This Program Project interactively uses organic synthesis, bioanalytical chemistry, structural biology, and molecular biology to elucidate the molecular details by which exogenous and endogenous bifunctional alkylating adducts degrade DNA replication and repair. Efforts will focus on agents in which the two sites of possible nucleophilic attack by the DNA are separated by either two or three carbon atoms. Chlorooxirane, a metabolite of vinyl chloride, is an example of the former and alpha, beta-unsaturated aldehydes, such as acrolein, crotonaldehyde and 4-hydroxynonenal, are examples of the latter. A central hypothesis of this Program Project is that bis-electrophiles can form inter- and intrastrand DNA crosslinks and such crosslinks contribute significantly in the biology of the adducts. Project 1 will develop synthetic routes to the various types of adducts that can be formed by these electrophiles and strategies for their site-specific incorporation into DNA with defined regiochemistry and stereochemistry. The proposed studies are designed to address hypotheses concerning the following: 1) the characterization of intrastrand enal crosslinks and the processing of the intrastrand crosslinks by lesion bypass polymerases;2) the synthesis and study of N1-dA and N3-dC adducts of Chlorooxirane and acrolein and their deamination products;3) identification of DNA crosslinks of enals from biological samples and 4) the synthesis and characterization of FAPgamma lesions that are derived from hydrolysis of N7-dG adducts. The DNA adducts to be studied are derived from widely dispersed environmental pollutants or produced endogenously through lipid peroxidation. Given the wide exposure to these compounds, our studies will have direct applications to human health concerns.
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