Conformational changes of a benzo[a]pyrene diol epoxide-N2-dG adduct induced by a 5′-flanking 5-methyl-substituted cytosine in a MeCG double-stranded oligonucleotide sequence context

Xuanwei Huang, Katharine C. Colgate, Aleksandr Kolbanovskiy, Shantu Amin, Nicholas Geacintov

Research output: Contribution to journalArticle

Abstract

Mutations in p53 genes are one of the most common genetic alterations in human cancers. A disproportionate number of mutations are found in certain codons of the p53 gene, mostly at CpG dinucleotide sequences, which are highly methylated in human tissues. The reactivities of the mutagenic metabolite of benzo[a]pyrene, the bay region diol epoxide r7,t8-dihydroxy-t9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), to yield adducts with guanine at the exocyclic amino group (e.g., trans-anti-BPDE-N2-dG, or G*), are enhanced when the cytosine in CpG sequences in DNA is methylated at its 5-position (MeCpG). However, methylation may also affect the characteristics of these adducts, and we have therefore investigated whether adduct conformations are different in double-stranded DNA in methylated MeCpG* and in unmethylated CpG* sequence contexts in the oligonucleotide model system duplex 5′-d(CCAT-[5XC]G*CTACC)·d(GGTAGCGATGG) with X = H or -CH3. The (-)-trans-adduct exhibits a striking conformational change from a minor groove structure external to the DNA duplex in the unmethylated CpG* sequence, to an intercalative conformation in the MeCG* sequence context. In contrast, the conformation of the stereoisomeric (+)-trans-adduct is predominantly of the minor groove type in both the methylated and unmethylated sequences. These results indicate that methylation of CpG sequences may affect not only chemical reactivities of chemically reactive intermediates with DNA, but also the conformational properties of the DNA adducts formed. Thus, both factors must be considered in evaluating the effects of cytosine methylation in CpG sequences on the biological consequences of the DNA adducts formed.

Original languageEnglish (US)
Pages (from-to)438-444
Number of pages7
JournalChemical Research in Toxicology
Volume15
Issue number3
DOIs
StatePublished - 2002

Fingerprint

Benzo(a)pyrene
Cytosine
Epoxy Compounds
Oligonucleotides
Methylation
DNA Adducts
p53 Genes
Conformations
DNA
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Mutation
Genes
Guanine
Codon
Chemical reactivity
Metabolites
Tissue
Neoplasms

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Conformational changes of a benzo[a]pyrene diol epoxide-N2-dG adduct induced by a 5′-flanking 5-methyl-substituted cytosine in a MeCG double-stranded oligonucleotide sequence context. / Huang, Xuanwei; Colgate, Katharine C.; Kolbanovskiy, Aleksandr; Amin, Shantu; Geacintov, Nicholas.

In: Chemical Research in Toxicology, Vol. 15, No. 3, 2002, p. 438-444.

Research output: Contribution to journalArticle

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abstract = "Mutations in p53 genes are one of the most common genetic alterations in human cancers. A disproportionate number of mutations are found in certain codons of the p53 gene, mostly at CpG dinucleotide sequences, which are highly methylated in human tissues. The reactivities of the mutagenic metabolite of benzo[a]pyrene, the bay region diol epoxide r7,t8-dihydroxy-t9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), to yield adducts with guanine at the exocyclic amino group (e.g., trans-anti-BPDE-N2-dG, or G*), are enhanced when the cytosine in CpG sequences in DNA is methylated at its 5-position (MeCpG). However, methylation may also affect the characteristics of these adducts, and we have therefore investigated whether adduct conformations are different in double-stranded DNA in methylated MeCpG* and in unmethylated CpG* sequence contexts in the oligonucleotide model system duplex 5′-d(CCAT-[5XC]G*CTACC)·d(GGTAGCGATGG) with X = H or -CH3. The (-)-trans-adduct exhibits a striking conformational change from a minor groove structure external to the DNA duplex in the unmethylated CpG* sequence, to an intercalative conformation in the MeCG* sequence context. In contrast, the conformation of the stereoisomeric (+)-trans-adduct is predominantly of the minor groove type in both the methylated and unmethylated sequences. These results indicate that methylation of CpG sequences may affect not only chemical reactivities of chemically reactive intermediates with DNA, but also the conformational properties of the DNA adducts formed. Thus, both factors must be considered in evaluating the effects of cytosine methylation in CpG sequences on the biological consequences of the DNA adducts formed.",
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T1 - Conformational changes of a benzo[a]pyrene diol epoxide-N2-dG adduct induced by a 5′-flanking 5-methyl-substituted cytosine in a MeCG double-stranded oligonucleotide sequence context

AU - Huang, Xuanwei

AU - Colgate, Katharine C.

AU - Kolbanovskiy, Aleksandr

AU - Amin, Shantu

AU - Geacintov, Nicholas

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N2 - Mutations in p53 genes are one of the most common genetic alterations in human cancers. A disproportionate number of mutations are found in certain codons of the p53 gene, mostly at CpG dinucleotide sequences, which are highly methylated in human tissues. The reactivities of the mutagenic metabolite of benzo[a]pyrene, the bay region diol epoxide r7,t8-dihydroxy-t9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), to yield adducts with guanine at the exocyclic amino group (e.g., trans-anti-BPDE-N2-dG, or G*), are enhanced when the cytosine in CpG sequences in DNA is methylated at its 5-position (MeCpG). However, methylation may also affect the characteristics of these adducts, and we have therefore investigated whether adduct conformations are different in double-stranded DNA in methylated MeCpG* and in unmethylated CpG* sequence contexts in the oligonucleotide model system duplex 5′-d(CCAT-[5XC]G*CTACC)·d(GGTAGCGATGG) with X = H or -CH3. The (-)-trans-adduct exhibits a striking conformational change from a minor groove structure external to the DNA duplex in the unmethylated CpG* sequence, to an intercalative conformation in the MeCG* sequence context. In contrast, the conformation of the stereoisomeric (+)-trans-adduct is predominantly of the minor groove type in both the methylated and unmethylated sequences. These results indicate that methylation of CpG sequences may affect not only chemical reactivities of chemically reactive intermediates with DNA, but also the conformational properties of the DNA adducts formed. Thus, both factors must be considered in evaluating the effects of cytosine methylation in CpG sequences on the biological consequences of the DNA adducts formed.

AB - Mutations in p53 genes are one of the most common genetic alterations in human cancers. A disproportionate number of mutations are found in certain codons of the p53 gene, mostly at CpG dinucleotide sequences, which are highly methylated in human tissues. The reactivities of the mutagenic metabolite of benzo[a]pyrene, the bay region diol epoxide r7,t8-dihydroxy-t9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), to yield adducts with guanine at the exocyclic amino group (e.g., trans-anti-BPDE-N2-dG, or G*), are enhanced when the cytosine in CpG sequences in DNA is methylated at its 5-position (MeCpG). However, methylation may also affect the characteristics of these adducts, and we have therefore investigated whether adduct conformations are different in double-stranded DNA in methylated MeCpG* and in unmethylated CpG* sequence contexts in the oligonucleotide model system duplex 5′-d(CCAT-[5XC]G*CTACC)·d(GGTAGCGATGG) with X = H or -CH3. The (-)-trans-adduct exhibits a striking conformational change from a minor groove structure external to the DNA duplex in the unmethylated CpG* sequence, to an intercalative conformation in the MeCG* sequence context. In contrast, the conformation of the stereoisomeric (+)-trans-adduct is predominantly of the minor groove type in both the methylated and unmethylated sequences. These results indicate that methylation of CpG sequences may affect not only chemical reactivities of chemically reactive intermediates with DNA, but also the conformational properties of the DNA adducts formed. Thus, both factors must be considered in evaluating the effects of cytosine methylation in CpG sequences on the biological consequences of the DNA adducts formed.

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