Effects of camptothecin analogues on DNA transformations mediated by calf thymus and human DNA topoisomerases I

Xiangyang Wang, Glenn F. Short, William D. Kingsbury, Randall K. Johnson, Sidney Hecht

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Camptothecin (CPT) and 10 structural analogues were studied to characterize their effects on specific rearrangements of DNA structure mediated by human and calf thymus DNA topoisomerases I. A 30 base pair DNA duplex containing a single high-efficiency topoisomerase cleavage site was incubated with each of the enzymes in the presence of the inhibitors. Individual inhibitors stabilized the covalent enzyme-DNA binary complex to different extents, as anticipated. However, for several of the inhibitors, the extent of ternary complex formation differed substantially for the human and calf thymus enzymes. In common with calf thymus topoisomerase I, the human enzyme was shown to mediate the rearrangement of branched, nicked, and gapped DNA substrates that constitute models for illegitimate recombination. However, some of these rearrangements proceeded with different rates and efficiencies in the presence of human topoisomerase I. When inhibition of three of the rearrangements by CPT analogues was studied, most of the analogues exhibited differential effects on a given transformation, depending on the source of the enzyme employed.

Original languageEnglish (US)
Pages (from-to)1352-1360
Number of pages9
JournalChemical Research in Toxicology
Volume11
Issue number11
DOIs
StatePublished - 1998
Externally publishedYes

Fingerprint

Thymus
Camptothecin
Type I DNA Topoisomerase
DNA
Enzymes
Thymus Gland
Gene Rearrangement
Base Pairing
Genetic Recombination
human TOP1 protein
calf thymus DNA
Substrates

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Effects of camptothecin analogues on DNA transformations mediated by calf thymus and human DNA topoisomerases I. / Wang, Xiangyang; Short, Glenn F.; Kingsbury, William D.; Johnson, Randall K.; Hecht, Sidney.

In: Chemical Research in Toxicology, Vol. 11, No. 11, 1998, p. 1352-1360.

Research output: Contribution to journalArticle

Wang, Xiangyang ; Short, Glenn F. ; Kingsbury, William D. ; Johnson, Randall K. ; Hecht, Sidney. / Effects of camptothecin analogues on DNA transformations mediated by calf thymus and human DNA topoisomerases I. In: Chemical Research in Toxicology. 1998 ; Vol. 11, No. 11. pp. 1352-1360.
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