Document Detail


The effect of camptothecin on topoisomerase I catalysis.
MedLine Citation:
PMID:  8993500     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The existence of a covalent intermediate in topoisomerase I catalysis allows uncoupling of the cleavage and ligation half-reactions on partially single-stranded DNA substrates containing a highly preferred interaction site. Using this model DNA substrate system we have demonstrated that the cleavage reaction requires bipartite interaction with two distinct DNA duplex regions; One located around the cleavage site (region A) and another located on the side holding the 5'-OH end generated by cleavage (region B). The postcleavage complexes containing the enzyme covalently attached at an internal position are capable of ligating DNA strands matching the noncleaved strand. Previously, we have characterized the effect of the antitumor agent camptothecin on the two half-reactions of topoisomerase I catalysis on DNA substrates allowing bipartite DNA interaction. The obtained results demonstrated that the drug only inhibited the ligation reaction leaving the cleavage reaction unaffected at the studied site. Here, we report that camptothecin also impairs ligation of the cleaved strand to a dinucleotide within region A in the absence of additional DNA contacts. When these results are taken together with the observation that camptothecin-trapped topoisomerase I-DNA complexes preferentially are generated at sites containing guanine immediately 3' to the cleavage position, it suggests that camptothecin inhibits the ligation reaction by forming a reversible ternary complex with the enzyme and DNA at the cleavage site within region A.
Authors:
K Christiansen; O Westergaard
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Annals of the New York Academy of Sciences     Volume:  803     ISSN:  0077-8923     ISO Abbreviation:  Ann. N. Y. Acad. Sci.     Publication Date:  1996 Dec 
Date Detail:
Created Date:  1997-01-29     Completed Date:  1997-01-29     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7506858     Medline TA:  Ann N Y Acad Sci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  50-9     Citation Subset:  IM    
Affiliation:
Department of Molecular and Structural Biology, University of Aarhus, Denmark.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / pharmacology*
Binding Sites
Camptothecin / pharmacology*
Catalysis / drug effects
DNA / metabolism
DNA Topoisomerases, Type I / antagonists & inhibitors*,  genetics,  metabolism
Dinucleoside Phosphates / metabolism
Dinucleotide Repeats
Enzyme Inhibitors / pharmacology*
Humans
Recombinant Proteins / drug effects,  genetics
Saccharomyces cerevisiae
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Dinucleoside Phosphates; 0/Enzyme Inhibitors; 0/Recombinant Proteins; 2382-65-2/cytidylyl-3'-5'-guanosine; 7689-03-4/Camptothecin; 9007-49-2/DNA; EC 5.99.1.2/DNA Topoisomerases, Type I

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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