Document Detail

DNA strand cleavage is required for replication fork arrest by a frozen topoisomerase-quinolone-DNA ternary complex.
MedLine Citation:
PMID:  8824300     Owner:  NLM     Status:  MEDLINE    
The formation of a topoisomerase-quinolone-DNA ternary complex leads to cell death. We show here that an active strand breakage and reunion activity is required for formation of a norfloxacin-topoisomerase IV-DNA ternary complex that can arrest the progression of replication forks in vitro. Mutant topoisomerases containing either an active site mutation, a quinolone resistance-conferring mutation, or both, could all bind DNA as well as the wild-type, but unlike the wild-type, could not halt replication fork progression. The collision between the replication fork and the frozen topoisomerase converted the cleavable complex to a nonreversible form but did not generate a double-stranded break. Thus, the cytotoxicity of this class of topoisomerase inhibitors likely results from a two-step process: (i) conversion of the frozen topoisomerase-quinolone-DNA ternary complex to an unreversible form; and (ii) generation of a double-strand break by subsequent denaturation of the topoisomerase, perhaps by an aborted repair attempt.
H Hiasa; D O Yousef; K J Marians
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  271     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1996 Oct 
Date Detail:
Created Date:  1996-11-26     Completed Date:  1996-11-26     Revised Date:  2008-08-29    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  26424-9     Citation Subset:  IM    
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA.
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MeSH Terms
DNA / metabolism*
DNA Replication*
DNA Topoisomerase IV
DNA Topoisomerases, Type II / genetics,  metabolism*
Deoxyribonucleases, Type II Site-Specific / metabolism
Electrophoresis, Polyacrylamide Gel
Escherichia coli
Mutagenesis, Site-Directed
Norfloxacin / pharmacology
Nucleic Acid Conformation
Quinolones / metabolism*
Grant Support
Reg. No./Substance:
0/Quinolones; 70458-96-7/Norfloxacin; 9007-49-2/DNA; EC type II deoxyribonucleases; EC, Type II Site-Specific; EC 5.99.1.-/DNA Topoisomerase IV; EC Topoisomerases, Type II

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