Inhibition of Eukaryotic DNA Topoisomerase I: Understanding the Mechanisms of Cell Death and Drug Resistance

The helical structure of duplex DNA allows for the faithful duplication and transmission of genetic information from one generation to the next, at the same time maintaining the integrity of the polynucleotide chains. The complementary nature of the antiparallel DNA strands enables each to serve as a template for the synthesis of the respective daughter DNA strands. The intertwining of these polynucleotide chains in duplex DNA further ensures the integrity of the DNA helix by physically linking the individual strands in a structure stabilized by hydrogen bonding and stacking interactions between the hydrophobic bases (Bjornsti and Osheroff, 1999). Soon after the double-helical structure was proposed for DNA (Watson and Crick, 1953a), the replication of the circular DNA molecule of a prokaryote raised an intriguing question: How did the two sisters double-stranded DNA (dsDNA) molecules disentangle? This mechanical problem of separating two intertwined chains became a topological one. In such a molecule, the two single stranded rings are topologically linked and therefore, cannot come apart without at least one transient break in one of the two strands. The order or extent of topological linkage of the two strands is expressed by their linking number (Lk). Lk is defined as the number of times the two single strands revolve around each other. A right handed double helix with n base pairs will make one full turn every 10.5 base pairs under the physiological conditions in its most stable structure