Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast.

Elsea, Sarah H.; Osheroff, Neil; Nitiss, John L.

doi:10.1016/s0021-9258(18)42185-0

Cited by 109 publications

(27 citation statements)

References 30 publications

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“…Levels of cleavage complexes generated by the enzyme on relaxed DNA were between those generated on positively and negatively supercoiled plasmid. Gyrase also maintained the distinction between over and underwound DNA in the presence of ciprofloxacin or levofloxacin, two other clinically relevant quinolones; CP-115,953, a quinolone that displays high activity against both bacterial and eukaryotic type II topoisomerases; − and two quinolone-derived drugs, 8-methyl-moxifloxacin and 3′-(AM)P-dione, which overcome quinolone resistance caused by mutations in M. tuberculosis gyrase , (Figure ). These results suggest that, although gyrase in M. tuberculosis has adapted to perform some of the functions of topoisomerase IV, it still retains the characteristics that make gyrase a safe enzyme to function ahead of replication forks and other DNA tracking systems such as RNA polymerase.…”

Section: Resultsmentioning

confidence: 98%

Recognition of DNA Supercoil Geometry byMycobacterium tuberculosisGyrase

Ashley¹,

Blower

Osheroff

2017

Biochemistry

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Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M. tuberculosis gyrase on positively supercoiled DNA were investigated. Results indicate that the enzyme acts rapidly on overwound DNA and removes positive supercoils much faster than it introduces negative supercoils into relaxed DNA. Canonical gyrase and topoisomerase IV distinguish supercoil handedness differently during the DNA cleavage reaction: while gyrase maintains lower levels of cleavage complexes on overwound DNA, topoisomerase IV maintains similar levels of cleavage complexes on both over- and underwound substrates. M. tuberculosis gyrase maintained lower levels of cleavage complexes on positively supercoiled DNA in the absence and presence of quinolone-based drugs. By retaining this important feature of canonical gyrase, the dual function M. tuberculosis type II enzyme remains a safe enzyme to act in front of replication forks and transcription complexes. Finally, the N-terminal gate region of the enzyme appears to be necessary to distinguish supercoil handedness during DNA cleavage, suggesting that the capture of the transport segment may influence how gyrase maintains cleavage complexes on substrates with different topological states.

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Section: Resultsmentioning

confidence: 98%

Recognition of DNA Supercoil Geometry byMycobacterium tuberculosisGyrase

Ashley¹,

Blower

Osheroff

2017

Biochemistry

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“…As seen in Figure 4, relatively little increase in homologous recombination was observed in the repair-competent parental TOP2 strain following exposure to etoposide, the etoposide derivative TOP-53 or the quinolone CP-115,953, all of which have been demonstrated to target topoisomerase II in yeast (37,38,75,89). Thus, it appears that the level of topoisomerase II-generated DNA damage induced by drugs in the TOP2 strain was insuf®cient to increase the levels of homologous recombination in the YCpHR reporter plasmid above drugindependent levels.…”

Section: Homologous Recombination Triggered By Topoisomerase IImentioning

confidence: 99%

Yeast recombination pathways triggered by topoisomerase II-mediated DNA breaks

Sabourin

Nitiss²,

Nitiss³

et al. 2003

Nucleic Acids Research

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Topoisomerase II is a ubiquitous enzyme that removes knots and tangles from the genetic material by generating transient double-strand DNA breaks. While the enzyme cannot perform its essential cellular functions without cleaving DNA, this scission activity is inherently dangerous to chromosomal integrity. In fact, etoposide and other clinically important anticancer drugs kill cells by increasing levels of topoisomerase II-mediated DNA breaks. Cells rely heavily on recombination to repair double-strand DNA breaks, but the specific pathways used to repair topoisomerase II-generated DNA damage have not been defined. Therefore, Saccharomyces cerevisiae was used as a model system to delineate the recombination pathways that repair DNA breaks generated by topoisomerase II. Yeast cells that expressed wild-type or a drug-hypersensitive mutant topoisomerase II or overexpressed the wild-type enzyme were examined. Based on cytotoxicity and recombination induced by etoposide in different repair-deficient genetic backgrounds, double-strand DNA breaks generated by topoisomerase II appear to be repaired primarily by the single-strand invasion pathway of homologous recombination. Non-homologous end joining also was triggered by etoposide treatment, but this pathway was considerably less active than single-strand invasion and did not contribute significantly to cell survival in S.cerevisiae.

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“… 52 These enzymes perform critical tasks in many basic nuclear processes, 53 and are necessary for eukaryotic cells survival. 54 …”

Section: Resultsmentioning

confidence: 99%