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 E. Geacintov

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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
Issue number3
StatePublished - 2002

ASJC Scopus subject areas

  • Toxicology


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