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.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China.
EMBO J. 2024 Jul;43(14):3044-3071. doi: 10.1038/s44318-024-00134-0. Epub 2024 Jun 10.
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 (PGCs) 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.
MCM8 已成为生殖衰老的核心基因，对于减数分裂同源重组修复至关重要。它还通过协调有丝分裂过程中的复制应激反应来维持基因组稳定性，但它在有丝分裂生殖细胞中的功能仍不清楚。在这里，我们发现敲除小鼠中的 MCM8 会导致原始生殖细胞（PGC）的增殖缺陷，最终导致生育能力受损。我们进一步证明，MCM8 与两个已知的解旋酶 DDX5 和 DHX9 相互作用，并且由于 MCM8 减少了这些解旋酶在 R 环上的保留，导致 R 环积累，从而诱导基因组不稳定。表达与 DDX5 相互作用减少的 MCM8 早发性卵巢功能不全致病突变体的细胞显示出增加的 R 环水平。这些结果表明 MCM8 与 R 环解析因子相互作用，以防止 R 环诱导的 DNA 损伤，这可能有助于维持 PGC 的基因组完整性和生殖储备的建立。因此，我们的研究结果揭示了 MCM8 在 PGC 发育中的重要作用，并提高了我们对有丝分裂生殖细胞中基因组不稳定性导致生殖衰老的理解。
