This program project brings together five established investigators to study the mechanisms of mutagenesis for environmental mutagens. Mutagens will be synthesized to produce an array of DNA adducts that cover the distribution and molecular weight range of adducts found from the action of environmental mutagens on DNA. The dose response curve will be determined using adducts per deoxynucleotide as dose and sex-linked recessive lethals and specific locus mutations at the alcohol dehydrogenase locus in Drosophila melanogaster as the genetic response in Project I. The distribution of adducts among target sites of DNA will be determined in Project II. The effect of repair on mutation frequency in both repair competent and repair deficient oocytes of D. melanogaster will be determined in Project III. The repair process will be studied in vitro in Project IV using enzymes extracted from the stocks used in Project III. Compounds used to produce these DNA adducts along with appropriate standards of modified bases will be synthesized in Project V. Protein produced by mutations recovered in this program project will be characterized in Project VI. DNA at the mutant loci will be cloned and sequenced in Project VII. A core facility will provide the Drosophila stocks for all the projects, will test newly synthesized mutagens, and will maintain clones of mutant DNA and Drosophila mutants in Project VIII. The projects taken as a whole will enable us to study the mechanisms of mutation from adduct formation through the repair processes to the characterization of the DNA of the mutant gene and any protein that may be produced.
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