PI: John M. Essigmann, Departments of Chemistry and Biological Engineering, MIT
The proposed project leverages the complementary expertise of MIT and Skoltech chemists to uncover how living cells respond to ultra-low doses of damaged nucleo-bases in DNA. The work will help reveal how inflammation causes or promotes genetic diseases that have an inflammatory etiologic component. Oligonucleotides will be constructed containing four modified bases: 7,8-dihydro-8-oxoguanine (8OG), 7,8-dihydro-8-oxoadenine (8OA), 1,N6-ethenoadenine (εA) and 8-oxo-1,N6-ethenoadenine (8OεA). The first three are produced by oxidative stress and the last is a structural probe created at Skoltech. Using MIT technology, oligonucleotides containing these bases, with every possible 5’ and 3’ neighbor, will be inserted into the genome of a virus and replicated in cells that are either wild type or possess replication or repair defects. The patterns of mutations observed will be compared to patterns of mutations seen in databases of human diseases, including cancers. The project helps to explain the role of inflammation in genetic diseases.