Research Specialty: Function and biology of DNA topoisomerases The goal of my laboratory is to define the function and biology of eukaryotic topoisomerase II. To this end, four broad-based projects are currently underway. First, the enzymatic mechanism, active sites, and structure of topoisomerase II are being characterized. Current studies have delineated a number of individual steps in the catalytic cycle of the enzyme. Second, the mechanism by which chemotherapeutic drugs act on topoisomerase II is being explored. Work in this area has contributed to our understanding of drug action and also has identified at least two novel classes of potential anticancer agents. Third, the mechanism(s) by which topoisomerase II becomes resistant or hypersensitive to anticancer drugs is being addressed. In support of this project, a number of mutant type II topoisomerases with altered drug sensitivity have been isolated and are being characterized. Fourth, interactions between topoisomerase II and DNA lesions are being investigated. Initial work indicates that the enzyme interacts with specific forms of DNA damage and that lesions alter topoisomerase II activity in a manner similar to that of anticancer drugs. These findings indicate a novel physiological function for topoisomerase II and a mechanism by which the enzyme can selectively remove damaged cells from a population. Furthermore, it provides a teleological thread that links the chemotherapeutic actions of clinically relevant anticancer drugs to a natural cellular process.