The Antitumor Agent Cisplatin Inhibits DNA Gyrase and Preferentially Induces gyrB Gene Expression inEscherichia coli

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Abstract
Cisplatin is a widely used anticancer agent that exerts its biological activity principally by damaging DNA. Although detailed knowledge exists concerning mechanisms that lead to cisplatin adducts in DNA, there are few insights into the processes that result in its antitumor action. To explore some of the cellular responses elicited by cisplatin treatment, we studied its influence on DNA supercoiling and DNA gyrase gene expression in E. coli. We found that cisplatin inhibits DNA gyrase in a concentration-dependent manner leading to a transient alteration of DNA supercoiling and to an induction of gyrase gene expression. The induction effect was asymmetrical, affecting gyrB stronger than gyrA. Furthermore, we studied the influence of cisplatin on the supercoiling activity of purified DNA gyrase in vitro and found that cisplatin was an efficient inhibitor of DNA gyrase in the standard assay. However, cisplatin was an excellent inhibitor when added to DNA gyrase before it could interact with its substrate. In this assay GyrB was also more affected by cisplatin than GyrA. This strongly suggests that cisplatin inhibits DNA gyrase primarily by direct interaction with the enzyme. The data from this work present evidence that further cellular responses following cisplatin treatment include DNA gyrase inhibition, altered DNA supercolling and enhanced DNA gyrase gene expression. This suggests an important role of DNA topology in the induction of defense mechanisms against the action of cisplatin in addition to the processes related to DNA damage and repair.