Several drugs have recently been identified as specific inhibitors of eukaryotic DNA topoisomerases. We have shown that these inhibitors affect the regulation of eukaryotic heat shock gene expression suggesting a role for these enzymes in this highly conserved eukaryotic cell function. The emphasis of this proposal is to use these inhibitors to delineate the function of DNA topoisomerases in regulating eukaryotic gene expression. The Drosophila heat-shock system will be used as a model for these studies.