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Nucleic Acids Research, 1990, Vol. 18, No. 8 1983-1989
© 1990

MOLECULAR BIOLOGY

Distamycin inhibition of topoisomerase I-DNA interaction: a mechanistic analysis

Uffe H. Mortensen, Tinna Stevnsner+, Susanne Krogh, Kjeld Olesen, Ole Westergaard and Bjarne J. Bonven*

Department of Molecular Biology and Plant Physiology, University of Aarhus DK-8000 Århus C, Denmark

* To whom correspondence should be addressed

Received January 24, 1990. Accepted March 16, 1990.

Inhibition of eukaryotic DNA topoisomerase I by the minor groove binding ligand, distamycin A, was investigated. Low concentrations of the ligand selectively prevented catalytic action at a high affinity topoisomerase I binding sequence. A restriction enzyme protection assay indicated that the catalytic cycle was blocked at the binding step. Distamycin binding sites on DNA were localized by hydroxyl radical footprinting. A strongly preferred site mapped to a homopolymeric (dA)·(dT)-tract partially included in the essential topoisomerase I binding region. Mutational elimination of the stable helix curvature associated with this ligand binding site demonstrated that (i) the intrinsic bend was inessential for efficient binding of topoisomerase I, and (ii) distamycin inhibition did not occur by deformation of a stable bend. Alternative modes of inhibition are discussed.

+ Present address: National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA


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