Pourquier P, Ueng L M, Kohlhagen G, Mazumder A, Gupta M, Kohn K W, Pommier Y
Laboratory of Molecular Pharmacology, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 1997 Mar 21;272(12):7792-6. doi: 10.1074/jbc.272.12.7792.
Abasic sites and deamination of cytosine to uracil are probably the most common types of endogenous DNA damage. The effects of such lesions on DNA topoisomerase I (top1) activity were examined in oligonucleotides containing a unique top1 cleavage site. The presence of uracils and abasic sites within the first 4 bases immediately 5' to the cleavage site suppressed normal top1 cleavage and induced new top1 cleavage sites. Uracils immediately 3' to the cleavage site increased cleavage and produced a camptothecin mimicking effect. A mismatch with a bulge or abasic sites immediately 3' to the top1 cleavage site irreversibly trapped top1 cleavable complexes in the absence of camptothecin and produced a suicide cleavage complex. These results demonstrate that top1 activity is sensitive to physiological, environmental, and pharmacological DNA modifications and that top1 can act as a specific mismatch- and abasic site-nicking enzyme.
