Our DNA is under continuous attack – by physical or chemical agents produced by or introduced into the body. These agents can modify DNA, forming DNA adducts, which – if not properly repaired – can cause mutations that contribute to deregulated gene expression and cancer.
Linlin Zhao, F. Peter Guengerich, the Harry Pearson Broquist Professorship in Biochemistry, and colleagues (laboratories of Martin Egli and Carmelo Rizzo) sought to understand how an unstable DNA adduct (N2,3-ethenoguanine), which is produced by exposure to the occupational carcinogen vinyl chloride, causes mutations. They used a chemical strategy to stabilize the adduct for detailed biochemical, kinetic and structural studies.
The results, reported in the journal Angewandte Chemie, revealed the miscoding tendencies of this DNA lesion and highlighted the diversity of biological effects that can result from DNA adducts. Structural insights suggested that this adduct may be relevant to vinyl chloride-induced tumors, and its presence in unexposed humans (where it is a product of oxidative stress) may be an issue in disease.
This research was supported in part by grants from the National Institute of Environmental Health Sciences (ES010546, ES010375, ES005355, ES007028, ES000267) of the National Institutes of Health.