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To date, the pivotal molecular mechanisms governing meiosis remain incompletely understood. This study demonstrates that CMTR2 (Cap methyltransferase 2) exerts a critical regulatory function in male germ cell meiosis through a mechanism independent of its methyltransferase activity. Germ cell-specific Cmtr2 knockout mice (Ddx4-GcKO) exhibited meiotic prophase I zygotene arrest and male sterility. Ddx4-GcKO spermatocytes displayed phenotypic abnormalities, including defective DNA double-strand break repair and compromised crossover formation and recombination. Subsequent investigations revealed a marked reduction in the messenger RNA (mRNA) stability of key meiotic genes, Speedy\/RINGO cell cycle regulator family member A (Spdya) and moloney leukemia virus 10 Like 1 (Mov10l1), in Ddx4-GcKO testes. Mechanistic studies indicated that CMTR2 directly interacts with the 5\u2032 untranslated regions of these genes. Importantly, CMTR2 selectively mediates 2\u2032-O-methylation of Spdya mRNA, whereas its regulation of Mov10l1 mRNA stability is independent of its enzymatic activity. This study is the first to uncover the non-canonical role of CMTR2 in meiotic regulation, enhancing our comprehension of meiotic molecular mechanisms and offering novel insights into the etiology of male sterility.<\/jats:p>","DOI":"10.1093\/nar\/gkag699","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T09:50:42Z","timestamp":1783504242000},"source":"Crossref","is-referenced-by-count":1,"title":["Cap 2\u2032-O-methyltransferase CMTR2 regulates male meiosis independent of its methyltransferase activity"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1496-0753","authenticated-orcid":false,"given":"Bo","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine , Hangzhou 310016 ,","place":["China"]},{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University , Suzhou 215002 ,","place":["China"]},{"name":"Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University , Suzhou 215002 ,","place":["China"]},{"name":"The First Clinical Medical College of Xuzhou Medical University , Xuzhou 221004 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University , Suzhou 215002 ,","place":["China"]},{"name":"Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital 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