GENETIC CONTROL OF MUTATION IN DROSOPHILA

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This project is designed to determine the relationship between DNA repair, chromosome structure and mutagenesis in Drosophila melanogaster. A mutation that increases the mutation frequency (a mutator) has been identified and characterized. The mutator greatly reduces the efficacy of repair of x-ray induced chromosome breaks, thereby allowing a previously undescribed repair pathway to be observed. By this newly identified repair pathway broken chromosome ends are "capped" with a new telomere. The new chromosome ends are protected from degradation by other repair mechanisms, but do not replicate effectively and DNA sequences are lost from the capped ends. The DNA at the ends of several of these chromosomes have been sequenced and found to have no DNA distal to the genomic breakpoint. Quasi-stable derivatives of the capped ends have been isolated and found to have gained a telomere specific DNA sequence which is associated with DNA sequences that suggest it is included in a retrotransposon. Our current model of replication at chromosome ends in Drosophila is that gradual loss of DNA at the chromosome end is balanced by occasional transposition of new DNA onto the end, and that the new DNA is gradually lost via incomplete replication. We are also developing a rapid assay for the mutator to facilitate genetic analysis, investigating cell specificity of mutator activity, and mapping the mutator gene with the intent of cloning it.