Growth signals, such as extracellular nutrients and growth factors, have significant impacts on genome integrity, while 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 signaling, phosphorylates RNF168 at Ser60 to inhibit its E3 ligase activity, accelerate its proteolysis, and impair its function in DNA damage response, leading to accumulated unrepaired DNA and genome instability. Moreover, loss of the tumor suppressor LKB1/STK11 hyper-activates the mTORC1-S6K signaling and decreases RNF168 expression, resulting in defects of 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 the mTORC1-S6K signaling in DNA damage response and suggest a general mechanism connecting cell growth signaling to genome stability control.

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