哺乳动物卵巢储备形成中的DNA损伤修复

doi:10.12280/gjszjk.20210121

摘要/Abstract

摘要：

在哺乳动物卵巢储备的形成过程中,生殖细胞处于DNA复制、交换和重组的活跃期,对各种内外损伤因素敏感,易发生DNA损伤。多条DNA损伤修复途径在此期间发挥作用。同源重组途径修复DNA双键断裂,保护和重启停滞复制叉;范可尼贫血途径修复链间交联,促进复制叉重启;碱基切除修复途径是全基因组的表观遗传编程的重要机制;错配修复途径维持减数分裂进程,促进重组过程的交叉形成和稳定;核苷酸切除修复途径促进修复链间交联等。这些功能对于维持生殖细胞基因组稳定、减少生殖细胞凋亡、促进生殖细胞增殖和多能性表达以调节原始生殖细胞发育形成卵巢储备至关重要。更好了解哺乳动物卵巢储备形成中的DNA损伤修复,为原发性卵巢功能不全的病因学解析提供理论基础。

关键词: 卵巢储备功能, DNA损伤, DNA修复, 卵泡, 生殖细胞

Abstract:

In the process of the formation of ovarian reserve, the mammalian germ cells are in the active stage of DNA replication, exchange and recombination. DNA of this stage is sensitive to various internal and external damage factors, so it is predisposed to DNA damage. There are multiple pathways of DNA repair during this period. Homologous recombination (HR) pathway repairs DNA double-strand breaks, protects and restarts the stalled replication forks. Fanconi anemia (FA) pathway repairs interstrand crosslinks and promotes the replication forks to restart. Base excision repair (BER) pathway is an important mechanism of genome-wide epigenetic programming. Mismatch repair (MMR) pathway maintains the meiosis process and promotes the crossover formation and stabilization of the recombination process. Nucleotide excision repair (NER) pathway facilitates the repair of interstrand crosslinks. These pathways are essential for maintaining genomic stability of germ cell, reducing germ cell apoptosis, promoting germ cell proliferation and pluripotency expression to regulate the development of primordial germ cells so as to form ovarian reserve. To understand well the DNA damage and repair during ovarian reserve formation provides a theoretical basis for the etiological analysis of primary ovarian insufficiency (POI).

Key words: Ovarian reserve, DNA damage, DNA repair, Ovarian follicle, Germ cells

周志贤, 朱芳, 殷缓, 苏叶, 蔡海奕, 符淳. 哺乳动物卵巢储备形成中的DNA损伤修复[J]. 国际生殖健康/计划生育, 2021, 40(5): 391-396.

ZHOU Zhi-xian, ZHU Fang, YIN Huan, SU Ye, CAI Hai-yi, FU Chun. DNA Damage and Repair during Ovarian Reserve Formation[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(5): 391-396.

图/表 5

表1 原始卵泡形成过程中的DNA损伤修复途径

修复途径	作用阶段	损伤因素	损伤类型	修复作用
BER途径	表观遗传修饰	内源烷基化剂、内源代谢物、辐射	小DNA损伤和加合物	替换单个受损核苷酸
MMR途径	DNA复制、减数分裂重组	自发性dNTP错配、辐射	碱基错配、插入、缺失	修复dNTP错误匹配
HR途径	有丝分裂、减数分裂重组	减数分裂重组诱导、辐射	DSB、停滞复制叉	修复DSB、恢复停滞复制叉
FA途径	有丝分裂、减数分裂重组	内源代谢物、链间交联剂、辐射	ICL、停滞复制叉	修复ICL、协调多种DNA修复活动
NER途径	DNA交联	DNA交联、辐射	大块DNA加合物、严重DNA损伤	更换大段DNA

图1 原始卵泡形成过程中的DNA损伤修复途径

图2 卵巢储备形成过程（从原始生殖细胞到原始卵泡）

图3 HR途径修复DSB,保护和重启复制叉注：a. HR修复DSB成CO或NCO。减数分裂重组过程中,DSB被SPO11诱导形成。MRN复合物定位于DNA保持断端连接。在酶作用下产生3′端单链DNA尾巴被复制蛋白A（replication protein A,RPA）包裹。在BRCA2的协助下,RAD51和DMC1取代RPA并协助损伤的DNA入侵同源模板链。由此DSB修复,在合成依赖链复性（synthesis-dependent strand annealing,SDSA）路径中形成NCO;在另一路径中双霍尼迪结（dHJ）形成,随后发生不对称裂解,最终形成CO。b. HR和FA途径保护复制叉。DNA损伤使复制叉停滞。BRCA1、BRCA2和FANCD2蛋白稳定RAD51以保护停滞复制叉和新生链,阻止核酸酶MRE11对新生链的降解作用。c. HR重启停滞复制叉。（i）HR途径修复单侧DSB或主导链间隙,解决主导链停滞。（ii）HR途径修复滞后链间隙,解决滞后链停滞。最终复制叉重启。

图4 FA途径修复ICL 注：两个复制叉在ICL位点汇集并停滞。锚复合物（FANCM-FAAP24、10、16）识别定位于ICL。FA核心复合物（FANCA、B、C、E、F、G、L和FAAP20、100）被募集,随后催化FANCI-FANCD2异二聚体的泛素化激活过程。FANCI-FANCD2作为平台招募其他FA蛋白。FANCP和FANCQ催化ICL脱钩。FANCV组成的多亚基聚合酶绕过DNA损伤实现跨病变DNA合成。NER途径去除脱钩后残余加合物。最后,ICL修复产生的DSB由HR修复。

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