3′ UTR lengthening as a novel mechanism in regulating cellular senescence
- Meng Chen1,7,
- Guoliang Lyu2,7,
- Miao Han1,7,
- Hongbo Nie1,7,
- 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 and
- Ting Ni1
- 1State 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;
- 2MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871 China;
- 3Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 4Human Aging Research Institute and School of Life Sciences, Nanchang University, Nanchang, 330031 China;
- 5State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438 China;
- 6School of Pharmacy, Fudan University, Shanghai, 201203 China
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↵7 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.224451.117.
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Freely available online through the Genome Research Open Access option.
- Received April 28, 2017.
- Accepted January 24, 2018.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
