Methylation of cytosine at C5 in a CpG sequence context causes a conformational switch of a benzo[a]pyrene diol epoxide-N2-guanine adduct in DNA from a minor groove alignment to intercalation with base displacement Journal Article
| Authors: | Zhang, N.; Lin, C.; Huang, X.; Kolbanovskiy, A.; Hingerty, B. E.; Amin, S.; Broyde, S.; Geacintov, N. E.; Patel, D. J. |
| Article Title: | Methylation of cytosine at C5 in a CpG sequence context causes a conformational switch of a benzo[a]pyrene diol epoxide-N2-guanine adduct in DNA from a minor groove alignment to intercalation with base displacement |
| Abstract: | It is well known that CpG dinucleotide steps in DNA, which are highly methylated at the 5-position of cytosine (meC) in human tissues, exhibit a disproportionate number of mutations within certain codons of the p53 gene. There is ample published evidence indicating that the reactivity of guanine with anti-B[a]PDE (a metabolite of the environmental carcinogen benzo[a]pyrene) at CpG mutation hot spots is enhanced by the methylation of the cytosine residue flanking the target guanine residue on the 5′-side. In this work we demonstrate that such a methylation can also dramatically affect the conformational characteristics of an adduct derived from the reaction of one of the two enantiomers of anti-B[a]PDE with the exocyclic amino group of guanine ([BP]G adduct). A detailed NMR study indicates that the 10R (-)-trans-anti-[BP]G adduct undergoes a transition from a minor groove-binding alignment of the aromatic BP ring system in the unmethylated C-[BP]G sequence context, to an intercalative BP alignment with a concomitant displacement of the modified guanine residue into the minor groove in the methylated meC-[BP]G sequence context. By contrast, a minor groove-binding alignment was observed for the stereoisomeric 10S (+)-trans-anti-[BP]G adduct in both the C-[BP]G and meC-[BP]G sequence contexts. This remarkable conformational switch resulting from the presence of a single methyl group at the 5-position of the cytosine residue flanking the lesion on the 5′-side, is attributed to the hydrophobic effect of the methyl group that can stabilize intercalated adduct conformations in an adduct stereochemistry-dependent manner. Such conformational differences in methylated and unmethylated CpG sequences may be significant because of potential alterations in the cellular processing of the [BP]G adducts by DNA transcription, replication, and repair enzymes. © 2005 Elsevier Ltd. All rights reserved. |
| Keywords: | mutation; dna repair; molecular dynamics; dna methylation; molecular mechanics; guanine; sequence alignment; cpg island; cpg islands; magnetic resonance spectroscopy; base sequence; benzo[a]pyrene; dna adduct; dna sequence; benzo(a)pyrene; dna adducts; protons; conformation; nucleic acid conformation; codon; stereochemistry; stereoisomerism; calculation; epoxy compounds; cytosine; hydrophobicity; enantiomer; cytosine methylation; dihydroxybenzo[a]pyrene oxide; b[a]pde; conformational switch; p53 mutation hot spot |
| Journal Title: | Journal of Molecular Biology |
| Volume: | 346 |
| Issue: | 4 |
| ISSN: | 0022-2836 |
| Publisher: | Academic Press Inc., Elsevier Science |
| Date Published: | 2005-03-04 |
| Start Page: | 951 |
| End Page: | 965 |
| Language: | English |
| DOI: | 10.1016/j.jmb.2004.12.027 |
| PUBMED: | 15701509 |
| PROVIDER: | scopus |
| PMCID: | PMC4694590 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 23" - "Export Date: 24 October 2012" - "CODEN: JMOBA" - "Source: Scopus" |
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