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PWWP3A, one of the PWWP domain proteins, is a reader of H3K36me2\/H3K36me3 and a response factor to DNA damage. However, the physiological role of PWWP3A in spermatogenesis and fertility remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The goal of this study was to explore the function and mechanism of PWWP3A in the process of spermatogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We generated <jats:italic>V5\u2010Pwwp3a<\/jats:italic> KI mice and PWWP3A polyclonal antibody to observe the localization of PWWP3A in vivo. Meanwhile, <jats:italic>Pwwp3a<\/jats:italic> KO mice was used to explore the function in spermatogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We reported that PWWP3A is a predominant expression in the testis of mice. During spermatogenesis, PWWP3A exhibits the temporal expression from early\u2010pachytene to the round spermatids. The results of spermatocyte spreading and immunostaining showed that PWWP3A aggregated on the XY body, which then diffused as the XY chromosome separated at late\u2010diplotene. Although the depletion of PWWP3A had no obvious reproductive defects in young male mice, there were observed morphological abnormalities in sperm heads. Immunoprecipitation demonstrated the interaction of PWWP3A with DNA repair proteins SMC5\/6; however, PWWP3A deficiency did not result in any meiotic defects. Notably, the testes of aged male <jats:italic>Pwwp3a<\/jats:italic> KO mice displayed pronounced degeneration, and were characterized by the presence of vacuolated seminiferous tubules. Furthermore, RNA\u2010seq analysis revealed an upregulation in the expression of genes which may be involving in immunoregulatory and inflammatory response pathways in aged <jats:italic>Pwwp3a<\/jats:italic> KO mice with testicular degeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study showed that PWWP3A was highly enriched in the mouse testis, and the <jats:italic>Pwwp3a<\/jats:italic> KO mice were fertile. However, the aged <jats:italic>Pwwp3a<\/jats:italic> KO male mice displayed testicular atrophy that may be due to changes in the immune micro\u2010environment or abnormal repair of DNA damage.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.13774","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T04:19:11Z","timestamp":1728015551000},"page":"1236-1250","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PWWP3A deficiency accelerates testicular senescence in aged mice"],"prefix":"10.1111","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-4602","authenticated-orcid":false,"given":"Zhen","family":"Chen","sequence":"first","affiliation":[{"name":"Provincial Key Laboratory of Developmentally Originated Disease TaiKang Center for Life and Medical Sciences School of Basic Medical Sciences Wuhan University  Wuhan China"},{"name":"Frontier Science Center for Immunology and 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