NEW YORK (Reuters Health) - A carcinogen found in cigarette smoke causes a conformational change in a mutation hot-spot in the DNA sequence of the tumor suppressor gene p53, according to a report in the March 4th Journal of Molecular Biology.
Methylation of certain cytosine residues is known to enhance the interaction of the carcinogen benzo[a]pyrene with mutation hot spots, the authors explain, but the reason behind this enhancement has not been determined.
Dr. Dinshaw J. Patel from Memorial Sloan-Kettering Cancer Center, New York and colleagues used nuclear magnetic resonance (NMR) to investigate the effects of methylating the 5-position cytosine flanking the guanine modified by a benzo[a]pyrene metabolite (B[a]PDE) in the sequence of p53.
Methylation of the cytosine residue caused a conformational change in the sequence, the authors report, significantly changing the ability of the carcinogen metabolite to interact with it.
When the cytosine residue is methylated, the report indicates, the sequence assumes a conformation that allows intercalation of the carcinogen residue between adjacent base pairs.
In contrast, when the cytosine residue is not methylated, the sequence conformation forces the carcinogen to reside externally in a minor groove of the DNA double helix.
“Such conformational differences in methylated and unmethylated CpG sequences may be significant because of potential alterations in the cellular processing of the adducts by DNA transcription, replication, and repair enzymes,” the researchers note.
“The finding of a profound conformational switch in a B[a]PDE adduct induced by cytosine methylation may impact the mutational hot spot phenomenon, in part through differential repair, and perhaps in part by affecting translesion synthesis during replication,” the investigators explain.
“The full details of such effects remain to be elucidated,” the authors conclude.
Source: J Mol Biol 2005;346:951-965. [ Google search on this article ]
MeSH Headings:Alkylation: Biological Sciences: Biology: Chemistry: Chemistry, Organic: Genetics: Genetics, Biochemical: Methylation: Molecular Biology: Physical Sciences: Genes, p53: DNA Methylation: Biological Sciences: Physical SciencesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
