的治疗提供了新的方向。

Abstract: Premature Ovarian Insufficiency (POI) refers to the significant decline or loss of ovarian function in women before the age of 40, and it is now a major cause of reduced fertility and infertility in women. The etiology of POI is complex and exhibits high genetic heterogeneity. In recent years, with the rapid development of whole-genome sequencing technology and whole-exome sequencing technology, in-depth research on the genetic etiology of POI has been promoted. Currently, abnormalities in DNA damage repair are recognized as one of its primary pathogenic mechanisms, and most of the important pathogenic genes identified so far (such as ATM, HFM1, MSH4, and ERCC6) are enriched in signaling pathways closely related to DNA damage repair. Three members of the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) protein family—DNA-PK, ATM, and ATR—are the three key kinases that play a dominant role in the DNA damage response (DDR). Their mutations are closely associated with the development of POI. In recent years, a number of studies have revealed the potential value of DNA-PK, ATM, and ATR inhibitors in the protection of the reproductive system, providing a new direction for the treatment of POI.