Apurinic sites are position-specific topoisomerase II poisons.
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.
Kingma
P S
PS
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Osheroff
N
N
D000818:Animals; D001080:Apurinic Acid / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism; D004331:Drosophila melanogaster; D005047:Etoposide / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data
D001080:Apurinic Acid; D005047:Etoposide; D004247:DNA; D004250:DNA Topoisomerases, Type II