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

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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.

LanguageEnglish
Pages427-438
Number of pages12
JournalOncogene
Volume37
Early online date2 Oct 2017
DOIs
StatePublished - 25 Jan 2018

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DNA Repair
Phosphotransferases
Down-Regulation
DNA Damage
Recombinational DNA Repair
Neoplasms
Double-Stranded DNA Breaks
Genomic Instability
Phosphatidylinositol 3-Kinases
Oncogenes
Colon
Carcinogenesis
Fibroblasts
Carcinoma
mechanistic target of rapamycin complex 1
Therapeutics

Cite this

Piscitello, D., Varshney, D., Lilla, S., Vizioli, M. G., Reid, C., Gorbunova, V., ... Adams, P. D. (2018). AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. Oncogene, 37, 427-438. DOI: 10.1038/onc.2017.340
Piscitello, D. ; Varshney, D. ; Lilla, S. ; Vizioli, M. G. ; Reid, C. ; Gorbunova, V. ; Seluanov, A. ; Gillespie, D. A. ; Adams, P. D./ AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. In: Oncogene. 2018 ; Vol. 37. pp. 427-438
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title = "AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11",
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.",
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note = "Work in the Adams lab was supported by the CRUK programme grant C10652/A16566. DA Gillespie acknowledges the IMBRAIN Project (FP7-REGPOT-2012-CT2012-31637-IMBRAIN: EU FP7 and Gobierno de Canarias) for financial support. V Gorbunova acknowledges the NIA P01AG047200.",
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Piscitello, D, Varshney, D, Lilla, S, Vizioli, MG, Reid, C, Gorbunova, V, Seluanov, A, Gillespie, DA & Adams, PD 2018, 'AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11' Oncogene, vol. 37, pp. 427-438. DOI: 10.1038/onc.2017.340

AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. / Piscitello, D.; Varshney, D.; Lilla, S.; Vizioli, M. G.; Reid, C.; Gorbunova, V.; Seluanov, A.; Gillespie, D. A. (Lead / Corresponding author); Adams, P. D. (Lead / Corresponding author).

In: Oncogene, Vol. 37, 25.01.2018, p. 427-438.

Research output: Contribution to journalArticle

TY - JOUR

T1 - AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11

AU - Piscitello,D.

AU - Varshney,D.

AU - Lilla,S.

AU - Vizioli,M. G.

AU - Reid,C.

AU - Gorbunova,V.

AU - Seluanov,A.

AU - Gillespie,D. A.

AU - Adams,P. D.

N1 - Work in the Adams lab was supported by the CRUK programme grant C10652/A16566. DA Gillespie acknowledges the IMBRAIN Project (FP7-REGPOT-2012-CT2012-31637-IMBRAIN: EU FP7 and Gobierno de Canarias) for financial support. V Gorbunova acknowledges the NIA P01AG047200.

PY - 2018/1/25

Y1 - 2018/1/25

N2 - 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.

AB - 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.

U2 - 10.1038/onc.2017.340

DO - 10.1038/onc.2017.340

M3 - Article

VL - 37

SP - 427

EP - 438

JO - Oncogene

T2 - Oncogene

JF - Oncogene

SN - 0950-9232

ER -

Piscitello D, Varshney D, Lilla S, Vizioli MG, Reid C, Gorbunova V et al. AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. Oncogene. 2018 Jan 25;37:427-438. Available from, DOI: 10.1038/onc.2017.340