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DNA Polymerase ß Mediates Protection of Mammalian Cells against Ganciclovir-induced Cytotoxicity and DNA Breakage¹

Division of Applied Toxicology, Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany [M. T. T., B. K.]; Institute for Antiviral Chemotherapy, Friedrich Schiller University, D-07745 Jena, Germany [R. T.]; and Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [R. W. S.]

The efficacy of suicide herpes simplex virus-1 thymidine kinase (HSVtk)/ganciclovir (GCV) gene therapy is often limited by intrinsic resistance of tumor cells. Here we show that repair of GCV incorporated in DNA is a factor involved in GCV resistance. A protective role of DNA repair in GCV-induced cell killing is supported by the following findings: (a) GCV-exposed Chinese hamster ovary-HSVtk cells exhibited both reduced repair of GCV and cloning efficiency in the presence of a specific polymerase ß (ß-pol) inhibitor, prunasin; (b) DNA ß-pol-deficient mouse fibroblasts were more sensitive to the cytotoxic, apoptosis-inducing, and genotoxic (DNA breakage and chromosomal aberration-inducing) effects of GCV as compared with wild-type and ß-pol-complemented cell lines; (c) methoxyamine, an inhibitor of ß-pol-dependent short-patch base excision repair, sensitized wild-type and complemented ß-pol cells to GCV, whereas it had no effect on the sensitivity of ß-pol-null cells to GCV. Because methoxyamine-mediated sensitization of ß-pol wild-type and ß-pol-complemented cells to GCV did not reach the level of null cells, we suggest that both ß-pol-dependent short- and long-patch base excision repair are involved in protection of cells to GCV. Some implications for HSVtk/GCV gene therapy are being discussed.

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