PMID- 29403037 OWN - NLM STAT- MEDLINE DCOM- 20190410 LR - 20211204 IS - 1476-4679 (Electronic) IS - 1465-7392 (Print) IS - 1465-7392 (Linking) VI - 20 IP - 3 DP - 2018 Mar TI - The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168. PG - 320-331 LID - 10.1038/s41556-017-0033-8 [doi] AB - 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. FAU - Xie, Xiaoduo AU - Xie X AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Hu, Hongli AU - Hu H AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Tong, Xinyuan AU - Tong X AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Li, Long AU - Li L AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Liu, Xiangyuan AU - Liu X AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Chen, Min AU - Chen M AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Yuan, Huairui AU - Yuan H AD - 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 Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China. FAU - Xie, Xia AU - Xie X AD - 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, Chinese Academy of Sciences, Shanghai, China. FAU - Li, Qingrun AU - Li Q AUID- ORCID: 0000-0002-1644-0508 AD - 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, Chinese Academy of Sciences, Shanghai, China. FAU - Zhang, Yuxue AU - Zhang Y AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Ouyang, Huafang AU - Ouyang H AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Wei, Mengqi AU - Wei M AD - National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. AD - Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China. FAU - Huang, Jing AU - Huang J AD - National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. AD - Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China. FAU - Liu, Pengda AU - Liu P AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. AD - Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Gan, Wenjian AU - Gan W AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. FAU - Liu, Yong AU - Liu Y AD - Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China. FAU - Xie, Anyong AU - Xie A AD - Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. FAU - Kuai, Xiaoling AU - Kuai X AD - Department of Gastroenterology, Nantong University Affiliated Hospital, Nantong, Jiangsu, China. FAU - Chirn, Gung-Wei AU - Chirn GW AD - OrigiMed Co. Ltd, Shanghai, China. FAU - Zhou, Hu AU - Zhou H AD - Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. FAU - Zeng, Rong AU - Zeng R AD - 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, Chinese Academy of Sciences, Shanghai, China. FAU - Hu, Ronggui AU - Hu R AD - 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, Chinese Academy of Sciences, Shanghai, China. FAU - Qin, Jun AU - Qin J AD - 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 Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China. FAU - Meng, Fei-Long AU - Meng FL AD - 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, Chinese Academy of Sciences, Shanghai, China. FAU - Wei, Wenyi AU - Wei W AUID- ORCID: 0000-0003-0512-3811 AD - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. FAU - Ji, Hongbin AU - Ji H AUID- ORCID: 0000-0003-0891-6390 AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. FAU - Gao, Daming AU - Gao D AUID- ORCID: 0000-0003-4374-1055 AD - 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 Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. dgao@sibcb.ac.cn. LA - eng GR - K99 CA181342/CA/NCI NIH HHS/United States GR - R00 CA181342/CA/NCI NIH HHS/United States GR - T32 HL007893/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180205 PL - England TA - Nat Cell Biol JT - Nature cell biology JID - 100890575 RN - EC 2.3.2.27 (RNF168 protein, human) RN - EC 2.3.2.27 (RNF168 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa) RN - EC 2.7.11.1 (Rps6ka1 protein, mouse) RN - EC 2.7.11.1 (STK11 protein, human) RN - EC 2.7.11.1 (Stk11 protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (ribosomal protein S6 kinase, 70kD, polypeptide 1) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - A549 Cells MH - AMP-Activated Protein Kinase Kinases MH - AMP-Activated Protein Kinases MH - Animals MH - *Cell Proliferation MH - DNA Breaks, Double-Stranded MH - *DNA Repair MH - Female MH - HCT116 Cells MH - HEK293 Cells MH - Humans MH - Male MH - Mechanistic Target of Rapamycin Complex 1/genetics/metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Mice, Transgenic MH - Neoplasms/*enzymology/genetics/pathology MH - Phosphorylation MH - Protein Serine-Threonine Kinases/genetics/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/genetics/*metabolism MH - Ribosomal Protein S6 Kinases, 90-kDa/genetics/*metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/genetics/*metabolism MH - Tumor Burden MH - Ubiquitin-Protein Ligases/genetics/*metabolism PMC - PMC5826806 MID - NIHMS930405 COIS- Competing Financial Interests. The authors declare no competing financial interests. EDAT- 2018/02/07 06:00 MHDA- 2019/04/11 06:00 PMCR- 2018/08/05 CRDT- 2018/02/07 06:00 PHST- 2017/09/21 00:00 [received] PHST- 2017/12/22 00:00 [accepted] PHST- 2018/02/07 06:00 [pubmed] PHST- 2019/04/11 06:00 [medline] PHST- 2018/02/07 06:00 [entrez] PHST- 2018/08/05 00:00 [pmc-release] AID - 10.1038/s41556-017-0033-8 [pii] AID - 10.1038/s41556-017-0033-8 [doi] PST - ppublish SO - Nat Cell Biol. 2018 Mar;20(3):320-331. doi: 10.1038/s41556-017-0033-8. Epub 2018 Feb 5.