The ultimate goal of this program is to achieve a more thorough understanding of the mechanisms employed by higher organisms to contend with DNA damage induced by chemicals or radiation. Analysis of Drosophila mutants with DNA repair deficiencies analogues to known human disorders should contribute to an increased understanding of those human deficiencies. Studies of DNA repair will also indirectly further our understanding of the processes of mutation and recombination. The foundation for these studies consists of a collection of mutants which identify over 30 different genetic loci that potentially play a role in DNA repair. Deficiencies in at least one major repair pathway have thus far been identified in mutants at 13 of these loci. The next step in this analysis will be to dissect these major repair pathways biochemically with the aid of the mutant blocks. Two problems have been selected for concentrated study: in both cases mutants have been identified which alter a biochemically detectable response to mutagenic insult. In the first of these studies the key repair enzyme apurinic/apyrimidinic endonuclease will be thoroughly characterized and its function analyzed in conjunction with genetic studies. By exploiting recently identified enzyme deficiencies in mutant stocks, we should achieve an improved understanding of the control and function of this enzyme class. Some of the mutants to be employed are formally analogous to selected cases of the human genetic disorder xeroderma pigmentosum. Simultaneously we will investigate a series of mutants which exhibit a complementary phenotype to the human disorder ataxia telangiectasia. The genetic defects in both organisms modify DNA synthesis in unmutagenized cells. In mutagenized cells the human disorder fails to respond normally to ionizing radiation, whereas the Drosophila mutants respond abnormally to chemical mutagens. The Drosophila mutants therefore represent a new variation of the defense mechanism identified in ataxia telangiectasia. We will employ a combined biochemical and genetic approach to investigate this mechanism.
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