Mutagenic Properties of 3-(Deoxyguanosin-N2-yl)-2-acetylaminofluorene, a Persistent Acetylaminofluorene-Derived DNA Adduct in Mammalian Cells†
Identifieur interne : 003086 ( Main/Exploration ); précédent : 003085; suivant : 003087Mutagenic Properties of 3-(Deoxyguanosin-N2-yl)-2-acetylaminofluorene, a Persistent Acetylaminofluorene-Derived DNA Adduct in Mammalian Cells†
Auteurs : Manabu Yasui [Japon] ; Huan Dong [Japon] ; Radha R. Bonala [Japon] ; Naomi Suzuki [Japon] ; Haruo Ohmori [Japon] ; Fumio Hanaoka [Japon] ; Francis Johnson [Japon] ; Arthur P. Grollman [Japon] ; Shinya Shibutani [Japon, États-Unis]Source :
- Biochemistry [ 0006-2960 ] ; 2004.
Abstract
The carcinogen 2-acetylaminofluorene is metabolically activated in cells and reacts with DNA to form N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF), N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF), and 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene (dG-N2-AAF) DNA adducts. The dG-N2-AAF adduct is the least abundant of the three isomers, but it persists in the tissues of animals treated with this carcinogen. The miscoding and mutagenic properties of dG-C8-AAF and dG-C8-AF have been established; these adducts are readily excised by DNA repair enzymes engaged in nucleotide excision repair. In the present study, oligodeoxynucleotides modified site-specifically with dG-N2-AAF were used as DNA templates in primer extension reactions catalyzed by mammalian DNA polymerases. Reactions catalyzed by pol α were strongly blocked at a position one base before dG-N2-AAF and also opposite this lesion. In contrast, during translesion synthesis catalyzed by pol η or pol κ nucleotides were incorporated opposite the lesion. Both pol η and pol κ incorporated dCMP, the correct base, opposite dG-N2-AAF. In reactions catalyzed by pol η, small amounts of dAMP misincorporation and one-base deletions were detected at the lesion site. With pol κ, significant dTMP misincorporation was observed opposite the lesion. Steady-state kinetic analysis confirmed the results obtained from primer extension studies. Single-stranded shuttle vectors containing 5‘TCCTCCTCXCCTCTC (X = dG-N2-AAF, dG-C8-AAF, or dG) were used to establish the frequency and specificity of dG-N2-AAF-induced mutations in simian kidney (COS-7) cells. Both lesions promote G → T transversions overall, with dG-N2-AAF being less mutagenic than dG-C8-AAF (3.4% vs 12.5%). We conclude from this study that dG-N2-AAF, by virtue of its persistence in tissues, contributes significantly to the mutational spectra observed in AAF-induced mutagenesis and that pol η, but not pol κ, may play a role in this process.
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DOI: 10.1021/bi048279+
Affiliations:
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Persistent Acetylaminofluorene-Derived DNA Adduct in Mammalian Cells<ref type="bib" target="#bi0482791AF2">†</ref></title><author><name sortKey="Yasui, Manabu" sort="Yasui, Manabu" uniqKey="Yasui M" first="Manabu" last="Yasui">Manabu Yasui</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Dong, Huan" sort="Dong, Huan" uniqKey="Dong H" first="Huan" last="Dong">Huan Dong</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Bonala, Radha R" sort="Bonala, Radha R" uniqKey="Bonala R" first="Radha R." last="Bonala">Radha R. Bonala</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Suzuki, Naomi" sort="Suzuki, Naomi" uniqKey="Suzuki N" first="Naomi" last="Suzuki">Naomi Suzuki</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Ohmori, Haruo" sort="Ohmori, Haruo" uniqKey="Ohmori H" first="Haruo" last="Ohmori">Haruo Ohmori</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Hanaoka, Fumio" sort="Hanaoka, Fumio" uniqKey="Hanaoka F" first="Fumio" last="Hanaoka">Fumio Hanaoka</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Johnson, Francis" sort="Johnson, Francis" uniqKey="Johnson F" first="Francis" last="Johnson">Francis Johnson</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Grollman, Arthur P" sort="Grollman, Arthur P" uniqKey="Grollman A" first="Arthur P." last="Grollman">Arthur P. Grollman</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Shibutani, Shinya" sort="Shibutani, Shinya" uniqKey="Shibutani S" first="Shinya" last="Shibutani">Shinya Shibutani</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook,Stony Brook, New York 11794-8651, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, Graduate School ofFrontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, and Discovery Research Institute, RIKEN, and CREST,JST, Wako, Saitama 351-0198</wicri:regionArea><wicri:noRegion>Saitama 351-0198</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Biochemistry</title><title level="j" type="abbrev">Biochemistry</title><idno type="ISSN">0006-2960</idno><idno type="eISSN">1520-4995</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2004</date><date type="published">2004</date><biblScope unit="vol">43</biblScope><biblScope unit="issue">47</biblScope><biblScope unit="page" from="15005">15005</biblScope><biblScope unit="page" to="15013">15013</biblScope></imprint><idno type="ISSN">0006-2960</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2960</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The carcinogen 2-acetylaminofluorene is metabolically activated in cells and reacts with DNA to form N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF), N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF), and 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene (dG-N2-AAF) DNA adducts. The dG-N2-AAF adduct is the least abundant of the three isomers, but it persists in the tissues of animals treated with this carcinogen. The miscoding and mutagenic properties of dG-C8-AAF and dG-C8-AF have been established; these adducts are readily excised by DNA repair enzymes engaged in nucleotide excision repair. In the present study, oligodeoxynucleotides modified site-specifically with dG-N2-AAF were used as DNA templates in primer extension reactions catalyzed by mammalian DNA polymerases. Reactions catalyzed by pol α were strongly blocked at a position one base before dG-N2-AAF and also opposite this lesion. In contrast, during translesion synthesis catalyzed by pol η or pol κ nucleotides were incorporated opposite the lesion. Both pol η and pol κ incorporated dCMP, the correct base, opposite dG-N2-AAF. In reactions catalyzed by pol η, small amounts of dAMP misincorporation and one-base deletions were detected at the lesion site. With pol κ, significant dTMP misincorporation was observed opposite the lesion. Steady-state kinetic analysis confirmed the results obtained from primer extension studies. Single-stranded shuttle vectors containing 5‘TCCTCCTCXCCTCTC (X = dG-N2-AAF, dG-C8-AAF, or dG) were used to establish the frequency and specificity of dG-N2-AAF-induced mutations in simian kidney (COS-7) cells. Both lesions promote G → T transversions overall, with dG-N2-AAF being less mutagenic than dG-C8-AAF (3.4% vs 12.5%). We conclude from this study that dG-N2-AAF, by virtue of its persistence in tissues, contributes significantly to the mutational spectra observed in AAF-induced mutagenesis and that pol η, but not pol κ, may play a role in this process.</div></front></TEI><affiliations><list><country><li>Japon</li><li>États-Unis</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Yasui, Manabu" sort="Yasui, Manabu" uniqKey="Yasui M" first="Manabu" last="Yasui">Manabu Yasui</name></noRegion><name sortKey="Bonala, Radha R" sort="Bonala, Radha R" uniqKey="Bonala R" first="Radha R." last="Bonala">Radha R. Bonala</name><name sortKey="Dong, Huan" sort="Dong, Huan" uniqKey="Dong H" first="Huan" last="Dong">Huan Dong</name><name sortKey="Grollman, Arthur P" sort="Grollman, Arthur P" uniqKey="Grollman A" first="Arthur P." last="Grollman">Arthur P. Grollman</name><name sortKey="Hanaoka, Fumio" sort="Hanaoka, Fumio" uniqKey="Hanaoka F" first="Fumio" last="Hanaoka">Fumio Hanaoka</name><name sortKey="Johnson, Francis" sort="Johnson, Francis" uniqKey="Johnson F" first="Francis" last="Johnson">Francis Johnson</name><name sortKey="Ohmori, Haruo" sort="Ohmori, Haruo" uniqKey="Ohmori H" first="Haruo" last="Ohmori">Haruo Ohmori</name><name sortKey="Shibutani, Shinya" sort="Shibutani, Shinya" uniqKey="Shibutani S" first="Shinya" last="Shibutani">Shinya Shibutani</name><name sortKey="Suzuki, Naomi" sort="Suzuki, Naomi" uniqKey="Suzuki N" first="Naomi" last="Suzuki">Naomi Suzuki</name></country><country name="États-Unis"><noRegion><name sortKey="Shibutani, Shinya" sort="Shibutani, Shinya" uniqKey="Shibutani S" first="Shinya" last="Shibutani">Shinya Shibutani</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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