A PROTEIN-MEDIATED MECHANISM FOR THE DNA SEQUENCE-SPECIFIC ACTION OF TOPOISOMERASE-II POISONS

Chemical agents able to interfere with DNA topoisomerases are widespre ad in nature, and some of them have outstanding therapeutic efficacy i n human cancer and infectious diseases. DNA topoisomerases are essenti al enzymes that govern DNA topology during fundamental nuclear metabol ic processes. Topoisomerase-interfering compounds can be divided into two general categories based on the mechanism of drug action: poisons and catalytic inhibitors. In past years, investigations of the DNA seq uence selectivity of topoisomerase II poisons have identified structur al and molecular determinants of drug activity, and indicated that the drug receptor is likely to be at the protein-DNA interface. Moreover, the available results indicate that the biologically relevant DNA-bin ding activity of topoisomerase poisons is basically protein-mediated a nd this is discussed in this issue by Giovanni Capranico and colleague s. This suggests that topoisomerase poisons may represent a useful par adigm for small compounds able to bind to protein-DNA interfaces in a site-selective manner, thus increasing the affinity of DNA-binding pro teins for specific genomic sites.