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 Hu; Gang Wei; Wei Tao; Ting Ni

doi:10.1101/gr.224451.117

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

Genome Res. 2018 Feb 12;28(3):285-294. doi: 10.1101/gr.224451.117. Online ahead of print.

Authors

Meng Chen^#¹, Guoliang Lyu^#², Miao Han^#¹, Hongbo Nie^#¹, Ting Shen¹, Wei Chen¹, Yichi Niu¹, Yifan Song¹, Xueping Li¹, Huan Li¹, Xinyu Chen¹, Ziyue Wang¹, Zheng Xia³, Wei Li³, Xiao-Li Tian⁴, Chen Ding⁵, Jun Gu², Yufang Zheng¹, Xinhua Liu⁶, Jinfeng Hu⁶, Gang Wei¹, Wei Tao², Ting Ni¹

Affiliations

¹ State Key Laboratory of Genetic Engineering and Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, 200438 China.
² MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871 China.
³ Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
⁴ Human Aging Research Institute and School of Life Sciences, Nanchang University, Nanchang, 330031 China.
⁵ State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438 China.
⁶ School of Pharmacy, Fudan University, Shanghai, 201203 China.

^# Contributed equally.

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.