title: ATR/Chk1/Smurf1 pathway determines cell fate after DNA damage by controlling RhoB abundance.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Qingang
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Taoling
authors.initials: T
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Yikai
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Mingdong
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Surgery, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.affiliation: 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China [2] Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518057, China.
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002458:Cell Fractionation; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008741:Methyl Methanesulfonate / Q000009:adverse effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D008741:Methyl Methanesulfonate; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D020743:rhoB GTP-Binding Protein