The mTOR–S6K pathway links growth signalling to DNA damage response by targeting RNF168

被引：0
作者：
Xiaoduo Xie
Hongli Hu
Xinyuan Tong
Long Li
Xiangyuan Liu
Min Chen
Huairui Yuan
Xia Xie
Qingrun Li
Yuxue Zhang
Huafang Ouyang
Mengqi Wei
Jing Huang
Pengda Liu
Wenjian Gan
Yong Liu
Anyong Xie
Xiaoling Kuai
Gung-Wei Chirn
Hu Zhou
Rong Zeng
Ronggui Hu
Jun Qin
Fei-Long Meng
Wenyi Wei
Hongbin Ji
Daming Gao
机构：
[1] University of Chinese Academy of Sciences,State Key Laboratory of Cell Biology, CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and
[2] University of Chinese Academy of Sciences,The Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Ton
[3] Chinese Academy of Sciences,State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences
[4] Chinese Academy of Sciences,CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences
[5] Chinese Academy of Sciences,National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences
[6] Chinese Academy of Sciences,Shanghai Science Research Center
[7] Harvard Medical School,Department of Pathology, Beth Israel Deaconess Medical Center
[8] Shanghai Jiaotong University,Department of Radiation Oncology, Shanghai General Hospital
[9] Zhejiang University School of Medicine,Sir Run Run Shaw Hospital and Institute of Translational Medicine
[10] Hangzhou,Department of Gastroenterology
[11] Nantong University Affiliated Hospital,Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica
[12] OrigiMed Co. Ltd,Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center
[13] University of Chinese Academy of Sciences,undefined
[14] Chinese Academy of Sciences,undefined
[15] University of North Carolina at Chapel Hill,undefined
来源：
Nature Cell Biology | 2018年 / 20卷
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摘要：
Growth signals, such as extracellular nutrients and growth factors, have substantial effects on genome integrity; however, the direct underlying link remains unclear. Here, we show that the mechanistic target of rapamycin (mTOR)–ribosomal S6 kinase (S6K) pathway, a central regulator of growth signalling, phosphorylates RNF168 at Ser60 to inhibit its E3 ligase activity, accelerate its proteolysis and impair its function in the DNA damage response, leading to accumulated unrepaired DNA and genome instability. Moreover, loss of the tumour suppressor liver kinase B1 (LKB1; also known as STK11) hyperactivates mTOR complex 1 (mTORC1)–S6K signalling and decreases RNF168 expression, resulting in defects in the DNA damage response. Expression of a phospho-deficient RNF168-S60A mutant rescues the DNA damage repair defects and suppresses tumorigenesis caused by Lkb1 loss. These results reveal an important function of mTORC1–S6K signalling in the DNA damage response and suggest a general mechanism that connects cell growth signalling to genome stability control.
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页码：320 / 331
页数：11
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  • [1] Langie SA(2015)Causes of genome instability: the effect of low dose chemical exposures in modern society Carcinogenesis 36 S61-S88
  • [2] Ciccia A(2010)The DNA damage response: making it safe to play with knives Mol. Cell. 40 179-204
  • [3] Elledge SJ(2011)Double-strand break end resection and repair pathway choice Annu. Rev. Genet. 45 247-271
  • [4] Symington LS(2001)DNA double-strand breaks: signaling, repair and the cancer connection Nat. Genet. 27 247-254
  • [5] Gautier J(2002)Sensing and repairing DNA double-strand breaks Carcinogenesis 23 687-696
  • [6] Khanna KK(2007)RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly Cell 131 901-914
  • [7] Jackson SP(2007)Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase Science 318 1637-1640
  • [8] Jackson SP(2009)RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins Cell 136 435-446
  • [9] Huen MS(2009)The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage Cell 136 420-434
  • [10] Kolas NK(2012)mTOR signaling in growth control and disease Cell 149 274-293
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