GENETIC CONTROL OF MUTATION IN DROSOPHILA

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Summary of Work: This project is designed to determine the relationships among DNA repair, chromosome structure, and mutagenesis in Drosophila melanogaster. Mutations that increase the mutant frequency (mutators) have been identified in the mu2 gene and characterized. The mutators reduce meiotic recombination and 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. Mutator mutations appear to disrupt chromatin structure in the oocyte, but not the sperm chromosomes, so that oocyte chromosomes are not repaired properly. Given that mu2 mutations also increase mitotic recombination, it is reasonable to expect that the MU2 protein also associates with somatic chromosomes. This is confirmed by the observation that mu2 mRNA is found in oocytes and some somatic tissues, but not testes. Two independent mutant alleles eliminate this mRNA from these tissues. The mu2 sequence does not have a strong resemblance to any other genes in the database, although the carboxy half of the protein is extremely basic and lysine-rich, consistent with the notion that the protein associates with chromatin. The genomic region including the transcription unit has been reintroduced into the genome to ascertain complementation with mu2 mutations. These tests are in progress. If the mu2 transgene complements the mu2 mutants, antibodies will be made to the protein to ascertain intracellular localization. We also plan to look for other gene products that might interact with MU2 in chromatin.