Solution Structure of an Oligodeoxynucleotide Duplex Containing the Exocyclic Lesion 3,<i>N</i><sup>4</sup>-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyadenosine, Determined by NMR Spectroscopy and Restrained Molecular Dynamics

Korobka, Alex; Cullinan, David B.; Cosman, Monique; Ap, Grollman; Dj, Patel; Eisenberg, Moisés; C, de los Santos

doi:10.1021/bi9605696

Cited by 17 publications

(32 citation statements)

References 24 publications

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“…NMR studies reveal that PdG disrupts duplex DNA (39,40,43,44). At neutral pH, and similar to the present observations for the 1,N 2 -εdG adduct, it has not been possible to obtain a refined structure for PdG positioned opposite cytosine in duplex DNA.…”

Section: Structural Comparison To the 1n 2 -Propano-2′-deoxyguanosinsupporting

confidence: 60%

Structure of the 1,N²-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Shanmugam

Goodenough

Kozekov

et al. 2007

Chem. Res. Toxicol.

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The structure of the 1,N 2 -εdG adduct, arising from the reaction of vinyl chloride with dG, was determined in the oligonucleotide duplex 5′-d(CGCATXGAATCC)-3′•5′-d(GGATTCCATGCG)-3′ (X=1,N 2 -εdG) at pH 8.6 using high resolution NMR spectroscopy. The exocyclic lesion prevented Watson-Crick base-pairing capability at the adduct site and resulted in an ~17 °C of the C decrease in T m oligodeoxynucleotide duplex. At neutral pH, conformational exchange resulted in spectral line broadening near the adducted site, and it was not possible to determine the structure. However, at pH 8.6, it was possible to obtain well-resolved 1 H NMR spectra. This enabled a total of 385 NOE based distance restraints to be obtained, consisting of 245 intra-and 140 inter-nucleotide distances. The 31 P NMR spectra exhibited two downfield-shifted resonances, suggesting a localized perturbation of the DNA backbone. The two downfield 31 P resonances were assigned to G 7 and C 19 . The solution structure was refined by molecular dynamics calculations restrained by NMR derived distance and dihedral angle restraints, using a simulated annealing protocol. The generalized Born approximation was used to simulate solvent. The emergent structures indicated that the 1,N 2 -εdG-induced structural perturbation was localized at the X 6 •C 19 base pair, and its 5′-neighbor T 5 •A 20 . Both 1,N 2 -εdG and the complementary dC adopted the anti conformation about the glycosyl bonds. The 1,N 2 -εdG adduct was inserted into the duplex but was shifted towards the minor groove as compared to dG in a normal Watson-Crick C•G base pair. The complementary cytosine was displaced toward the major groove. The 5′-neighbor T 5 •A 20 base pair was destabilized with respect to Watson-Crick base pairing. The refined structure predicted a bend in the helical axis associated with the adduct site.

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Section: Structural Comparison To the 1n 2 -Propano-2′-deoxyguanosinsupporting

confidence: 60%

Structure of the 1,N²-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Shanmugam

Goodenough

Kozekov

et al. 2007

Chem. Res. Toxicol.

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“…Assignment of the base and sugar protons on the C‚dG duplex allowed us to identify large variations in the proton chemical shifts. These values may be compared with those recently reported for C‚T and C‚dA duplexes, whose sequences only differ in the residue positioned opposite the adduct, T and dA, respectively Korobka et al, 1996). Figure 7 depicts chemical shift differences observed for the nonexchangeable base and sugar protons of the three central base pairs of the duplexes, and Tables 2S and 3S (Supporting Information) list differences for all the protons of the sequence.…”

Section: Assignment Of the Nonexchangeable Protonsmentioning

confidence: 83%

Solution Structure of a DNA Duplex Containing the Exocyclic Lesion 3,N⁴-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyguanosine

et al. 1997

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Vinyl chloride reacts with cellular DNA producing 3,N4-etheno-2'-deoxycytidine (epsilonC) along with other exocyclic adducts. The solution structure of an oligodeoxynucleotide duplex containing an epsilonC.dG base pair was determined by high-resolution NMR spectroscopy and molecular dynamics simulations. NMR data indicated that the duplex adopts a right-handed helical structure having all residues in anti orientation around the glycosylic torsion angle. The epsilonC adduct has a sugar pucker in the C3'-endo/C4'-exo region while the rest of the residues are in the C2'-endo/C3'-exo range. NOE interactions established Watson-Crick alignments for canonical base pairs of the duplex. The imino proton of the lesion-containing base pair resonated as a sharp signal that was resistant to water exchange, suggesting hydrogen bonding. Restrained molecular dynamics simulations generated three-dimensional models in excellent agreement with the spectroscopic data. The refined structures are slightly bent at the lesion site without major perturbations of the sugar-phosphate backbone. The adduct is displaced and shifted toward the major groove of the helix while its partner on the complementary strand remains stacked. The epsilonC(anti).dG(anti) base pair alignment is sheared and stabilized by the formation of hydrogen bonds. The biological implications of structures of epsilonC-containing DNA duplexes are discussed.

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“…Sci. USA 95 (1998) duplexes containing C͞T, C͞G, or C͞A mismatches (42)(43)(44), will be of interest for structural investigations aiming to elucidate the molecular mechanisms involved in the catalytic action of the dsUDG. Therefore, the human and the E. coli enzymes exhibit the same substrate specificity.…”

mentioning

confidence: 99%

3, N ⁴ -ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase

Saparbaev

Laval²

1998

Proc. Natl. Acad. Sci. U.S.A.

168

170

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Exocyclic DNA adducts are generated in cellular DNA by various industrial pollutants such as the carcinogen vinyl chloride and by endogenous products of lipid peroxidation. The etheno derivatives of purine and pyrimidine bases 3,N 4 -ethenocytosine (C), 1,N 6 -ethenoadenine (A), N 2 ,3-ethenoguanine, and 1,N 2 -ethenoguanine cause mutations. The A residues are excised by the human and the Escherichia coli 3-methyladenine-DNA glycosylases (ANPG and AlkA proteins, respectively), but the enzymes repairing C residues have not yet been described. We have identified two homologous proteins present in human cells and E. coli that remove C residues by a DNA glycosylase activity. The human enzyme is an activity of the mismatch-specific thymine-DNA glycosylase (hTDG). The bacterial enzyme is the double-stranded uracil-DNA glycosylase (dsUDG) that is the homologue of the hTDG. In addition to uracil and C-DNA glycosylase activity, the dsUDG protein repairs thymine in a G͞T mismatch. The fact that C is recognized and efficiently excised by the E. coli dsUDG and hTDG proteins in vitro suggests that these enzymes may be responsible for the repair of this mutagenic lesion in vivo and be important contributors to genetic stability.

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Solution Structure of an Oligodeoxynucleotide Duplex Containing the Exocyclic Lesion 3,N⁴-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyadenosine, Determined by NMR Spectroscopy and Restrained Molecular Dynamics

Cited by 17 publications

References 24 publications

Structure of the 1,N²-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Structure of the 1,N²-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Solution Structure of a DNA Duplex Containing the Exocyclic Lesion 3,N⁴-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyguanosine

3, N ⁴ -ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase

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Solution Structure of an Oligodeoxynucleotide Duplex Containing the Exocyclic Lesion 3,N4-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyadenosine, Determined by NMR Spectroscopy and Restrained Molecular Dynamics

Cited by 17 publications

References 24 publications

Structure of the 1,N2-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Structure of the 1,N2-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Solution Structure of a DNA Duplex Containing the Exocyclic Lesion 3,N4-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyguanosine

3, N 4 -ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase

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Solution Structure of an Oligodeoxynucleotide Duplex Containing the Exocyclic Lesion 3,N⁴-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyadenosine, Determined by NMR Spectroscopy and Restrained Molecular Dynamics

Structure of the 1,N²-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Structure of the 1,N²-Etheno-2′-Deoxyguanosine Adduct in Duplex DNA at pH 8.6

Solution Structure of a DNA Duplex Containing the Exocyclic Lesion 3,N⁴-Etheno-2‘-deoxycytidine Opposite 2‘-Deoxyguanosine

3, N ⁴ -ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase