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The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168
- Source :
- Nature cell biology
- Publication Year :
- 2017
-
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.
- Subjects :
- 0301 basic medicine
Genome instability
Male
DNA Repair
DNA repair
DNA damage
Ubiquitin-Protein Ligases
Mice, Nude
P70-S6 Kinase 1
Mice, Transgenic
mTORC1
AMP-Activated Protein Kinases
Mechanistic Target of Rapamycin Complex 1
Protein Serine-Threonine Kinases
Ribosomal Protein S6 Kinases, 90-kDa
Article
03 medical and health sciences
Mice
AMP-Activated Protein Kinase Kinases
Neoplasms
Animals
Humans
DNA Breaks, Double-Stranded
Phosphorylation
Mechanistic target of rapamycin
PI3K/AKT/mTOR pathway
Cell Proliferation
Mice, Inbred BALB C
biology
TOR Serine-Threonine Kinases
Ribosomal Protein S6 Kinases, 70-kDa
Cell Biology
HCT116 Cells
3. Good health
Cell biology
Tumor Burden
030104 developmental biology
HEK293 Cells
A549 Cells
biology.protein
Female
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 14764679
- Volume :
- 20
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Nature cell biology
- Accession number :
- edsair.doi.dedup.....56f3ec368cc7733e066fda066d4f04be