title: Type II topoisomerases--inhibitors, repair mechanisms and mutations.
abstract: Type II topoisomerases are ubiquitous enzymes that play an essential role in the control of replicative DNA synthesis and share structural and functional homology among different prokaryotic and eukaryotic organisms. Antibacterial fluoroquinolones target prokaryotic topoisomerases at concentrations 100- to 1000-fold lower than mammalian enzymes, the preferred targets of anticancer drugs such as etoposide. The mechanisms of action of both of these types of inhibitors involve the fixation of an intermediate reaction step, where the enzyme is covalently bound to an enzyme-mediated DNA double-strand break (DSB). The resulting ternary drug-enzyme-DNA complexes can then be converted to cleavage complexes that block further movement of the DNA replication fork, subsequently inducing stress responses. In haploid prokaryotic cells, stress responses include error-free and error-prone DNA damage repair pathways, such as homologous recombination and translesion synthesis, respectively. The latter can result in the acquisition of point mutations. Diploid mammalian cells are assumed to preferentially use recombination mechanisms for the repair of DSBs, an example of which, non-homologous end joining, is a major error-prone repair mechanism associated with an increased frequency of detectable small deletions, insertions and translocations. However, results obtained from safety testing of novel fluoroquinolones at high concentrations indicate that point mutations may also occur in mammalian cells. Recent data provide evidence for translesion synthesis catalysed by error-prone repair polymerases as a damage-tolerance repair mechanism of DSBs in eukaryotic cells. This paper discusses possible roles of different mechanisms for the repair of DSBs operating in both eukaryotic and prokaryotic cells that result in recombinational rearrangements, deletions/insertions as well as point mutations.
authors.affiliation: Pharmaceutical Biology and Microbiology, Department of Chemistry, University of Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany. heisig@chemie.uni-hamburg.de
authors.forename: Peter
authors.initials: P
authors.lastname: Heisig
mesh_terms: D000818:Animals; D001419:Bacteria / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D017354:Point Mutation; D011995:Recombination, Genetic; D059005:Topoisomerase II Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II