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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055678-02
Application #
3200191
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1992-02-15
Project End
1995-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Arts and Sciences
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Patra, Amritraj; Banerjee, Surajit; Johnson Salyard, Tracy L et al. (2015) Structural Basis for Error-Free Bypass of the 5-N-Methylformamidopyrimidine-dG Lesion by Human DNA Polymerase ? and Sulfolobus solfataricus P2 Polymerase IV. J Am Chem Soc 137:7011-4
Politica, Dustin A; Malik, Chanchal K; Basu, Ashis K et al. (2015) Base-Displaced Intercalated Structure of the N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone DNA Adduct. Chem Res Toxicol 28:2253-66
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