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

Area of Science:

• Molecular Biology
• Cellular Biology
• Genetics

Background:

• Cellular growth signals significantly impact genome integrity, but the precise mechanisms remain elusive.
• The mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) pathway is a key regulator of growth signaling.
• RNF168 plays a critical role in the DNA damage response.

Purpose of the Study:

• To elucidate the direct link between growth signaling pathways and genome integrity.
• To investigate the role of the mTOR-S6K pathway in regulating RNF168 function and DNA damage response.
• To understand the implications of LKB1 loss on genome stability via the mTORC1-S6K-RNF168 axis.

Main Methods:

• Investigated the phosphorylation of RNF168 by the mTOR-S6K pathway.
• Assessed the impact of RNF168 phosphorylation on its E3 ligase activity and proteolysis.
• Utilized LKB1-deficient cancer models to study DNA damage response defects.
• Employed a phospho-deficient RNF168 mutant (RNF168-S60A) to rescue DNA repair deficiencies.

Main Results:

• The mTOR-S6K pathway phosphorylates RNF168 at Ser60, inhibiting its E3 ligase activity and accelerating its degradation.
• This phosphorylation impairs RNF168's function in DNA damage response, leading to unrepaired DNA and genome instability.
• Loss of LKB1 results in hyperactivation of mTORC1-S6K signaling, decreased RNF168 expression, and defective DNA damage response.
• Expression of RNF168-S60A mutant rescues DNA repair defects and suppresses tumorigenesis in LKB1-deficient cells.

Conclusions:

• mTORC1-S6K signaling is crucial for maintaining genome stability by regulating RNF168.
• A novel mechanism connects cell growth signaling to genome stability control through the mTORC1-S6K-RNF168 pathway.
• Dysregulation of this pathway, as seen in LKB1 loss, contributes to tumorigenesis by compromising DNA repair.