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Open AccessArticle

Restraining Akt1 Phosphorylation Attenuates the Repair of Radiation-Induced DNA Double-Strand Breaks and Reduces the Survival of Irradiated Cancer Cells

1
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital Essen Virchowstrasse 173, 45147 Essen, Germany
2
Institute of Medical Radiation Biology, University of Duisburg-Essen, University Hospital Essen, Virchowstrasse 171, 45147 Essen, Germany
3
Department of Therapeutic Radiology, Yale University School of Medicine, 15 York Street, New Haven, CT 06520, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(8), 2233; https://doi.org/10.3390/ijms19082233
Received: 20 June 2018 / Revised: 21 July 2018 / Accepted: 24 July 2018 / Published: 31 July 2018
(This article belongs to the Special Issue Advances and Challenges in Biomolecular Radiation Research)
The survival kinase protein kinase B (Akt) participates in the regulation of essential subcellular processes, e.g., proliferation, growth, survival, and apoptosis, and has a documented role in promoting resistance against genotoxic stress including radiotherapy, presumably by influencing the DNA damage response and DNA double-strand break (DSB) repair. However, its exact role in DSB repair requires further elucidation. We used a genetic approach to explore the consequences of impaired phosphorylation of Akt1 at one or both of its key phosphorylation sites, Threonine 308 (T308) or Serine 473 (S473), on DSB repair and radiosensitivity to killing. Therefore, we overexpressed either the respective single or the double phosphorylation-deficient mutants (Akt1-T308A, Akt1-S473A, or Akt1-T308A/S473A) in TRAMPC1 murine prostate cancer cells (TrC1) and measured the DSB repair kinetics and clonogenic cell survival upon irradiation. Only the expression of the Akt1-T308A/S473A induced a significant delay in the kinetics of DSB repair in irradiated TrC1 as determined by the γH2A.X (H2A histone family, member X) assay and the neutral comet assay, respectively. Moreover, Akt1-T308A/S473A-expressing cells were characterized by increased radiosensitivity compared to Akt1-WT (wild type)-expressing cells in long-term colony formation assays. Our data reveal that Akt1’s activation state is important for the cellular radiation response, presumably by modulating the phosphorylation of effector proteins involved in the regulation of DSB repair. View Full-Text
Keywords: Akt; protein kinase B; Akt-phosphorylation; radiosensitivity; T308A; S473A; DNA-PK; MERIT40; radiation; DNA damage; DSB repair Akt; protein kinase B; Akt-phosphorylation; radiosensitivity; T308A; S473A; DNA-PK; MERIT40; radiation; DNA damage; DSB repair
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Szymonowicz, K.; Oeck, S.; Krysztofiak, A.; Van der Linden, J.; Iliakis, G.; Jendrossek, V. Restraining Akt1 Phosphorylation Attenuates the Repair of Radiation-Induced DNA Double-Strand Breaks and Reduces the Survival of Irradiated Cancer Cells. Int. J. Mol. Sci. 2018, 19, 2233.

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