School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea.
BioMedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
Int J Mol Sci. 2021 Jul 26;22(15):7951. doi: 10.3390/ijms22157951.
Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells; however, its function in vivo is not well understood due to its early embryonic lethality in null mice exhibiting spontaneous DNA damage, cell cycle delays, and defects in check point activation. Here, we generated germ cell-specific knock-out (KO) mice to evaluate the function of PRMT1 in spermatogenesis. Our findings demonstrate that PRMT1 is vital for male fertility in mice. Spermatogenesis in KO mice was arrested at the zygotene-like stage of the first meiotic division due to an elevated number of DNA double-strand breaks (DSBs). There was a loss of methylation in meiotic recombination 11 (MRE11), the key endonuclease in MRE11/RAD50/NBS 1 (MRN) complex, resulting in the accumulation of SPO11 protein in DSBs. The ATM-mediated negative feedback control over SPO11 was lost and, consequently, the repair pathway of DSBs was highly affected in PRMT1 deficient male germ cells. Our findings provide a novel insight into the role of PRMT1-mediated asymmetric demethylation in mouse spermatogenesis.
精氨酸甲基转移酶 1（PRMT1）是一种主要的酶，负责在哺乳动物细胞中形成甲基精氨酸；然而，由于其在表现出自发 DNA 损伤、细胞周期延迟和检查点激活缺陷的 null 小鼠中具有早期胚胎致死性，其在体内的功能尚不清楚。在这里，我们生成了生殖细胞特异性敲除（KO）小鼠，以评估 PRMT1 在精子发生中的功能。我们的研究结果表明，PRMT1 对小鼠的雄性生育力至关重要。由于 DNA 双链断裂（DSBs）数量增加，KO 小鼠的精子发生在第一次减数分裂的合线期样阶段被阻断。在 MRE11/RAD50/NBS1（MRN）复合物中的关键内切酶减数分裂重组 11（MRE11）的甲基化丢失，导致 SPO11 蛋白在 DSBs 中积累。ATM 介导的对 SPO11 的负反馈控制丢失，因此，PRMT1 缺陷的雄性生殖细胞中的 DSBs 修复途径受到高度影响。我们的研究结果为 PRMT1 介导的不对称去甲基化在小鼠精子发生中的作用提供了新的见解。
