1. The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168.
- Author
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Xie X, Hu H, Tong X, Li L, Liu X, Chen M, Yuan H, Xie X, Li Q, Zhang Y, Ouyang H, Wei M, Huang J, Liu P, Gan W, Liu Y, Xie A, Kuai X, Chirn GW, Zhou H, Zeng R, Hu R, Qin J, Meng FL, Wei W, Ji H, and Gao D
- Subjects
- A549 Cells, AMP-Activated Protein Kinase Kinases, AMP-Activated Protein Kinases, Animals, DNA Breaks, Double-Stranded, Female, HCT116 Cells, HEK293 Cells, Humans, Male, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, Transgenic, Neoplasms genetics, Neoplasms pathology, Phosphorylation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Ribosomal Protein S6 Kinases, 70-kDa genetics, Ribosomal Protein S6 Kinases, 90-kDa genetics, Signal Transduction, TOR Serine-Threonine Kinases genetics, Tumor Burden, Ubiquitin-Protein Ligases genetics, Cell Proliferation, DNA Repair, Neoplasms enzymology, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Ribosomal Protein S6 Kinases, 90-kDa metabolism, TOR Serine-Threonine Kinases metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
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.
- Published
- 2018
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