The objective of this program project is to obtain fundamental information on the molecular mechanisms of action of two chemical classes of environmental carcinogens, polycyclic aromatic hydrocarbons (PAH) and aromatic amines. Utilizing a combination of cell culture and subcellular techniques we will elucidate the chemical structures and stereochemistry of carcinogen-nucleic acid and carcinogen protein adducts. A series of structurally related compounds will be studied to reveal factors related to nucleic acid binding and carcinogen potency. The effects of carcinogen adducts on the conformation of modified nucleic acids will be analyzed by several physical techniques. Functional effects on nucleic acid replication, transcription and translation and on nucleic acid-protein interactions, and on cellular mitochondria, will also be studied. Utilizing DNA transformation, cloning, and sequencing techniques, we will study the genetic mechanisms responsible for the tumor cell phenotype in cells transformed by chemical carcinogens. The possibility that DNA damage in mammalian cells induces cellular responses analogous to the """"""""SOS"""""""" response in bacteria will be examined. Finally, new methods of computer graphics will be developed as an aid to analyzing the conformational and dynamic aspects of carcinogen-nucleic acid interactions. This multidisciplinary approach should provide basic knowledge of the mechanisms of action of chemical carcinogens which is essential for rational approaches to carcinogen detection, risk extrapolation and cancer prevention.
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