Sequence-dependent effect of camptothecin on human topoisomerase I DNA cleavage

Eigil Kjeldsen*, Steen Mollerup, Bo Thomsen, Bjarne Juul Bonven, Lars Bolund, Ole Westergaard

*Corresponding author for this work

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    74 Citations (Scopus)

    Abstract

    We have studied the effect of the antitumor drug, camptothecin, on the interaction of human topoisomerase I with DNA at the sequence level. At a low molar ratio of enzyme to DNA, cleavage is prominent and unique, located at a previously described hexadecameric recognition sequence, while a number of strong additional cleavage sites appear in the presence of the drug. Camptothecin stimulates cleavage at the recognition sequence less than twofold, whereas cleavage at the additional sites is stimulated up to 200-fold. Camptothecin greatly enhances the stability of the cleavable complexes formed at the additional sites, whereas the complex formed at the hexadecameric sequence is only marginally affected. Cleavage was eliminated at certain sites in the presence of camptothecin. Taken together these observations demonstrate that at least three types of potential eukaryotic topoisomerase I cleavage sites can be distinguished by the use of camptothecin. Comparison of the sequences at the additional cleavage sites in the presence of camptothecin reveals that the most frequently cleaved dinucleotide is TG with no consensus for the flanking nucleotides.

    Original languageEnglish
    JournalJournal of Molecular Biology
    Volume202
    Issue2
    Pages (from-to)333-342
    Number of pages10
    ISSN0022-2836
    DOIs
    Publication statusPublished - 20 Jul 1988

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