4 - Topoisomerase genes and resistance to topoisomerase inhibitors

Summary

DNA topoisomerase genes and their functions

DNA topoisomerases are vital enzymes present in all living cells, and essential to the resolution of DNA topology. They modify the topological structure of DNA, leaving intact its nucleotide sequence. The activity of topoisomerases is required in order to separate the two intertwined chains of DNA, and allow several important physiological steps such as DNA replication and transcription. In eukaryotic cells there are essentially two types of DNA topoisomerases: DNA topoisomerase I (topo I) and DNA topoisomerase II (topo II).

Several steps are performed by topoisomerases in their dynamic interaction with DNA: DNA binding, DNA cleavage, DNA strand passage (single-strand for topo I and double-strand for topo II), religation, and enzyme turnover (Osheroff, 1989). Topo I determines one strand break at a time, followed by passage of the other strand of the double-stranded DNA helix and by religation. Topo II cuts both strands of DNA, and forms a gap through which a whole DNA double strand can pass, followed by religation.

Both type topoisomerases interact with the DNA through a tyrosine residue, by forming an enzyme–DNA ester bond; after the strand passage the deoxyribose hydroxyl group at the broken end reforms the DNA phosphodiester linkage and frees the enzyme for the next round of reactions.