Tempo-spatial alternative polyadenylation analysis reveals that 3' UTR lengthening of Mdm2 regulates p53 expression and cellular senescence in aged rat testis.

Although tissue aging is accompanied with cellular senescence, it is much complicated than senescence given both types and number of cells change with age. Alternative polyadenylation (APA) had shown tissue specificity and APA-mediated 3' untranslated region lengthening could regulate senescence-associated phenotypes. However, whether tissue aging shows similar trends remains unknown. Here, we performed a comprehensive analysis on RNA-seq datasets derived from multiple cells and rat tissues of young and old age. Although APA-mediated lengthening in various senescent cells reinforced the previous discovery, tissue aging showed much more complexity in APA. Interestingly, testis was the only tissue displaying dramatic duanyu3 lengthening and decreased expression trend of corresponding genes in aged rat. Genes with longer duanyu3 in aged testis were enriched in senescence-associated pathways, among which, Mdm2, encoding an E3 ligase of p53, favored distal poly(A) site resulting in lengthened duanyu3 and decreased expression. Longer duanyu3 of Mdm2 generated less protein, and decreased Mdm2 expression led to senescence-associated phenotypes along with increased p53 and p21 protein abundance, which could all be reversed by Mdm2 overexpression. Our work revealed complicated APA changes during tissue aging and discovered APA-mediated duanyu3 lengthening of Mdm2 is a hidden layer in regulating the well-known senescence-related p53-p21 signal axis during testis aging, and also has potential implications regarding declined male fertility along aging.

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