The basis for camptothecin enhancement of DNA breakage by eukaryotic topoisomerase I.
AUTOR(ES)
Porter, S E
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=335024Documentos Relacionados
- Characterization of an altered DNA catalysis of a camptothecin-resistant eukaryotic topoisomerase I.
- Resolution of Holliday junctions by eukaryotic DNA topoisomerase I.
- Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks.
- Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I.
- SCT1 mutants suppress the camptothecin sensitivity of yeast cells expressing wild-type DNA topoisomerase I.
