Differential poisoning of topoisomerases by menogaril and nogalamycin dictated by the minor groove-binding nogalose sugar.

Abstract

The effect of DNA binding on poisoning of human DNA TOP1 has been studied using a pair of related anthracyclines which differ only by a nogalose sugar ring. We show that the nogalose sugar ring of nogalamycin, which binds to the minor groove of DNA, plays an important role in affecting topoisomerase-specific poisoning. Using purified mammalian topoisomerases, menogaril is shown to poison topoisomerase II but not topoisomerase I. By contrast, nogalamycin poisons topoisomerase I but not topoisomerase II. Consistent with the biochemical studies, CEM/VM-1 cells which express drug-resistant TOP2alpha are cross-resistant to menogaril but not nogalamycin. The mechanism by which nogalamycin poisons topoisomerase I has been studied by analyzing a major topoisomerase I-mediated DNA cleavage site induced by nogalamycin. This site is mapped to a sequence embedded in an AT-rich region with four scattered GC base pairs (bps) (at -10, -6, +2, and +12 positions). GC bps embedded in AT-rich regions are known to be essential for nogalamycin binding. Surprisingly, DNase I footprinting analysis of nogalamycin-DNA complexes has revealed a drug-free region from -2 to +9 encompassing the major cleavage site. Our results suggest that nogalamycin, in contrast to camptothecin, may stimulate TOP1 cleavage by binding to a site(s) distal to the site of cleavage.

• Authors: S P Sim, B Gatto, C Yu, A A Liu, T K Li, D S Pilch, E J LaVoie, L F Liu
• Journal: Biochemistry (Biochemistry) Vol. 36 Issue 43 Pg. 13285-91 (Oct 28 1997) ISSN: 0006-2960 [Print] United States
• PMID: 9341219 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Methylmannosides
• Tetracyclines
• nogalose
• Menogaril
• DNA
• Deoxyribonuclease I
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II
• Nogalamycin

Topics

• Anti-Bacterial Agents (toxicity)
• Base Sequence (drug effects)
• DNA (drug effects, metabolism)
• DNA Damage (drug effects)
• DNA Footprinting
• DNA Topoisomerases, Type I (drug effects, physiology)
• DNA Topoisomerases, Type II (metabolism)
• Deoxyribonuclease I
• Enzyme Stability (drug effects)
• Menogaril (toxicity)
• Methylmannosides (chemistry, metabolism)
• Nogalamycin (chemistry, toxicity)
• Tetracyclines