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NYU and MSKCC research provides model for understanding chemically induced cancer initiation

A team from the chemistry and biology departments of New York University, in collaboration with Memorial Sloan Kettering Cancer Center (MSKCC), has uncovered a conformational switch--a change in shape in a carcinogen-damaged DNA site--in tumor suppressor genes altered by a known cancer-causing chemical found in cigarette smoke. This finding may open new horizons for understanding the initiation of chemically induced cancers.

The findings appear as the cover story in the latest issue of the Journal of Molecular Biology. This team was headed by Dinshaw Patel at MSKCC, Nicholas Geacintov, chair of NYU's chemistry department, and Suse Broyde, a professor in NYU's biology department.

The studied gene, p53, is an important tumor suppressor gene that plays critical roles in cellular functions such as cell-cycle control, differentiation, and DNA repair. Many different chemical carcinogens, including those that are primary components of cigarette smoke, are known to damage DNA. This damage occurs at special positions of the p53 gene, called mutation hot spots, which have been previously linked with cigarette smoke. This molecular link between chemical DNA damage and cigarette-associated lung cancer has been called the "smoking gun."

In the study, the conformational switch discovered by the research team entails a change in the conformation of a carcinogen-damaged site in a DNA model sequence similar to that in a p53 mutation hot spot. The change is brought about by the presence of a single methyl group (composed only of one carbon and three hydrogen atoms) on a cytosine base adjacent to the damaged site. Without this methyl group, the bulky chemical carcinogen resides at an external binding site in the minor groove of the DNA double helix. However, in the presence of this single methyl group, it assumes an intercalated structure in which the carcinogenic residue is sandwiched between adjacent base pairs in the double helix.

"Such conformational differences in methylated and unmethylated DNA sequences may be significant because of potential alterations in the cellular processing of these lesions by DNA transcription, replication, and repair enzymes," said NYU's Geacintov.

"Because environmental chemical carcinogens, including those present in cigarette smoke, are a significant threat to human health, it is imperative to understand how chemicals can induce mutations and cancer at the molecular level," added NYU's Broyde. "Such information is needed for devising novel preventive and therapeutic strategies for addressing the problem of cancer induction by environmental chemical carcinogens."

The researchers added that the finding opens new horizons, at the molecular level, for understanding the effects of methylation at p53 mutation hot spots on the properties of carcinogen-DNA lesions. Current thinking in the field of chemical carcinogenesis is that the mutation-prone, or error-free processing of such carcinogen-damaged p53 genes by DNA repair proteins and DNA and RNA polymerases can determine whether these lesions ultimately contribute to the development of lung and other cancers.


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Source:New York University


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