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Nucleic Acids Res. 1989 Nov 11;17(21):8521-32.

The basis for camptothecin enhancement of DNA breakage by eukaryotic topoisomerase I.

Author information

1
Department of Microbiology, University of Washington, Seattle 98195.

Abstract

The eukaryotic topoisomerase I (topo I) is the target of the cytotoxic alkaloid camptothecin (CTT). In vitro, CTT enhances the breakage of DNA by topo I when the reaction is stopped with detergent. Although breakage at some sites is enhanced to a great extent while breakage at others is enhanced only minimally, CTT does not significantly change the breakage specificity of topo I in vitro. It has been suggested that CTT acts by slowing the reclosure step of the nicking-closing reaction. To test this hypothesis, we have measured the rate of reclosure for different break sites in the presence of CTT after adding 0.5 M NaCl to a standard low salt reaction. In support of the hypothesis, we find that topo I-mediated DNA breakage is enhanced the greatest at those sites where closure of the break is the slowest. These results suggest a mechanism for the toxicity of CTT in vivo.

PMID:
2555774
PMCID:
PMC335024
DOI:
10.1093/nar/17.21.8521
[Indexed for MEDLINE]
Free PMC Article

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