Cancer-causing chemicals can bind to the nucleotide bases of DNA (adenine, guanine, cytosine and thymine) and form lesions known as “adducts,” potentially causing errors in the copying and transcription of DNA. One such adduct, N2,3-ethenoguanine, or N2,3-εG, can result from exposure to industrial chemicals like vinyl chloride, a known human carcinogen. Instability of a bond in the adduct has limited previous studies on how N2,3-εG leads to genetic mistakes (“miscoding”).
F. Peter Guengerich, Ph.D., Martin Egli, Ph.D., Carmelo Rizzo, Ph.D., and colleagues were able to stabilize this adduct and investigate its miscoding potential. The researchers found that, in the presence of all human Y-family DNA polymerases (enzymes that catalyze replication and DNA repair), this adduct incorrectly – and persistently – forms bonds with thymine instead of its normal binding partner cytosine. The bonds that form between the bases differ from normal “Watson-Crick” bonding.
The findings, featured on the cover of the Oct. 12 Journal of Biological Chemistry, provide clues to how this adduct may cause DNA errors that spark cancer formation.
The research was supported by grants from the National Institute of Environmental Health Sciences (ES010546, ES010375, ES05355, ES007028, and ES000267) of the National Institutes of Health.