Molecular Mechanisms of Genetic Recombination

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of the research proposed here is to determine the molecular mechanism of homologous genetic recombination. This objective is approached by a combination of genetic analysis of mutants altered in recombination and biochemical analysis of DNA from cells. This research uses the fission yeast Schizosaccharomyces pombe, a widely studied, highly tractable model organism with features similar to those of multicellular eukaryotes, including humans. The studies are focused on meiotic recombination, whose high rates of recombination facilitate both genetic and biochemical analyses. Specific aims are to (1) determine how meiotic DNA double-strand break (DSB) formation is differentially regulated along chromosome arms by sister chromatid cohesins, linear element proteins, and protein kinases, (2) determine how meiotic DSB formation is repressed specifically in heterochromatic centromeres, and (3) determine how the Mus81-Eme1 Holliday junction resolvase is regulated in meiosis. These aims will be attacked by a combination of genetic analysis of mutants, fluorescence microscopy of intracellular proteins, physical analysis of DNA intermediates from meiotic cells, and enzymology of isolated proteins. The results of these studies will elucidate the molecular mechanism of recombination as well as the controls on recombination that ensure that it occurs at the proper place along chromosomes to promote faithful segregation of homologs at the first meiotic division. Recombination is important for faithful meiotic chromosome segregation, for repair of DNA double-strand breaks, and for generating diversity at both the organismal and cellular levels. Aberrancies of recombination can generate chromosomal rearrangements, such as translocations, duplications, and deletions, which are often associated with or the cause of birth defects and cancers. Understanding the molecular mechanism of recombination is important in determining the causes of these diseases and possibly preventing them.