FROM DNA TOPOLOGY TO CLINICAL ACTIVE ANTI BIOTICS AND ANTITUMOR AGENTS

The control of DNA topology and the multiple processes linked to DNA m etabolism, i.e. gene expression, replication or recombination, are ach ieved by specialized enzymes named DNA topoisomerases. These ubiquitou s enzymes form a fast growing family of proteins with a common basic m echanism : they are all able to produce transient breaks in the DNA ba ckbone and to allow the passage of DNA segments through these beaks be fore resealing. They are usually divided into two classes : type I top oisomerases produce transient single-strand breaks, while type II topo isomerases can simultaneously cleave both eave strands. These latter e nzymes form a rather homogeneous group of proteins by their biochemica l properties as well as their sequence similarities. On the contrary, type I topoisomerases are heterogeneous, with important differences in their structural and biochemical properties, depending on their archa ebacterial, eubacterial or eukaryotic origin. DNA topoisomerases (I or II) are the intracellular targets of several classes of antitumor or antibacterial agents. Knowing the precise modes of interaction of thes e compounds with topoisomerases and DNA would permit to better underst and the basis of their activity. In addition, the long pathway from pr oduction of lesions in the DNA molecule to cell death begins to be elu cidated. These studies open promising developments for the rational de sign of new antitumor, antibacterial and antiviral agents with conside rably more selective and more powerful activities.