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Global lengthening of 3′ untranslated regions of mRNAs by alternative cleavage and polyadenylation in cellular senescence

By Miao Han, Guoliang Lv, Hongbo Nie, Ting Shen, Yichi Niu, Xueping Li, Meng Chen, Xia Zheng, Wei Li, Chen Ding, Gang Wei, Jun Gu, Xiao-Li Tian, Yufang Zheng, Xinhua Liu, Jinfeng Hu, Wei Tao, Ting Ni

Posted 02 Dec 2015
bioRxiv DOI: 10.1101/033480

Cellular senescence has been viewed as an irreversible cell cycle arrest that acts to prevent cancer. Recent studies discovered widespread shortening of 3′ untranslated regions (3′ UTRs) by alternative cleavage and polyadenylation (APA) in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. We thus applied our published PA-seq method to investigate APA regulation in different passages of mouse embryonic fibroblasts (MEFs) and aortic vascular smooth muscle cells (VSMCs) from rats of different ages. We found that genes in senescent cells tended to use distal poly(A) sites (pAs). An independent RNA-seq analysis gave rise to the same conclusion. Interestingly, the level of expression of genes preferred to use distal pAs in senescent MFEs and VSMCs tended to decrease. More importantly, genes that preferred to use distal pAs in senescent MFEs and VSMCs were enriched in common senescence-related pathways such as ubiquitin-mediated proteolysis and cell cycle. Further, the longer 3′ UTRs of the genes that tended to use distal pAs introduced more conserved binding sites of senescence-related microRNAs (miRNAs) and RNA binding proteins (RBPs). Noteworthy, the expression level of core factors involved in cleavage and the polyadenylation tended to decrease, while those factors showed opposite trend in cancer cells. In summary, we showed, for the first time, that APA is a hidden layer of post-transcriptional gene expression regulation involved in cellular senescence.

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