This program project is a bridge between studies on DNA adducts and germ line mutations analyzed at the molecular level. For comparisons among species, including man, DNA adducts provide a point of commonality in comparing dose while the description of mutations as to the alteration of DNA provides a point of commonality for comparing mutations. The mechanism of mutagenesis is studied in the various germ cell stages of Drosophila melanogaster with an emphasis on mechanisms that are relevant to chronic exposure in repair competent cells. From our current research it is likely that at chronic exposure levels only a small fraction of adducts produces lesions that induce mutations transmitted to successive generations. The identification of these important lesions will be done through understanding the mechanism of mutagenesis for transmitted mutations. In this program project the mechanism of mutagenesis is studied in five projects by determining the following: (Project I) relation of DNA adducts in germ cells to induced mutations transmitted to successive generations; (Project II) distribution of adducts of DNA; (Project III) analysis of mutations by the complementation test and sequencing so that the mutational change in DNA can be characterized for changes ranging from large deletions to single base substitutions; (Project IV) dominance of mutant genes in specific tissues, enzymatic activity and stability of both homodymers and heterodymers determined by using immunochemica and radiotracer methodologies; and (Project V) theories, derived from the forward mutation test in projects I through IV, to be tested using site specific mutagenesis. A core project will provide support for all of the projects including the maintenance of Drosophila stocks, P-element transformation and P-element mutagenesis. Collectively these studies will enable us to understand how initial lesions formed by alkylation of DNA are transformed into mutations transmitted to successive generations.
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