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

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)

Research output: Contribution to journalArticle

14 Citations (Scopus)
162 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)427-438
Number of pages12
JournalOncogene
Volume37
Issue number4
Early online date2 Oct 2017
DOIs
Publication statusPublished - 25 Jan 2018

    Fingerprint

Keywords

  • DNA Damage/radiation effects
  • Down-Regulation
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic/radiation effects
  • Genomic Instability/genetics
  • HCT116 Cells
  • Humans
  • MRE11 Homologue Protein/antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1/genetics
  • Neoplasms/genetics
  • PTEN Phosphohydrolase/deficiency
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors
  • Pyrimidinones/pharmacology
  • RNA, Small Interfering/metabolism
  • Radiation Tolerance/genetics
  • Recombinational DNA Repair/genetics
  • Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors
  • Signal Transduction/genetics
  • Thiones/pharmacology
  • X-Rays/adverse effects

Cite this

Piscitello, D., Varshney, D., Lilla, S., Vizioli, M. G., Reid, C., Gorbunova, V., Seluanov, A., Gillespie, D. A., & Adams, P. D. (2018). AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. Oncogene, 37(4), 427-438. https://doi.org/10.1038/onc.2017.340