Functional analysis of chemically-induced mutations at the flounder TP53 locus, the FACIM assay.
Identifieur interne : 000D60 ( France/Analysis ); précédent : 000D59; suivant : 000D61Functional analysis of chemically-induced mutations at the flounder TP53 locus, the FACIM assay.
Auteurs : J. Cachot [France] ; J. Couteau ; T. Frébourg ; F. Leboulenger ; J-M FlamanSource :
- Mutation research [ 0027-5107 ] ; 2004.
English descriptors
- KwdEn :
- MESH :
- chemical , toxicity : 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide, Mutagens.
- drug effects : Genes, p53.
- genetics : Flounder, Yeasts.
- methods : Mutagenicity Tests.
- Animals, DNA Mutational Analysis, Dose-Response Relationship, Drug, Mutation.
Abstract
A functional assay was developed in yeast to identify mutations induced by DNA-damaging agents at the flounder TP53 locus. This assay named FACIM for functional analysis of chemically-induced p53 mutations, is based on the assumption that most genotoxin-induced mutations inactivate transcriptional activity of the TP53 protein. The functional status of the protein expressed in yeast was measured using a p53-responsive reporter gene. The FACIM assay was used to evaluate the mutagenesis of the flounder TP53 exposed in vitro to benzo[a]pyrene diol epoxide (BPDE). A dose-dependent increase of p53 mutation rate was observed with increasing concentrations of BPDE and extension of exposure time. Flounder TP53 gene appeared highly sensitive to point mutations since most of those identified targeted different nucleotides. Mutated base-pairs corresponded predominantly to guanines located on the non-transcribed strand of the DNA. The general distribution of mutations along the flounder TP53 protein was different from that identified in the human homologue suggesting species-differences in mutagenesis of the TP53 gene. Most of flounder TP53 mutants were defective for transactivation and cell growth regulation but some maintained a partial wild-type phenotype. This functional assay in yeast could be used for both evaluation of the genotoxic potency of chemicals or environmental samples and screening of p53 mutations in fish tumours.
DOI: 10.1016/j.mrfmmm.2004.06.003
PubMed: 15288541
Affiliations:
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pubmed:15288541Le document en format XML
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Cachot</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Ecotoxicology, UPRES-EA 3222, IFRMP 23, University of Le Havre, 25 rue P. Lebon, BP 540, 76058 Le Havre Cedex, France. jerome.cachot@univ-lehavre.fr</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Ecotoxicology, UPRES-EA 3222, IFRMP 23, University of Le Havre, 25 rue P. Lebon, BP 540, 76058 Le Havre Cedex</wicri:regionArea><placeName><region type="region" nuts="2">Région Normandie</region><region type="old region" nuts="2">Haute-Normandie</region><settlement type="city">Le Havre</settlement></placeName></affiliation></author><author><name sortKey="Couteau, J" sort="Couteau, J" uniqKey="Couteau J" first="J" last="Couteau">J. Couteau</name></author><author><name sortKey="Frebourg, T" sort="Frebourg, T" uniqKey="Frebourg T" first="T" last="Frébourg">T. Frébourg</name></author><author><name sortKey="Leboulenger, F" sort="Leboulenger, F" uniqKey="Leboulenger F" first="F" last="Leboulenger">F. Leboulenger</name></author><author><name sortKey="Flaman, J M" sort="Flaman, J M" uniqKey="Flaman J" first="J-M" last="Flaman">J-M Flaman</name></author></analytic><series><title level="j">Mutation research</title><idno type="ISSN">0027-5107</idno><imprint><date when="2004" type="published">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide (toxicity)</term><term>Animals</term><term>DNA Mutational Analysis</term><term>Dose-Response Relationship, Drug</term><term>Flounder (genetics)</term><term>Genes, p53 (drug effects)</term><term>Mutagenicity Tests (methods)</term><term>Mutagens (toxicity)</term><term>Mutation</term><term>Yeasts (genetics)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide</term><term>Mutagens</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Genes, p53</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Flounder</term><term>Yeasts</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Mutagenicity Tests</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>DNA Mutational Analysis</term><term>Dose-Response Relationship, Drug</term><term>Mutation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A functional assay was developed in yeast to identify mutations induced by DNA-damaging agents at the flounder TP53 locus. This assay named FACIM for functional analysis of chemically-induced p53 mutations, is based on the assumption that most genotoxin-induced mutations inactivate transcriptional activity of the TP53 protein. The functional status of the protein expressed in yeast was measured using a p53-responsive reporter gene. The FACIM assay was used to evaluate the mutagenesis of the flounder TP53 exposed in vitro to benzo[a]pyrene diol epoxide (BPDE). A dose-dependent increase of p53 mutation rate was observed with increasing concentrations of BPDE and extension of exposure time. Flounder TP53 gene appeared highly sensitive to point mutations since most of those identified targeted different nucleotides. Mutated base-pairs corresponded predominantly to guanines located on the non-transcribed strand of the DNA. The general distribution of mutations along the flounder TP53 protein was different from that identified in the human homologue suggesting species-differences in mutagenesis of the TP53 gene. Most of flounder TP53 mutants were defective for transactivation and cell growth regulation but some maintained a partial wild-type phenotype. This functional assay in yeast could be used for both evaluation of the genotoxic potency of chemicals or environmental samples and screening of p53 mutations in fish tumours.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Haute-Normandie</li><li>Région Normandie</li></region><settlement><li>Le Havre</li></settlement></list><tree><noCountry><name sortKey="Couteau, J" sort="Couteau, J" uniqKey="Couteau J" first="J" last="Couteau">J. Couteau</name><name sortKey="Flaman, J M" sort="Flaman, J M" uniqKey="Flaman J" first="J-M" last="Flaman">J-M Flaman</name><name sortKey="Frebourg, T" sort="Frebourg, T" uniqKey="Frebourg T" first="T" last="Frébourg">T. Frébourg</name><name sortKey="Leboulenger, F" sort="Leboulenger, F" uniqKey="Leboulenger F" first="F" last="Leboulenger">F. Leboulenger</name></noCountry><country name="France"><region name="Région Normandie"><name sortKey="Cachot, J" sort="Cachot, J" uniqKey="Cachot J" first="J" last="Cachot">J. Cachot</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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