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

Sai Peng Sim, Barbara Gatto, Chiang Yu, Angela A. Liu, Tsai Kun Li, Daniel S. Pilch, Edmond J. LaVoie, Leroy-Fong Liu

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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 TOP2α 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.

Original languageEnglish
Pages (from-to)13285-13291
Number of pages7
JournalBiochemistry
Volume36
Issue number43
DOIs
Publication statusPublished - Oct 28 1997
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

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