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 · Tue Mar 01 04:00:00 EST 2005 · Journal of Molecular Biology

DOI:https://doi.org/10.1016/j.jmb.2004.12.027· OSTI ID:978257

Zhang, N ^[1]; Lin, C ^[1]; Huang, X ^[1]; Kolbanovskiy, A ^[1]; Hingerty, Brian E ^[2]; Amin, S ^[3]; Broyde, S ^[4]; Geactinov, N E ^[4]; Patel, D J ^[1]

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1. Memorial Sloan-Kettering Cancer Center
2. ORNL
3. American Health Foundation
4. New York University

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.

• Research Organization: Oak Ridge National Laboratory (ORNL)
• Sponsoring Organization: ORNL LDRD Seed-Money
• DOE Contract Number: AC05-00OR22725
• OSTI ID: 978257
• Journal Information: Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 4 Vol. 346; ISSN JMOBAK; ISSN 0022-2836
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
ADDUCTS
ALIGNMENT
ANIMAL TISSUES
AROMATICS
CARCINOGENS
CODONS
CYTOSINE
DNA
ENZYMES
GLYCOLS
GUANINE
HOT SPOTS
METABOLITES
METHYLATION
MUTATIONS
PROCESSING
REPAIR
RESIDUES
TARGETS
TRANSCRIPTION