Human DNA‐topoisomerase I activity is affected by bis‐netropsin's binding to DNA minor groove

Abstract

AbstractBis‐netropsins (bis‐Nts) are known to be efficient inhibitors of human DNA topoisomerase (topo) I with a higher antitumor activity than netropsin. New sequence‐specific derivatives of bis‐Nts were used for modulation of topo I‐mediated DNA cleavage with and without camptothecin (CPT). Relation between the bis‐Nts binding sites and topo I cleavage sites has been analyzed with the plasmid DNA constructs generated by insertion of synthetic oligonucleotides containing various topo I‐cleavage and bis‐Nt‐binding sites. These constructs offer an opportunity to study minor groove binders effects on the topo I reaction on DNA. Three major effects: (i) bis‐Nt ‐ mediated disappearance of some of the topo I cleavage sites; (ii) enhancement of some other sites, and, (iii) generation of new cleavage sites, have been fovnd and analyzed. These effects demonstrate that bis‐Nts drastically change the topo I‐mediated DNA cleavage.