Solution structure of the minor conformer of a DNA duplex containing a dG mismatch opposite a benzo[a]pyrene diol epoxide/dA adduct: Glycosidic rotation from syn to anti at the modified deoxyadenosine

J. L. Schwartz, J. S. Rice, B. A. Luxon, J. M. Sayer, G. Xie, H. J C Yeh, X. Liu, D. M. Jerina, D. G. Gorenstein

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    Abstract

    Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants whose metabolism in mammals results in deleterious cell transformation. Covalent modification of DNA by diol epoxides metabolically formed from PAHs such as benzo[a]pyrene (BaP) provides a mechanism for the genotoxicity, mutagenicity, and carcinogenicity of PAHs. We had previously reported NMR evidence for a minor conformer of the duplex d(G1G2T3C4A5*C6G7A8G9)·d(C10T11C12G13G14G15A16C17C 18) containing a dG14 mismatch opposite a dA5* residue modified at the exocyclic amino group by trans addition to (+)-(7R,8S,9S,10R)-7,8-dihydroxy- 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [Yeh, H. J. C., Sayer, J. M., Liu, X., Altieri, A. S., Byrd, R. A., Lashman, M. K., Yagi, H., Schurter, E. J., Gorenstein, D. G., and Jerina, D. M. (1995) Biochemistry 34, 13570- 13581]. In the present work, we describe the structure of this minor conformer (ca. 17% of the total conformer population). This represents the first structural determination of a minor conformer of a carcinogen-lesion DNA adduct. Two-dimensional NOESY, ROESY, TOCSY, and exchange-only spectra at 750 MHz allowed nearly complete sequential assignment of both conformers. In the minor conformer, the adducted base assumes an anti-glycosidic torsion angle whereas in the major conformer it assumes an unusual syn-glycosidic torsion angle. The aromatic hydrocarbon in the minor conformer is intercalated between dG13 and dG14, preserving the energetically favorable stacking interactions found in the major conformer. The major structural differences between the two conformers appear to be near the lesion site as evidenced by the large chemical shift differences between major and minor conformer protons near the lesion site; away from this site, the chemical shifts of the major and minor conformer protons are nearly identical. Because any of the conformations of benzo[a]pyrene diol epoxide- modified DNA may contribute to tumorigenic activity, structural determination of all conformations is essential for the elucidation of the mechanism of cell transformation initiated by covalent modification of DNA by PAHs.

    Original languageEnglish (US)
    Pages (from-to)11069-11076
    Number of pages8
    JournalBiochemistry
    Volume36
    Issue number37
    DOIs
    StatePublished - Sep 16 1997

    Fingerprint

    Benzo(a)pyrene
    Polycyclic Aromatic Hydrocarbons
    Epoxy Compounds
    DNA
    Chemical shift
    Torsional stress
    Conformations
    Protons
    7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
    Aromatic Hydrocarbons
    Biochemistry
    Mammals
    DNA Adducts
    Metabolism
    Carcinogens
    Nuclear magnetic resonance
    Impurities
    2'-deoxyadenosine
    Population

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    Solution structure of the minor conformer of a DNA duplex containing a dG mismatch opposite a benzo[a]pyrene diol epoxide/dA adduct : Glycosidic rotation from syn to anti at the modified deoxyadenosine. / Schwartz, J. L.; Rice, J. S.; Luxon, B. A.; Sayer, J. M.; Xie, G.; Yeh, H. J C; Liu, X.; Jerina, D. M.; Gorenstein, D. G.

    In: Biochemistry, Vol. 36, No. 37, 16.09.1997, p. 11069-11076.

    Research output: Contribution to journalArticle

    Schwartz, J. L. ; Rice, J. S. ; Luxon, B. A. ; Sayer, J. M. ; Xie, G. ; Yeh, H. J C ; Liu, X. ; Jerina, D. M. ; Gorenstein, D. G. / Solution structure of the minor conformer of a DNA duplex containing a dG mismatch opposite a benzo[a]pyrene diol epoxide/dA adduct : Glycosidic rotation from syn to anti at the modified deoxyadenosine. In: Biochemistry. 1997 ; Vol. 36, No. 37. pp. 11069-11076.
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    title = "Solution structure of the minor conformer of a DNA duplex containing a dG mismatch opposite a benzo[a]pyrene diol epoxide/dA adduct: Glycosidic rotation from syn to anti at the modified deoxyadenosine",
    abstract = "Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants whose metabolism in mammals results in deleterious cell transformation. Covalent modification of DNA by diol epoxides metabolically formed from PAHs such as benzo[a]pyrene (BaP) provides a mechanism for the genotoxicity, mutagenicity, and carcinogenicity of PAHs. We had previously reported NMR evidence for a minor conformer of the duplex d(G1G2T3C4A5*C6G7A8G9)·d(C10T11C12G13G14G15A16C17C 18) containing a dG14 mismatch opposite a dA5* residue modified at the exocyclic amino group by trans addition to (+)-(7R,8S,9S,10R)-7,8-dihydroxy- 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [Yeh, H. J. C., Sayer, J. M., Liu, X., Altieri, A. S., Byrd, R. A., Lashman, M. K., Yagi, H., Schurter, E. J., Gorenstein, D. G., and Jerina, D. M. (1995) Biochemistry 34, 13570- 13581]. In the present work, we describe the structure of this minor conformer (ca. 17{\%} of the total conformer population). This represents the first structural determination of a minor conformer of a carcinogen-lesion DNA adduct. Two-dimensional NOESY, ROESY, TOCSY, and exchange-only spectra at 750 MHz allowed nearly complete sequential assignment of both conformers. In the minor conformer, the adducted base assumes an anti-glycosidic torsion angle whereas in the major conformer it assumes an unusual syn-glycosidic torsion angle. The aromatic hydrocarbon in the minor conformer is intercalated between dG13 and dG14, preserving the energetically favorable stacking interactions found in the major conformer. The major structural differences between the two conformers appear to be near the lesion site as evidenced by the large chemical shift differences between major and minor conformer protons near the lesion site; away from this site, the chemical shifts of the major and minor conformer protons are nearly identical. Because any of the conformations of benzo[a]pyrene diol epoxide- modified DNA may contribute to tumorigenic activity, structural determination of all conformations is essential for the elucidation of the mechanism of cell transformation initiated by covalent modification of DNA by PAHs.",
    author = "Schwartz, {J. L.} and Rice, {J. S.} and Luxon, {B. A.} and Sayer, {J. M.} and G. Xie and Yeh, {H. J C} and X. Liu and Jerina, {D. M.} and Gorenstein, {D. G.}",
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    T1 - Solution structure of the minor conformer of a DNA duplex containing a dG mismatch opposite a benzo[a]pyrene diol epoxide/dA adduct

    T2 - Glycosidic rotation from syn to anti at the modified deoxyadenosine

    AU - Schwartz, J. L.

    AU - Rice, J. S.

    AU - Luxon, B. A.

    AU - Sayer, J. M.

    AU - Xie, G.

    AU - Yeh, H. J C

    AU - Liu, X.

    AU - Jerina, D. M.

    AU - Gorenstein, D. G.

    PY - 1997/9/16

    Y1 - 1997/9/16

    N2 - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants whose metabolism in mammals results in deleterious cell transformation. Covalent modification of DNA by diol epoxides metabolically formed from PAHs such as benzo[a]pyrene (BaP) provides a mechanism for the genotoxicity, mutagenicity, and carcinogenicity of PAHs. We had previously reported NMR evidence for a minor conformer of the duplex d(G1G2T3C4A5*C6G7A8G9)·d(C10T11C12G13G14G15A16C17C 18) containing a dG14 mismatch opposite a dA5* residue modified at the exocyclic amino group by trans addition to (+)-(7R,8S,9S,10R)-7,8-dihydroxy- 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [Yeh, H. J. C., Sayer, J. M., Liu, X., Altieri, A. S., Byrd, R. A., Lashman, M. K., Yagi, H., Schurter, E. J., Gorenstein, D. G., and Jerina, D. M. (1995) Biochemistry 34, 13570- 13581]. In the present work, we describe the structure of this minor conformer (ca. 17% of the total conformer population). This represents the first structural determination of a minor conformer of a carcinogen-lesion DNA adduct. Two-dimensional NOESY, ROESY, TOCSY, and exchange-only spectra at 750 MHz allowed nearly complete sequential assignment of both conformers. In the minor conformer, the adducted base assumes an anti-glycosidic torsion angle whereas in the major conformer it assumes an unusual syn-glycosidic torsion angle. The aromatic hydrocarbon in the minor conformer is intercalated between dG13 and dG14, preserving the energetically favorable stacking interactions found in the major conformer. The major structural differences between the two conformers appear to be near the lesion site as evidenced by the large chemical shift differences between major and minor conformer protons near the lesion site; away from this site, the chemical shifts of the major and minor conformer protons are nearly identical. Because any of the conformations of benzo[a]pyrene diol epoxide- modified DNA may contribute to tumorigenic activity, structural determination of all conformations is essential for the elucidation of the mechanism of cell transformation initiated by covalent modification of DNA by PAHs.

    AB - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants whose metabolism in mammals results in deleterious cell transformation. Covalent modification of DNA by diol epoxides metabolically formed from PAHs such as benzo[a]pyrene (BaP) provides a mechanism for the genotoxicity, mutagenicity, and carcinogenicity of PAHs. We had previously reported NMR evidence for a minor conformer of the duplex d(G1G2T3C4A5*C6G7A8G9)·d(C10T11C12G13G14G15A16C17C 18) containing a dG14 mismatch opposite a dA5* residue modified at the exocyclic amino group by trans addition to (+)-(7R,8S,9S,10R)-7,8-dihydroxy- 9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [Yeh, H. J. C., Sayer, J. M., Liu, X., Altieri, A. S., Byrd, R. A., Lashman, M. K., Yagi, H., Schurter, E. J., Gorenstein, D. G., and Jerina, D. M. (1995) Biochemistry 34, 13570- 13581]. In the present work, we describe the structure of this minor conformer (ca. 17% of the total conformer population). This represents the first structural determination of a minor conformer of a carcinogen-lesion DNA adduct. Two-dimensional NOESY, ROESY, TOCSY, and exchange-only spectra at 750 MHz allowed nearly complete sequential assignment of both conformers. In the minor conformer, the adducted base assumes an anti-glycosidic torsion angle whereas in the major conformer it assumes an unusual syn-glycosidic torsion angle. The aromatic hydrocarbon in the minor conformer is intercalated between dG13 and dG14, preserving the energetically favorable stacking interactions found in the major conformer. The major structural differences between the two conformers appear to be near the lesion site as evidenced by the large chemical shift differences between major and minor conformer protons near the lesion site; away from this site, the chemical shifts of the major and minor conformer protons are nearly identical. Because any of the conformations of benzo[a]pyrene diol epoxide- modified DNA may contribute to tumorigenic activity, structural determination of all conformations is essential for the elucidation of the mechanism of cell transformation initiated by covalent modification of DNA by PAHs.

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