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AKT1 represses gene conversion induced by different genotoxic stresses and induces supernumerary centrosomes and aneuploidy in hamster ovary cells

Oncogene volume 28, pages 2231–2237 (2009)Cite this article

Abstract

The oncogenic kinase AKT1 is frequently overexpressed or activated in sporadic breast and ovarian cancers. In human breast tumors, we have previously shown that AKT1 represses homologous recombination (HR) induced by one double-strand break (DSB). To further analyze the impact of AKT1 on HR, we ectopically expressed wild-type or mutant forms of AKT1 in a hamster ovary cell line containing an intrachromosomal substrate for monitoring HR. In this cell line, AKT1 repressed HR induced by different genotoxic stresses including ionizing radiation, UV-C and one single DSB introduced into the intrachromosomal substrate. Consistently, AKT1 disrupted RAD51 foci formation, showing that AKT1 specifically affects gene conversion. Concomitantly, AKT1 represses both BRCA1 foci formation and HR stimulation resulting from BRCA1 overexpression, showing that AKT1 affects BRCA1-mediated HR functions, also in another species (hamster) and in another type of cell tissue (ovary cells). Finally, consistent with the HR defects, active AKT1 expression induces supernumerary centrosomes and aneuploidy. In addition to its impact on cell proliferation and apoptosis, the present data propose a novel oncogenic function for AKT1, by producing genomic instability as a consequence of HR repression.

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Acknowledgements

We thank Dr Hemmings (Friedrich Miescher Institute, Basel, Switzerland) for providing us the wtAKT1, myrAKT1 and kdAKT1 expression vectors, and Dr Jasin (Sloan-Kettering Institute, NYC, USA) for providing us with the CHO-DRA10 cell line and the I-SceI expression plasmid. This work was supported by La Ligue Nationale contre le Cancer ‘Equipes labellisées, La Ligue 2005 and 2008’ and by l'Agence Nationale de la Recherche. IP was a recipient of an ARC fellowship.

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  1. Institut de Radiobiologie Cellulaire et Moléculaire, UMR CEA-CNRS 217, Fontenay-aux-Roses, Cedex, France

    I Plo & B Lopez

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Correspondence to B Lopez.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Plo, I., Lopez, B. AKT1 represses gene conversion induced by different genotoxic stresses and induces supernumerary centrosomes and aneuploidy in hamster ovary cells. Oncogene 28, 2231–2237 (2009). https://doi.org/10.1038/onc.2009.85

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