Nucleic Acids Research, 2000, Vol. 28, No. 9 1947-1954
© 2000 Oxford University Press
Sensitivity of human type II topoisomerases to DNA damage: stimulation of enzyme-mediated DNA cleavage by abasic, oxidized and alkylated lesions
1Department of Biochemistry and 2Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA
Type II topoisomerases are essential enzymes that are also the primary cellular targets for a number of important anticancer drugs. These drugs act by increasing levels of topoisomerase II-mediated DNA cleavage. Recent studies indicate that endogenous forms of DNA damage, such as abasic sites and base mismatches, also stimulate the DNA scission activity of the enzyme. To extend our understanding of how type II topoisomerases react to DNA damage, the effects of abasic sites, and oxidized and alkylated bases on DNA cleavage mediated by human topo-isomerase II
and ß were determined. Based on experiments that incorporated random abasic sites into plasmid DNA, human type II enzymes can locate lesions even within a background of several thousand undamaged base pairs. As determined by experiments that utilized site-specific forms of DNA lesions, oxidized or monoalkylated purines that allow base pairing and induce little distortion in the double helix have modest effects on topoisomerase II-mediated DNA cleavage. In contrast, 1,N6-ethenoadenine, a bulky lesion that disrupts base pairing, enhanced DNA cleavage ~10-fold. 1,N6-Ethenoadenine is the first lesion found to rival the stimulatory effects of apurinic sites on the DNA scission activity of eukaryotic type II topoisomerases.
* To whom correspondence should be addressed at: Department of Biochemistry, 654 Medical Research Building I, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. Tel: +1 615 322 4338; Fax: +1 615 343 1166; Email: osheron@ctrvax.vanderbilt.edu
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