OVEREXPRESSION OF DNA-POLYMERASE-BETA IN CELL RESULTS IN A MUTATOR PHENOTYPE AND A DECREASED SENSITIVITY TO ANTICANCER DRUGS

DNA polymerase beta (pol beta) is the most error prone of all known eu karyotic DNA polymerases tested in vitro. Here, we show that cells ove rexpressing pol beta cDNA have acquired a spontaneous mutator phenotyp e. By measuring the appearance of mutational events using three indepe ndent assays, we found that genetic instability increased in the cell lines that overexpressed pol beta. In addition, these cells displayed a decreased sensitivity to cancer chemotherapeutic, bifunctional, DNA- damaging agents such as cisplatin, melphalan, and mechlorethamine, res ulting in enhanced mutagenesis compared with control cells. By using c ell-free extracts and modified DNA substrates, we present data in supp ort of error-prone translesion replication as one of the key determina nts of tolerance phenotype. These results have implications for the po tential role of pol beta overexpression in cancer predisposition and t umor progression during chemotherapy.