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J Biol Chem, Vol. 274, Issue 11, 7292-7301, March 12, 1999

Mutation of a Conserved Serine Residue in a Quinolone-resistant Type II Topoisomerase Alters the Enzyme-DNA and Drug Interactions

Dirk Strumberg, John L. Nitiss§, Angela Rose§, Marc C. Nicklausparallel , and Yves Pommier

From the Laboratory of Molecular Pharmacology and the parallel  Laboratory of Medicinal Chemistry, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255 and the § Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

A Ser740 right-arrow Trp mutation in yeast topoisomerase II (top2) and of the equivalent Ser83 in gyrase results in resistance to quinolones and confers hypersensitivity to etoposide (VP-16). We characterized the cleavage complexes induced by the top2S740W in the human c-myc gene. In addition to resistance to the fluoroquinolone CP-115,953, top2S740W induced novel DNA cleavage sites in the presence of VP-16, azatoxin, amsacrine, and mitoxantrone. Analysis of the VP-16 sites indicated that the changes in the cleavage pattern were reflected by alterations in base preference. C at position -2 and G at position +6 were observed for the top2S740W in addition to the previously reported C-1 and G+5 for the wild-type top2. The VP-16-induced top2S740W cleavage complexes were also more stable. The most stable sites had strong preference for C-1, whereas the most reversible sites showed no base preference at positions -1 or -2. Different patterns of DNA cleavage were also observed in the absence of drug and in the presence of calcium. These results indicate that the Ser740 right-arrow Trp mutation alters the DNA recognition of top2, enhances its DNA binding, and markedly affects its interactions with inhibitors. Thus, residue 740 of top2 appears critical for both DNA and drug interactions.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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