Abstract
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 Prmt1 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 Prmt1 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.
Highlights
To investigate the importance of Protein arginine methyltransferase 1 (PRMT1) in spermatogenesis, we knocked out the Prmt1 gene in germ cells by mating Prmt1f/f mice with neurogenin 3 (Ngn3)-Cre mice that expressed the Cre recombinase enzyme driven by the Ngn3 promoter in germ cells as early as post-natal day 7 (P7) (Figure S1A,B)
We analyzed the levels of SPO11 in the PRMT1-deficient spermatocytes and found that SPO11 patches were substantially more prevalent in the leptotene and zygotene-like spermatocytes than their WT counterparts (Figure 6E). These results suggest that the loss of asymmetric dimethylarginine (ADMA) in meiotic recombination 11 (MRE11) in the absence of PRMT1 exacerbates the defects in the ataxia telangiectasia-mutated (ATM)-mediated DNA double strand breaks (DSB) repair pathway and SPO11-mediated DSB
We investigated the role of PRMT1 in the process of spermatogenesis by generating germ cell-specific Prmt1 KO mice using Ngn3-Cre, which is known to be expressed in the spermatogonia on P7
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Among a variety of known post-translational modifications occurring inside mammalian cells, the protein arginine methylation is one of the most common post-translational modifications mediated by the members of the protein arginine methyltransferase (PRMT). Family [1,2,3]. Nine members of the PRMT family have been identified in mammalian cells and PRMTs play major roles in pre-mRNA splicing, DNA damage signaling, mRNA translation, cell signaling, and cell fate decision [4,5,6] via the methylation of their histone [7,8] and nonhistone substrates [6]. PRMT type I (PRMT1-4, 6, and 8), type II (PRMT5 and 9), and type III (PRMT7) enzymes are able to generate ω-NG , NG -asymmetric dimethylarginine (ADMA), ω-NG , NG -symmetric dimethylarginine (SDMA), and ω-NG
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