The response of eukaryotic topoisomerases to DNA damage.
Beyond the known mutagenic properties of DNA lesions, recent evidence indicates that several forms of genomic damage dramatically influence the catalytic activities of DNA topoisomerases. Apurinic sites, apyrimidinic sites, base mismatches, and ultraviolet photoproducts all enhance topoisomerase I-mediated DNA cleavage when they are located in close proximity to the point of scission. Furthermore, when located between the points of scission of a topoisomerase II cleavage site, these same lesions (with the exception of ultraviolet photoproducts) greatly stimulate the cleavage activity of the type II enzyme. Thus, as found for anticancer drugs, lesions have the capacity to convert topoisomerases from essential cellular enzymes to potent DNA toxins. These findings raise exciting new questions regarding the mechanism of anticancer drugs, the physiological functions of topoisomerases, and the processing of DNA damage in the cell.
Kingma
P S
PS
Department of Biochemistry, 654 Medical Research Building I, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Osheroff
N
N
D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D019457:Chromosome Breakage / Q000235:genetics; D004247:DNA / Q000737:chemistry; D004249:DNA Damage / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D005057:Eukaryotic Cells; D016296:Mutagenesis / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects
D000970:Antineoplastic Agents; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II