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.

中文翻译：

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MCM8 与 DDX5 相互作用以提高 R 环分辨率。


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期间的复制应激反应来保护基因组稳定性，但其在有丝分裂生殖细胞中的功能仍然难以捉摸。在这里，我们发现在小鼠中禁用 MCM8 会导致原始生殖细胞 (PGC) 的增殖缺陷，并最终损害生育能力。我们进一步证明MCM8与两种已知的解旋酶DDX5和DHX9相互作用，并且MCM8的丢失通过减少这些解旋酶在R环上的保留而导致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 突变体的细胞表现出 R 环水平增加。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基因组不稳定引起的生殖衰老的理解。