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

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

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  • D. Piscitello
  • D. Varshney
  • S. Lilla
  • M. G. Vizioli
  • C. Reid
  • V. Gorbunova
  • A. Seluanov
  • D. A. Gillespie (Lead / Corresponding author)
  • P. D. Adams (Lead / Corresponding author)

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Original languageEnglish
Pages (from-to)427-438
Number of pages12
Early online date2 Oct 2017
StatePublished - 25 Jan 2018


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.Oncogene advance online publication, 2 October 2017; doi:10.1038/onc.2017.340.

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