TY - JOUR
T1 - 3′ UTR lengthening as a novel mechanism in regulating cellular senescence
AU - Chen, Meng
AU - Lyu, Guoliang
AU - Han, Miao
AU - Nie, Hongbo
AU - Shen, Ting
AU - Chen, Wei
AU - Niu, Yichi
AU - Song, Yifan
AU - Li, Xueping
AU - Li, Huan
AU - Chen, Xinyu
AU - Wang, Ziyue
AU - Xia, Zheng
AU - Li, Wei
AU - Tian, Xiao Li
AU - Ding, Chen
AU - Gu, Jun
AU - Zheng, Yufang
AU - Liu, Xinhua
AU - Hu, Jinfeng
AU - Wei, Gang
AU - Tao, Wei
AU - Ni, Ting
N1 - Funding Information:
We thank Dr. Haijian Wang for providing the psiCHECK-2 Vector, Professor Hongyan Wang for luciferase assay instrument support, and Professors Li Jin and Jun Zhu for insightful suggestions regarding bioinformatic analyses. This work was supported by the National Basic Research Program of China (973 program: 2013CB530700 and 2015CB943000), National Natural Science Foundation of China (31771336, 31471192, 31521003, and 31471205), and the 111 Project of China (B13016). We thank Genergy Biotech (Shanghai) Co., Ltd. for the deep sequencing service. We thank Jeremy Allen, PhD, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for language polishing of this manuscript.
Publisher Copyright:
© 2018 Chen et al.
PY - 2018/3
Y1 - 2018/3
N2 - 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.
AB - 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.
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U2 - 10.1101/gr.224451.117
DO - 10.1101/gr.224451.117
M3 - Article
AN - SCOPUS:85045708021
SN - 1088-9051
VL - 28
SP - 285
EP - 294
JO - PCR Methods and Applications
JF - PCR Methods and Applications
IS - 3
ER -