DNA structural alterations induced by bis-netropsins modulate human DNA topoisomerase I cleavage activity and poisoning by camptothecin.
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.
Sukhanova
Alyona
A
EA3306, Institut Fédératif de Recherche no. 53 Biomolécules, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France.
Grokhovsky
Sergei
S
Ermishov
Michael
M
Mochalov
Konstantin
K
Zhuze
Alexei
A
Oleinikov
Vladimir
V
Nabiev
Igor
I
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
D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D009429:Netropsin; C032161:bis-netropsin; D004247:DNA; D004264:DNA Topoisomerases, Type I