DNA strand cleavage is required for replication fork arrest by a frozen topoisomerase-quinolone-DNA ternary complex Journal Article

  


Authors: Hiasa, H.; Yousef, D. O.; Marians, K. J.
Article Title: DNA strand cleavage is required for replication fork arrest by a frozen topoisomerase-quinolone-DNA ternary complex
Abstract: 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.
Keywords: mutant protein; dna replication; cell death; dna repair; dna strand breakage; dna; double stranded dna; escherichia coli; mutagenesis, site-directed; drug cytotoxicity; nucleic acid conformation; site directed mutagenesis; dna topoisomerases, type ii; dna cleavage; dna topoisomerase iv; electrophoresis, polyacrylamide gel; dna topoisomerase; enzyme active site; gyrase inhibitor; drug dna binding; norfloxacin; deoxyribonucleases, type ii site-specific; quinolone derivative; quinolones; priority journal; article; dna drug complex; enzyme denaturation
Journal Title: Journal of Biological Chemistry
Volume: 271
Issue: 42
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 1996-10-18
Start Page: 26424
End Page: 26429
Language: English
DOI: 10.1074/jbc.271.42.26424
PUBMED: 8824300
PROVIDER: scopus
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0029859964&doi=10.1074%2fjbc.271.42.26424&partnerID=40&md5=c8febbc1569f2d8bcaab71370c9ca1cb
Notes: Article -- Export Date: 22 November 2017 -- Source: Scopus
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MSK Authors
  1. Kenneth Marians
    138 Marians
  2. Hiroshi Hiasa
    21 Hiasa
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