GENETIC CONTROL OF MUTATION IN DROSOPHILA

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This project is designed to determine the relationships among DNA repair, chromosome structure, and mutagenesis in Drosophila melanogaster. A mutation that increases the mutant frequency (a mutator) has been identified and characterized. The mutator greatly reduces the efficacy of repair of gamma-ray-induced chromosome breaks in oocytes, 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. Similar broken chromosome ends have now been recovered from irradiated, wild type (non-mutator) females, although at a much lower frequency. Mutator mutations appear to disrupt chromatin structure in the oocyte, but not the sperm chromosomes, so that oocyte chromosomes are not repaired properly. The mutator gene has been mapped to chromosome region 62B12-C1 using a nested set of 150 deletions. A yeast artificial chromosome that spans the region has been subcloned and the location of the deletion breakpoints limit the possible location of the left end of the gene to within 20 kilobasepairs. Two transcription units have been identified that probably relate to the two complementation groups in the region. These deletions have also been used to map two genes necessary to produce steroid hormones, plus genes for (a) lipid distribution in the embryo, (b) a component of the extracellular matrix, (c) a step in the Krebs cycle, and (d) a chromosomal protein identified by human CREST antiserum. A second gene necessary for delaying progress through the cell cycle in response to DNA damage has also been cloned. Mutant cells that progress through the cell cycle with broken chromosomes die. A comparison of these two mutants will identify processes that modulate DNA repair and determine repair outcomes.