Yeast topoisomerase II mutants resistant to anti-topoisomerase agents : identification and characterization of new yeast topoisomerase II mutants selected for resistance to etoposide

We describe a system that allows us to easily isolate and characterize mutants in yeast topoisomerase II that are resistant to antitumor agents that target this enzyme. The system uses yeast strains that are sensitive to those agents and that carry temperature-sensitive top2 mutations. The temperatu...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 1994-06, Vol.54 (11), p.2943-2951
Hauptverfasser: YA-XIA LIU, YUCHU HSIUNG, MEHRDAD JANNATIPOUR, YEH, Y, NITISS, J. L
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container_end_page 2951
container_issue 11
container_start_page 2943
container_title Cancer research (Chicago, Ill.)
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creator YA-XIA LIU
YUCHU HSIUNG
MEHRDAD JANNATIPOUR
YEH, Y
NITISS, J. L
description We describe a system that allows us to easily isolate and characterize mutants in yeast topoisomerase II that are resistant to antitumor agents that target this enzyme. The system uses yeast strains that are sensitive to those agents and that carry temperature-sensitive top2 mutations. The temperature-sensitive mutation allows the isolation of recessive drug-resistant mutations. The mutagenized TOP2 gene we have used is under the control of the yeast DED1 promoter; this overexpression of TOP2 is designed to avoid isolating mutants that are drug resistant solely because the mutated topoisomerase II has low enzymatic activity. We describe three mutants that we isolated using this system. Two of the three mutants show resistance to etoposide and amsacrine, while the third mutant is partially resistant to etoposide and fluoroquinolones but not to amsacrine. DNA sequence changes have been identified in all of these mutant TOP2 genes. The mutant with partial resistance to etoposide and fluoroquinolones has an amino acid change at position 738 of TOP2, which is three amino acids from the site homologous to Ser83 of E. coli gyrA, an amino acid which had previously been shown to be an important target for resistance to quinolones in bacteria. One of the alleles that confers resistance to both etoposide and amsacrine, top2-103, has changes in amino acid 824 and amino acid 1186 of TOP2. Reconstruction of the mutations by oligonucleotide-directed mutagenesis demonstrates that the change at amino acid 824 is responsible for the drug resistance of this allele.
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DNA sequence changes have been identified in all of these mutant TOP2 genes. The mutant with partial resistance to etoposide and fluoroquinolones has an amino acid change at position 738 of TOP2, which is three amino acids from the site homologous to Ser83 of E. coli gyrA, an amino acid which had previously been shown to be an important target for resistance to quinolones in bacteria. One of the alleles that confers resistance to both etoposide and amsacrine, top2-103, has changes in amino acid 824 and amino acid 1186 of TOP2. 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L</creatorcontrib><title>Yeast topoisomerase II mutants resistant to anti-topoisomerase agents : identification and characterization of new yeast topoisomerase II mutants selected for resistance to etoposide</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>We describe a system that allows us to easily isolate and characterize mutants in yeast topoisomerase II that are resistant to antitumor agents that target this enzyme. The system uses yeast strains that are sensitive to those agents and that carry temperature-sensitive top2 mutations. The temperature-sensitive mutation allows the isolation of recessive drug-resistant mutations. The mutagenized TOP2 gene we have used is under the control of the yeast DED1 promoter; this overexpression of TOP2 is designed to avoid isolating mutants that are drug resistant solely because the mutated topoisomerase II has low enzymatic activity. We describe three mutants that we isolated using this system. 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L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Yeast topoisomerase II mutants resistant to anti-topoisomerase agents : identification and characterization of new yeast topoisomerase II mutants selected for resistance to etoposide</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1994-06-01</date><risdate>1994</risdate><volume>54</volume><issue>11</issue><spage>2943</spage><epage>2951</epage><pages>2943-2951</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>We describe a system that allows us to easily isolate and characterize mutants in yeast topoisomerase II that are resistant to antitumor agents that target this enzyme. The system uses yeast strains that are sensitive to those agents and that carry temperature-sensitive top2 mutations. The temperature-sensitive mutation allows the isolation of recessive drug-resistant mutations. 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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research
subjects Amino Acid Sequence
Amsacrine - pharmacology
Antineoplastic agents
Base Sequence
Biological and medical sciences
DNA Topoisomerases, Type II - drug effects
DNA Topoisomerases, Type II - genetics
DNA Topoisomerases, Type II - isolation & purification
DNA, Fungal - chemistry
Drug Resistance - genetics
Etoposide - pharmacology
General aspects
Medical sciences
Molecular Sequence Data
Mutation - genetics
Pharmacology. Drug treatments
Saccharomyces cerevisiae
Sequence Analysis, DNA
Yeasts - enzymology
Yeasts - genetics
Yeasts - isolation & purification
title Yeast topoisomerase II mutants resistant to anti-topoisomerase agents : identification and characterization of new yeast topoisomerase II mutants selected for resistance to etoposide
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