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Oncogene. 2018 Jan 25;37(4):427-438. doi: 10.1038/onc.2017.340. Epub 2017 Oct 2.

AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11.

Author information

1
Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK.
2
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK.
3
Epigenetics of Cancer and Ageing, University of Glasgow, Glasgow, UK.
4
Department of Biology, University of Rochester, Rochester, NY, USA.
5
Instituto de Tecnologías Biomédicas, Centro de Investigaciones Biomédicas de Canarias, Facultad de Medicina, Universidad de La Laguna, La Laguna, Tenerife, Spain.

Abstract

Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway. MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. In primary human fibroblasts, activated AKT suppresses MRN complex expression to escalate RAS-induced DNA damage and thereby reinforce oncogene-induced senescence. Taken together, our data demonstrate that deregulation of the PI3K-AKT/ mTORC1/ p70S6K pathways, an event frequently observed in cancer, exert profound effects on genome stability via MRE11 with potential implications for tumour initiation and therapy.

PMID:
28967905
PMCID:
PMC5799716
DOI:
10.1038/onc.2017.340
[Indexed for MEDLINE]
Free PMC Article

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