Superfund Research Program
NDMA and DNA Alkylation Repair in the Liver: Impact of Gene-Environment Interactions on Cellular Responses, Mutations and Cancer
- Project Summary
The overriding goals of this project are to understand the biological impacts and genetic risk factors related to environmental alkylating agents (chemicals that create carbon-containing adducts on DNA). Many alkylating agents are carcinogenic because structural changes to the DNA can interfere with accurate copying, leading to mutations. N-nitrosodimethylamine (NDMA) is a potent mutagen that has been deemed a probable human carcinogen. In response to NDMA-induced 3-methyladenine lesions, the Alkyladenine DNA Glycosylase (Aag) removes the damaged base and initiates the Base Excision Repair (BER) pathway. While advantageous, single strand breaks are requisite intermediates in the process of stripping away damaged DNA and replacing it. As such, too little Aag is predicted to lead to increased 3-methyladenine-driven mutations, while too much Aag potentially induces toxic single strand breaks. Using genetically engineered mice, the research team showed that while mice with low levels of Aag were prone to cancer, mice with high levels of Aag were resistant to cancer, but at a cost: they suffered significant toxicity. People are known to be variable in their DNA repair capacity, raising the possibility that a person’s response to NDMA may depend on the levels of Aag. Ongoing studies include analysis of multi-omics and mutagenic responses (in collaboration with the Assessment of Genotoxic Health Risks at Superfund Sites through Mutational Signatures Project and the Systems Toxicology of Environmental Contaminants Project). These studies could lead to biomarkers that are predictive of either cancer or toxicity, opening doors to possible interventions to suppress the deleterious effects of NDMA. This work is described in a manuscript that is under revision for publication in Cell Reports.