ATR/Chk1/Smurf1 pathway determines cell fate after DNA damage by controlling RhoB abundance

Meilin Wang, Lei Guo, Qingang Wu, Taoling Zeng, Qi Lin, Yikai Qiao, Qun Wang, Mingdong Liu, Xin Zhang, Lan Ren, Sheng Zhang, Yihua Pei, Zhenyu Yin, Feng Ding and Hong-Rui Wang ()
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Meilin Wang: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Lei Guo: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Qingang Wu: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Taoling Zeng: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Qi Lin: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Yikai Qiao: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Qun Wang: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Mingdong Liu: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Xin Zhang: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Lan Ren: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Sheng Zhang: Zhongshan Hospital, Xiamen University
Yihua Pei: Central Laboratory, Zhongshan Hospital, Xiamen University
Zhenyu Yin: Zhongshan Hospital, Xiamen University
Feng Ding: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University
Hong-Rui Wang: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract ATM- and RAD3-related (ATR)/Chk1 and ataxia–telangiectasia mutated (ATM)/Chk2 signalling pathways play critical roles in the DNA damage response. Here we report that the E3 ubiquitin ligase Smurf1 determines cell apoptosis rates downstream of DNA damage-induced ATR/Chk1 signalling by promoting degradation of RhoB, a small GTPase recognized as tumour suppressor by promoting death of transformed cells. We show that Smurf1 targets RhoB for degradation to control its abundance in the basal state. DNA damage caused by ultraviolet light or the alkylating agent methyl methanesulphonate strongly activates Chk1, leading to phosphorylation of Smurf1 that enhances its self-degradation, hence resulting in a RhoB accumulation to promote apoptosis. Suppressing RhoB levels by overexpressing Smurf1 or blocking Chk1-dependent Smurf1 self-degradation significantly inhibits apoptosis. Hence, our study unravels a novel ATR/Chk1/Smurf1/RhoB pathway that determines cell fate after DNA damage, and raises the possibility that aberrant upregulation of Smurf1 promotes tumorigenesis by excessively targeting RhoB for degradation.

Date: 2014
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DOI: 10.1038/ncomms5901

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