DNA Polymerase ζ Regulates Cisplatin Cytotoxicity, Mutagenicity, and The Rate of Development of Cisplatin Resistance

Abstract

DNA polymerase zeta participates in translesional bypass replication. Here we show that reduced expression of the catalytic subunit hREV3 renders human fibroblasts more sensitive to the cytotoxic effect of cisplatin, reduces their sensitivity to the ability of cisplatin exposure to generate drug resistant variants in the surviving population, and reduces the rate of emergence of resistance to cisplatin at the population level. Reduction of REV3 mRNA did not alter the rate of cisplatin adduct removal but did impair both spontaneous and cisplatin-induced extrachromosomal homologous recombination and attenuated bypass replication as reflected by reduced ability to express luciferase from a platinated plasmid. Cisplatin induced a concentration- and time-dependent increase in hREV3 mRNA. The results indicate that, following formation of cisplatin adducts in DNA, REV3 mRNA levels increase, and polymerase zeta functions to promote both cell survival and the generation of drug-resistant variants in the surviving population. We conclude that when cisplatin adducts are present in the DNA, polymerase zeta is an important contributor to cisplatin-induced genomic instability and the subsequent emergence of resistance to this chemotherapeutic agent.