Abstract
We previously reported that overexpression of the 24 kDa basic fibroblast factor (or FGF-2) isoform provides protection from the cytotoxic effect of ionizing radiation (IR). DNA double-strand breaks (DSB), the IR-induced lethal lesions, are mainly repaired in human cells by non-homologous end joining system (NHEJ). NHEJ reaction is dependent on the DNA-PK holoenzyme (composed of a regulatory sub-unit, Ku, and a catalytic sub-unit, DNA-PKcs) that assembles at sites of DNA damage. We demonstrated here that the activity of DNA-PK was increased by twofold in two independent radioresistant cell lines, HeLa 3A and CAPAN A3, overexpressing the 24 kDa FGF-2. This increase was associated with an overexpression of the DNA-PKcs without modification of Ku expression or activity. This overexpression was due to an up-regulation of the DNA-PKcs gene transcription by the 24 kDa FGF-2 isoform. Finally, HeLa 3A cells exhibited the hallmarks of phenotypic changes associated with the overexpression of an active DNA-PKcs. Indeed, a faster repair rate of DSB and sensitization to IR by wortmannin was observed in these cells. Our results represent the characterization of a new mechanism of control of DNA repair and radioresistance in human tumor cells dependent on the overproduction of the 24 kDa FGF-2 isoform.
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Acknowledgements
We thank CW Anderson (Brookhaven National Laboratory, New York, USA) for DNA-PKcs reporter plasmid, T Lindhal (London, UK) for anti-ligase IV antibody. We also thank A Estival and F Clemente (INSERM U531, Toulouse, France) for providing CAPAN-1 and CAPAN A3 cells. This work was supported by the Ministere de la Recherche et de l'Enseignement Supérieur (I Ader, E Cohen-Jonathan, G Favre, C Muller and B Salles), by the Ligue Nationale Contre le Cancer, by Electricité de France (C Toulas) and by the Groupe de Recherche de l'Institut Claudius Regaud (C Toulas, E Cohen-Jonathan and G Favre).
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Ader, I., Muller, C., Bonnet, J. et al. The radioprotective effect of the 24 kDa FGF-2 isoform in HeLa cells is related to an increased expression and activity of the DNA dependent protein kinase (DNA-PK) catalytic subunit. Oncogene 21, 6471–6479 (2002). https://doi.org/10.1038/sj.onc.1205838
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DOI: https://doi.org/10.1038/sj.onc.1205838
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