title: DNA structural alterations induced by bis-netropsins modulate human DNA topoisomerase I cleavage activity and poisoning by camptothecin.
abstract: Bis-netropsins (bis-Nts) are efficient catalytic inhibitors of human DNA topoisomerase I (top I). These DNA minor groove binders are considered to serve as suppressors of top I-linked DNA breaks, which is generally believed to be related to their affinity to DNA. In this study, it was found that bis-Nts exhibit sequence-specificity of suppression of the strong top I-specific DNA cleavage sites and that this sequence-specificity is determined by differential ligand-induced structural alterations of DNA. Raman scattering analysis of bis-Nts interactions with double-stranded oligonucleotides, each containing the site of specific affinity to one of bis-Nts and a distinctly located top I degenerate consensus, demonstrated that bis-Nts induce not only structural changes in duplex DNA at their loading position, but also conformational changes in a distant top I-specific DNA cleavage site. The ability to alter the DNA structure correlates with the anti-top I inhibitory activities of the ligands. In addition, DNA structural alterations induced by bis-Nts were shown to be responsible for modulation of the camptothecin (CPT)-mediated DNA cleavage by top I. This effect is expressed in the bis-Nts-induced enhancement of some of the CPT-dependent DNA cleavage sites as well as in the CPT-induced enhancement of some of the top I-specific DNA cleavage sites suppressed by bis-Nts in the absence of CPT.
authors.affiliation: EA3306, Institut Fédératif de Recherche no. 53 Biomolécules, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France.
authors.forename: Alyona
authors.initials: A
authors.lastname: Sukhanova
authors.forename: Sergei
authors.initials: S
authors.lastname: Grokhovsky
authors.forename: Michael
authors.initials: M
authors.lastname: Ermishov
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mochalov
authors.forename: Alexei
authors.initials: A
authors.lastname: Zhuze
authors.forename: Vladimir
authors.initials: V
authors.lastname: Oleinikov
authors.forename: Igor
authors.initials: I
authors.lastname: Nabiev
mesh_terms: D001483:Base Sequence; D029769:Camptotheca / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D008969:Molecular Sequence Data; D009429:Netropsin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D013059:Spectrum Analysis, Raman; D059004:Topoisomerase I Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D009429:Netropsin; C032161:bis-netropsin; D004247:DNA; D004264:DNA Topoisomerases, Type I