The long-term goal of this research is to understand the structural biochemistry of adduct-induced frameshift mutagenesis. Adduct-induced mutagenesis is believed to be the initiating step within a complex cascade of events leading to chemical carcinogenesis. Frameshift mutations could cause the inactivation of tumor suppressor genes. Working with DNA adducts for which mutagenic data is available, testable hypotheses will be developed regarding the structural origin of specific mutations. These hypotheses will be examined using modified oligodeoxynucleotides designed to model specific structures. NMR spectroscopy will be the primary technique used to derive detailed structural information. Two projects are proposed during the initial grant period. In the first project, the propensity of aflatoxin B1 adducts to act as aberrant templates will be examined. Aflatoxin B1 will be incorporated into oligodeoxynucleotides in which the aflatoxin moiety will be opposite an extra nucleotide in the complementary strand. In the second project, oligodeoxynucleotides modified with N-acetylaminofluorene and aminofluorene will be used to examine adduct-induced strand-slippage frameshift mutagenesis. These compounds will be incorporated into oligodeoxynucleotides as unpaired adducted nucleotides. It will be determined whether the unpaired adducted nucleotide is stacked into the helix or is extrahelical. The structure of unpaired adducted nucleotides will be examined in the context of different DNA sequences, with particular emphasis on the nucleotide 5' to the modified base.
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