The broad and long term goals of this research is to determine on a molecular level the etiology of cancer initiation by DNA damage, produced by environmental and endogenous chemicals to which the human population is widely exposed. The overall hypotheses are: (1) The specific formation of damaged DNA is critical in determining if it is repaired or not;(2) if repair fails, the DNA conformation within a replicative polymerase determines whether blockage, normal or mutagenic bypass occurs;(3) if normal replication is impeded, then the altered DNA will encounter one or more bypass polymerases, and the specific conformation of the altered DNA will determine whether a mutation which may initiate cancer occurs. The PI will test these hypotheses by determining structural, dynamic and thermodynamic properties for two groups of lesions: (1) a series derived from carcinogenic aromatic amines/amide presenting tobacco smoke, automobile exhaust and cooked foods that are capable of Watson-Crick pairing and stacking, and (2) a severely distorting group incapable of Watson-Crick pairing, with impaired stacking;these include a lesion derived from a prominent hormone replacement drug, and one produced by endogenous and exogenous reactive oxygen species.
Specific aim 1 will determine detailed structural and thermodynamic properties of the lesions in duplex DNA as a function of adduct structure and thermodynamic factors that cause the adducts to impede replicative polymerases, and to delineate factors which could permit mutagenic or normal bypass of the lesions with lowered fidelity in Y-family bypass polymerases. Relevance to public health: this work will define precisely on a molecular level, the specific structural and energetic characteristics of DNA-containing lesions derived from carcinogenic environmental substances, and thus provided the molecular hallmarks that distinguish very harmful chemicals from benign ones. These studies will facilitate advances in biomonitoring of carcinogen - damaged DNA, since the structural and thermodynamic properties of the DNA lesions would provide a method for distinguishing highly genotoxic lesions from more benign ones.
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