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作者

Canxin Wen, Lili Cao, Shuhan Wang, Weiwei Xu, Yongze Yu, Simin Zhao, Fan Yang, Zi-Jiang Chen, Shidou Zhao, Yajuan Yang, Yingying Qin

作者单位

Affiliations ¹ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China. ² National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China. ³ Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China. ⁴ Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China. ⁵ Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China. ⁶ Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250012, China. ⁷ Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. ⁸ Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, China. ⁹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, China. ¹⁰ Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China. ¹¹ Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ¹² State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China. shidouzhao@sdu.edu.cn. ¹³ National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China. shidouzhao@sdu.edu.cn. ¹⁴ Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China. shidouzhao@sdu.edu.cn. ¹⁵ Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China. shidouzhao@sdu.edu.cn. ¹⁶ Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China. shidouzhao@sdu.edu.cn. ¹⁷ Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250012, China. shidouzhao@sdu.edu.cn. ¹⁸ Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. shidouzhao@sdu.edu.cn. ¹⁹ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China. YangYJ0204@sdu.edu.cn. ²⁰ National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China. YangYJ0204@sdu.edu.cn. ²¹ Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China. YangYJ0204@sdu.edu.cn. ²² Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China. YangYJ0204@sdu.edu.cn. ²³ Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China. YangYJ0204@sdu.edu.cn. ²⁴ Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250012, China. YangYJ0204@sdu.edu.cn. ²⁵ Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. YangYJ0204@sdu.edu.cn. ²⁶ State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, 250012, China. qinyingying@sdu.edu.cn. ²⁷ National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China. qinyingying@sdu.edu.cn. ²⁸ Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, 250012, China. qinyingying@sdu.edu.cn. ²⁹ Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China. qinyingying@sdu.edu.cn. ³⁰ Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China. qinyingying@sdu.edu.cn. ³¹ Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250012, China. qinyingying@sdu.edu.cn. ³² Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001), Jinan, Shandong, 250012, China. qinyingying@sdu.edu.cn.

刊名

The EMBO journal

年份

2024

ISSN

1460-2075

关键词

Fertility Genome Stability MCM8 Primordial Germ Cells R-loop.

分类号

572

摘要

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss...更多

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss of MCM8 led to R-loop accumulation by reducing the retention of these helicases at R-loops, thus inducing genome instability. Cells expressing premature ovarian insufficiency-causative mutants of MCM8 with decreased interaction with DDX5 displayed increased R-loop levels. These results show MCM8 interacts with R-loop-resolving factors to prevent R-loop-induced DNA damage, which may contribute to the maintenance of genome integrity of PGCs and reproductive reserve establishment. Our findings thus reveal an essential role for MCM8 in PGC development and improve our understanding of reproductive aging caused by genome instability in mitotic germ cells.收起

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