ArticleOncogene2018
AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 47 citations in OpenAlex.
- Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast-conserving surgery: a long-term follow-up of the SweBCG91-RT randomised trial.Molecular oncology · 2020Trial
- MRE11 Deficiency Occurs in a Small Group of Cancers from Various Different Tumor Entities.Diagnostics (Basel, Switzerland) · 2026Article
- TPTE, a testis-specific PTEN family member, drives spermatogenesis via PI(4,5)PCell death & disease · 2026Article
- βTrCP facilitates MRN complex localization on chromatin to enhance DNA repair.Communications biology · 2025Article
- Genome rearrangements induced by the stimulation of end-joining of DNA double strand breaks through multiple phosphorylation of MRE11 by the kinase PKB/AKT1.Nucleic acids research · 2025Article
- Targeting DNA damage sensors for cancer therapy.DNA repair · 2025Review
- S6K1 Controls DNA Damage Signaling Modulated by the MRN Complex to Induce Radioresistance in Lung Cancer.International journal of molecular sciences · 2024Article
- Exploiting the bile acid binding protein as transporter of a Cholic Acid/Mirin bioconjugate for potential applications in liver cancer therapy.Scientific reports · 2024Article
- PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex.British journal of cancer · 2024Article
- Ebselen: A Review on its Synthesis, Derivatives, Anticancer Efficacy and Utility in Combating SARS-COV-2.Mini reviews in medicinal chemistry · 2024Review
- Intranasal CEPO-FC prevents attention deficits in streptozotocin-induced rat model of Alzheimer's disease: Focus on synaptic plasticity-related factors.EXCLI journal · 2024Article
- Article
- Regulation of DNA damage response by trimeric G-proteins.iScience · 2023Article
- PARP inhibitors in the treatment of ARID1A mutant ovarian clear cell cancer: PI3K/Akt1-dependent mechanism of synthetic lethality.Frontiers in oncology · 2023Article
- S6 kinase 1 at the central node of cell size and ageing.Frontiers in cell and developmental biology · 2022Review
- Caloric restriction induced epigenetic effects on aging.Frontiers in cell and developmental biology · 2022Review
- Post-Translational Modifications of Proteins in Cytosolic Nucleic Acid Sensing Signaling Pathways.Frontiers in immunology · 2022Review
- Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy.Annals of translational medicine · 2021Review
- MAPK4 silencing together with a PARP1 inhibitor as a combination therapy in triple‑negative breast cancer cells.Molecular medicine reports · 2021Article
- Review
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.