DNA Topoisomerases: Essential Enzymes and Lethal Targets

INTRODUCTION In 1971, Wang (1) discovered the first DNA topoisomerase in Escherichia coli. The enzyme (E. coli DNA topoisomerase I, or w protein) catalyzed relaxation of negatively supercoiled DNA in the absence of any energy cofactor (1). Wang proposed that this enzyme also catalyzed transient nicking of the DNA double helix and possessed both DNase and ligase activity in one polypeptide (1). The lack of any energy cofactor for the reaction also led Wang to the proposal that the enzyme may form a high-energy covalent bond between itself and the transiently broken DNA phosphodiester bond (1). Both of these predictions have turned out to be correct (2). Since the discovery of E. coli topoisomerase I, investigators have isolated many other DNA topoisomerases from both prokaryotes and eukaryotes. In 1972, Champoux & Dulbecco isolated an enzyme with activity similar to that of E. coli topoisomerase I from mouse embryo cells (3). In 1976, Gellert and his colleagues identified an enzyme activity opposing E. coli DNA topoisomerase I (4). They demonstrated that this enzyme (E. coli DNA topoisomerase II, or gyrase) catalyzed the conversion of relaxed DNA into negatively supercoiled DNA in a reaction requiring ATP hydrolysis (4). These two opposing activities are important for maintaining the super­ helical state of the chromosomal DNA during various DNA transactions (5-8). In 1979, Liu et al (9) isolated an enzyme from bacteriophage