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Nucleic Acids Research, 1990, Vol. 18, No. 22 6611-6619
© 1990

MOLECULAR BIOLOGY

Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin

Giovanni Capranico+, Kurt W. Kohn and Yves Pommier*

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA

* To whom correspondence should be addressed

Received July 16, 1990. Revised October 15, 1990. Accepted October 15, 1990.

Doxorubicin, a DNA-intercalator, is one of several anti-cancer drugs that have been found to stabilizes topoisomerase II cleavage complexes at drug-specific DNA sites. The distribution and DNA sequence environments of doxorubicin-stabillzed sites were determined in the SV40 genome. The sites were found to be most concentrated in the major nuclear matrix-associated region and nearly absent in the vicinity of the replication origin including the enhancer sequences in the 21 -bp and 72-bp tandem repeats. Among 97 doxorubicin-stabilized sites that were localized at the DNA sequence level, none coincided with any of the 90 topoisomerase II cleavage sites detected in the same regions in the absence of drug. Cleavage at the 90 enzyme-only sites was inhibited by doxorubicin and never stimulated even at low drug concentrations. All of the doxorubicin-stabilized sites had an A at the 3' terminus of at least one member of each pair of strand breaks that would constitute a topoisomerase II double-strand scission. Conversely, none of the enzyme-only sites had an A simultaneously at the corresponding positions on opposite strands. The 3'-A requirement for doxorubicin-stabilized cleavage is therefore incompatible with enzyme-only cleavage and explains the mutual exclusivity of the two classes of sites.

+ Present address: Division of Experimental Oncology B, Istituto Nazionale Tumori, v. Venezian 1, 20133 Milan, Italy


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