1Y9H

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

Summary for 1Y9H

• Entry DOI: 10.2210/pdb1y9h/pdb
• Descriptor: 5'-D(*CP*CP*AP*TP*(5CM)P*(BPG)P*CP*TP*AP*CP*C)-3', 5'-D(*GP*GP*TP*AP*GP*CP*GP*AP*TP*GP*G)-3', 1,2,3-TRIHYDROXY-1,2,3,4-TETRAHYDROBENZO[A]PYRENE (3 entities in total)
• Functional Keywords: conformational switch, cytosine methylation, p53 mutation hot spot, dna adduct, benzo[a]pyrene, bpde, dna
• Total number of polymer chains: 2
• Total formula weight: 7026.76

Authors

Zhang, N.,Lin, C.,Huang, X.,Kolbanovskiy, A.,Hingerty, B.E.,Amin, S.,Broyde, S.,Geacintov, N.E.,Patel, D.J. (deposition date: 2004-12-15, release date: 2005-03-22, Last modification date: 2024-04-24)

Primary citation

Zhang, N.,Lin, C.,Huang, X.,Kolbanovskiy, A.,Hingerty, B.E.,Amin, S.,Broyde, S.,Geacintov, N.E.,Patel, D.J.
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.
J.Mol.Biol., 346:951-965, 2005

PubMed 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.

PubMed: 15701509
DOI: 10.1016/j.jmb.2004.12.027

Experimental method

SOLUTION NMR