DNA sequence dependence of guanine-O6 alkylation by the N-nitroso carcinogens N-methyl- and N-ethyl-N-nitrosourea.
Identifieur interne : 000688 ( Ncbi/Curation ); précédent : 000687; suivant : 000689DNA sequence dependence of guanine-O6 alkylation by the N-nitroso carcinogens N-methyl- and N-ethyl-N-nitrosourea.
Auteurs : K. Sendowski ; M F RajewskySource :
- Mutation research [ 0027-5107 ]
Descripteurs français
- KwdFr :
- MESH :
- métabolisme : ADN, Guanine.
- pharmacologie : 1-Méthyl-1-nitroso-urée, 1-Éthyl-1-nitroso-urée, Cancérogènes.
- ADN, Alkylation, Dosage radioimmunologique, Fixation compétitive, Séquence nucléotidique.
English descriptors
- KwdEn :
- MESH :
- chemical , drug effects : DNA.
- chemical , metabolism : DNA, Guanine.
- chemical , pharmacology : Carcinogens, Ethylnitrosourea, Methylnitrosourea.
- Alkylation, Base Sequence, Binding, Competitive, Radioimmunoassay.
Abstract
After intracellular in vitro exposure to the mutagenic and carcinogenic N-nitroso compounds N-methyl-N-nitrosourea (MeNU) or N-ethyl-N-nitrosourea (EtNU), respectively, the average relative amounts of the premutational lesion O6-alkylguanine represent about 6% and 8% of all alkylation products formed in genomic DNA. At the level of individual DNA molecules guanine-O6 alkylation does not occur at random; rather, the probability of a substitution reaction at the nucleophilic O6 atom is influenced by nucleotide sequence, DNA conformation, and chromatin structure. In the present study, 5 different double-stranded polydeoxynucleotides and 15 double-stranded oligodeoxynucleotides (24-mers) were reacted with MeNU or EtNU in vitro under standardized conditions. Using a competitive radioimmunoassay in conjunction with an anti-(O6-alkyl-2'-deoxyguanosine) monoclonal antibody, the frequency of guanine-O6 alkylation was found to be strongly dependent on the nature of the nucleotides flanking guanine on the 5' and 3' sides. Thus, a 5' neighboring guanine, followed by 5' adenine and 5' cytosine, provided an up to 10-fold more 'permissive' condition for O6-alkylation of the central guanine than a 5' thymine (with a 5-methylcytosine in the 5' position being only slightly less inhibitory). Thymine and cytosine were more 'permissive' when placed 3' in comparison with their effects in the 5' flanking position.
DOI: 10.1016/0027-5107(91)90171-j
PubMed: 1944330
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K. Sendowski<affiliation><nlm:affiliation>Institute of Cell Biology (Cancer Research), West German Cancer Center Essen, University of Essen Medical School.</nlm:affiliation><wicri:noCountry code="subField">University of Essen Medical School</wicri:noCountry></affiliation>Le document en format XML
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Sendowski</name><affiliation><nlm:affiliation>Institute of Cell Biology (Cancer Research), West German Cancer Center Essen, University of Essen Medical School.</nlm:affiliation><wicri:noCountry code="subField">University of Essen Medical School</wicri:noCountry></affiliation></author><author><name sortKey="Rajewsky, M F" sort="Rajewsky, M F" uniqKey="Rajewsky M" first="M F" last="Rajewsky">M F Rajewsky</name></author></analytic><series><title level="j">Mutation research</title><idno type="ISSN">0027-5107</idno></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alkylation</term><term>Base Sequence</term><term>Binding, Competitive</term><term>Carcinogens (pharmacology)</term><term>DNA (drug effects)</term><term>DNA (metabolism)</term><term>Ethylnitrosourea (pharmacology)</term><term>Guanine (metabolism)</term><term>Methylnitrosourea (pharmacology)</term><term>Radioimmunoassay</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>1-Méthyl-1-nitroso-urée (pharmacologie)</term><term>1-Éthyl-1-nitroso-urée (pharmacologie)</term><term>ADN ()</term><term>ADN (métabolisme)</term><term>Alkylation</term><term>Cancérogènes (pharmacologie)</term><term>Dosage radioimmunologique</term><term>Fixation compétitive</term><term>Guanine (métabolisme)</term><term>Séquence nucléotidique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>DNA</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>DNA</term><term>Guanine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Carcinogens</term><term>Ethylnitrosourea</term><term>Methylnitrosourea</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ADN</term><term>Guanine</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>1-Méthyl-1-nitroso-urée</term><term>1-Éthyl-1-nitroso-urée</term><term>Cancérogènes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Alkylation</term><term>Base Sequence</term><term>Binding, Competitive</term><term>Radioimmunoassay</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ADN</term><term>Alkylation</term><term>Dosage radioimmunologique</term><term>Fixation compétitive</term><term>Séquence nucléotidique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">After intracellular in vitro exposure to the mutagenic and carcinogenic N-nitroso compounds N-methyl-N-nitrosourea (MeNU) or N-ethyl-N-nitrosourea (EtNU), respectively, the average relative amounts of the premutational lesion O6-alkylguanine represent about 6% and 8% of all alkylation products formed in genomic DNA. At the level of individual DNA molecules guanine-O6 alkylation does not occur at random; rather, the probability of a substitution reaction at the nucleophilic O6 atom is influenced by nucleotide sequence, DNA conformation, and chromatin structure. In the present study, 5 different double-stranded polydeoxynucleotides and 15 double-stranded oligodeoxynucleotides (24-mers) were reacted with MeNU or EtNU in vitro under standardized conditions. Using a competitive radioimmunoassay in conjunction with an anti-(O6-alkyl-2'-deoxyguanosine) monoclonal antibody, the frequency of guanine-O6 alkylation was found to be strongly dependent on the nature of the nucleotides flanking guanine on the 5' and 3' sides. Thus, a 5' neighboring guanine, followed by 5' adenine and 5' cytosine, provided an up to 10-fold more 'permissive' condition for O6-alkylation of the central guanine than a 5' thymine (with a 5-methylcytosine in the 5' position being only slightly less inhibitory). Thymine and cytosine were more 'permissive' when placed 3' in comparison with their effects in the 5' flanking position.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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