Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Cell Prolif. 2024 Sep;57(9):e13685. doi: 10.1111/cpr.13685. Epub 2024 Jun 18.
In the meiotic prophase, programmed SPO11-linked DNA double-strand breaks (DSBs) are repaired by homologous recombination (HR). The MRE11-RAD50-NBS1 (MRN) complex is essential for initiating DNA end resection, the first step of HR. However, residual DNA end resection still occurs in Nbs1 knockout (KO) spermatocytes for unknown reasons. Here, we show that DNA end resection is completely abolished in Mre11 KO spermatocytes. In addition, Mre11 KO, but not Nbs1 KO, undifferentiated spermatogonia are rapidly exhausted due to DSB accumulation, proliferation defects, and elevated apoptosis. Cellular studies reveal that a small amount of MRE11 retained in the nucleus of Nbs1 KO cells likely underlies the differences between Mre11 and Nbs1 KO cells. Taken together, our study not only demonstrates an irreplaceable role of the MRE11 in DNA end resection at SPO11-linked DSBs but also unveils a unique function of MRE11 in maintaining the long-term viability of undifferentiated spermatogonia.
在减数分裂前期，由 SPO11 连接的 DNA 双链断裂（DSB）通过同源重组（HR）进行程序性修复。MRE11-RAD50-NBS1（MRN）复合物对于启动 DNA 末端切除至关重要，这是 HR 的第一步。然而，由于未知原因，Nbs1 敲除（KO）精母细胞中仍会残留 DNA 末端切除。在这里，我们表明 Mre11 KO 精母细胞中的 DNA 末端切除完全被废除。此外，Mre11 KO，但不是 Nbs1 KO，未分化的精原细胞由于 DSB 积累、增殖缺陷和凋亡升高而迅速耗尽。细胞研究表明，Nbs1 KO 细胞中保留在核内的少量 MRE11 可能是 Mre11 和 Nbs1 KO 细胞之间差异的基础。总之，我们的研究不仅证明了 MRE11 在 SPO11 连接的 DSB 处 DNA 末端切除中的不可替代性，而且还揭示了 MRE11 在维持未分化精原细胞长期存活中的独特功能。
