DAMAGE OF HUMAN CHROMATIN BY CARCINOGENS

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The broad objective of the present proposal is to determine whether different classes of environmentally-relevant carcinogens form different DNA adduct spectrums and distributions within the different structural regions of human chromatin, and whether these adducts alter the transitions between the different structural states of the chromatin fiber. Specifically, we plan to: (1) characterize the distribution and types of DNA and protein adducts formed by different classes of carcinogens within long chromatin fragments in vitro that mimic the different structural states and compositions of the chromatin fiber in vivo; (2) determine whether the chromatin fiber structure can be altered by the formation of adducts from different classes of carcinogens; (3) determine whether such alterations affect the structural transitions of the chromatin fiber; and (4) use these damaged, "model" chromatin fibers as substrates for damage specific endonucleases in vitro. These studies should lead the way for a careful, systematic analysis of the effects of DNA adduct variation, chromatin fiber structure and chromatin fiber composition on the competency of excision repair enzymes in vitro.