Apurinic sites are position-specific topoisomerase II poisons.

Kingma PS, Osheroff N
J Biol Chem. 1997 272 (2): 1148-55

PMID: 8995415 · DOI:10.1074/jbc.272.2.1148

Many anticancer drugs "poison" topoisomerase II by enhancing its double-stranded DNA cleavage activity. To determine whether DNA lesions act as endogenous topoisomerase II poisons, we characterized the effects of position-specific apurinic sites on enzyme activity. Lesions located within the 4-base overhang generated by enzyme-mediated DNA scission stimulated cleavage approximately 10-18-fold without altering the specificity of topoisomerase II. DNA breaks were double-stranded in nature, protein-linked, and readily reversible. In contrast, apurinic sites located immediately outside the cleavage overhang were inhibitory. Thus, apurinic sites, which are the most commonly formed lesion in DNA, are position-specific topoisomerase II poisons. A model is proposed that encompasses the actions of endogenous and exogenous topoisomerase II poisons and provides a pre-existing pathway for the cellular actions of topoisomerase II-targeted anticancer drugs.

MeSH Terms (10)

Animals Apurinic Acid Base Sequence Binding Sites DNA DNA Topoisomerases, Type II Drosophila melanogaster Etoposide Models, Molecular Molecular Sequence Data

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