Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA

Rebecca Guza, Delshanee Kotandeniya, Kristopher Murphy, Thakshila Dissanayake, Chen Lin, George Madalin Giambasu, Rahul R. Lad, Filip Wojciechowski, Shantu Amin, Shana J. Sturla, Robert H.E. Hudson, Darrin M. York, Ryszard Jankowiak, Roger Jones, Natalia Y. Tretyakova

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Abstract

Endogenous 5-methylcytosine (MeC) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational 'hotspots' for smoking induced lung cancer. MeC enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5′-CCCGGCACCC GC[15N3,13C1-G]TCCGCG-3′, + strand) were prepared containing [15N3, 13C1]-guanine opposite unsubstituted cytosine, MeC, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2′-deoxynucleosides, N2-BPDE-dG adducts formed at the [ 15N3, 13C1]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N 2-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N 2 position of guanine.

Original languageEnglish (US)
Pages (from-to)3988-4006
Number of pages19
JournalNucleic acids research
Volume39
Issue number9
DOIs
StatePublished - May 1 2011

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Benzo(a)pyrene
Cytosine
Epoxy Compounds
Nucleosides
Base Pairing
Guanine
5-Methylcytosine
DNA
Polycyclic Aromatic Hydrocarbons
p53 Genes
Tumor Suppressor Genes
Smoke
Tobacco Products
Lung Neoplasms
Mass Spectrometry
Hydrolysis
Fluorescence
Smoking

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Guza, Rebecca ; Kotandeniya, Delshanee ; Murphy, Kristopher ; Dissanayake, Thakshila ; Lin, Chen ; Giambasu, George Madalin ; Lad, Rahul R. ; Wojciechowski, Filip ; Amin, Shantu ; Sturla, Shana J. ; Hudson, Robert H.E. ; York, Darrin M. ; Jankowiak, Ryszard ; Jones, Roger ; Tretyakova, Natalia Y. / Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA. In: Nucleic acids research. 2011 ; Vol. 39, No. 9. pp. 3988-4006.
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title = "Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA",
abstract = "Endogenous 5-methylcytosine (MeC) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational 'hotspots' for smoking induced lung cancer. MeC enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5′-CCCGGCACCC GC[15N3,13C1-G]TCCGCG-3′, + strand) were prepared containing [15N3, 13C1]-guanine opposite unsubstituted cytosine, MeC, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2′-deoxynucleosides, N2-BPDE-dG adducts formed at the [ 15N3, 13C1]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N 2-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N 2 position of guanine.",
author = "Rebecca Guza and Delshanee Kotandeniya and Kristopher Murphy and Thakshila Dissanayake and Chen Lin and Giambasu, {George Madalin} and Lad, {Rahul R.} and Filip Wojciechowski and Shantu Amin and Sturla, {Shana J.} and Hudson, {Robert H.E.} and York, {Darrin M.} and Ryszard Jankowiak and Roger Jones and Tretyakova, {Natalia Y.}",
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Guza, R, Kotandeniya, D, Murphy, K, Dissanayake, T, Lin, C, Giambasu, GM, Lad, RR, Wojciechowski, F, Amin, S, Sturla, SJ, Hudson, RHE, York, DM, Jankowiak, R, Jones, R & Tretyakova, NY 2011, 'Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA', Nucleic acids research, vol. 39, no. 9, pp. 3988-4006. https://doi.org/10.1093/nar/gkq1341

Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA. / Guza, Rebecca; Kotandeniya, Delshanee; Murphy, Kristopher; Dissanayake, Thakshila; Lin, Chen; Giambasu, George Madalin; Lad, Rahul R.; Wojciechowski, Filip; Amin, Shantu; Sturla, Shana J.; Hudson, Robert H.E.; York, Darrin M.; Jankowiak, Ryszard; Jones, Roger; Tretyakova, Natalia Y.

In: Nucleic acids research, Vol. 39, No. 9, 01.05.2011, p. 3988-4006.

Research output: Contribution to journalArticle

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T1 - Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA

AU - Guza, Rebecca

AU - Kotandeniya, Delshanee

AU - Murphy, Kristopher

AU - Dissanayake, Thakshila

AU - Lin, Chen

AU - Giambasu, George Madalin

AU - Lad, Rahul R.

AU - Wojciechowski, Filip

AU - Amin, Shantu

AU - Sturla, Shana J.

AU - Hudson, Robert H.E.

AU - York, Darrin M.

AU - Jankowiak, Ryszard

AU - Jones, Roger

AU - Tretyakova, Natalia Y.

PY - 2011/5/1

Y1 - 2011/5/1

N2 - Endogenous 5-methylcytosine (MeC) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational 'hotspots' for smoking induced lung cancer. MeC enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5′-CCCGGCACCC GC[15N3,13C1-G]TCCGCG-3′, + strand) were prepared containing [15N3, 13C1]-guanine opposite unsubstituted cytosine, MeC, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2′-deoxynucleosides, N2-BPDE-dG adducts formed at the [ 15N3, 13C1]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N 2-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N 2 position of guanine.

AB - Endogenous 5-methylcytosine (MeC) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational 'hotspots' for smoking induced lung cancer. MeC enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5′-CCCGGCACCC GC[15N3,13C1-G]TCCGCG-3′, + strand) were prepared containing [15N3, 13C1]-guanine opposite unsubstituted cytosine, MeC, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2′-deoxynucleosides, N2-BPDE-dG adducts formed at the [ 15N3, 13C1]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N 2-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N 2 position of guanine.

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