3′ UTR lengthening as a novel mechanism in regulating cellular senescence

Meng Chen, Guoliang Lyu, Miao Han, Hongbo Nie, Ting Shen, Wei Chen, Yichi Niu, Yifan Song, Xueping Li, Huan Li, Xinyu Chen, Ziyue Wang, Zheng Xia, Wei Li, Xiao Li Tian, Chen Ding, Jun Gu, Yufang Zheng, Xinhua Liu, Jinfeng HuGang Wei, Wei Tao, Ting Ni

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3′ untranslated regions (3′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3′ UTRs and reduced gene expression. Genes that harbor longer 3′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes. Mechanistically, splicing factor TRA2B bound to a core "AGAA" motif located in the alternative 3′ UTR of Rras2, thereby reducing the RRAS2 protein level and causing senescence. Both proximal and distal poly(A) signals showed strong sequence conservation, highlighting the vital role of APA regulation during evolution. Our results revealed APA as a novel mechanism in regulating cellular senescence.

Original languageEnglish (US)
Pages (from-to)285-294
Number of pages10
JournalGenome Research
Volume28
Issue number3
DOIs
StatePublished - Mar 2018

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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