Microsatellites are regions of DNA in which a single base or a small number of bases is repeated multiple times. All eukaryotes examined thus far contain microsatellites. These sequences are inherently unstable, undergoing alterations in length at a much higher rate than that observed for """"""""normal"""""""" DNA sequences. Genome-wide microsatellite instability is associated with certain types of human cancer. In yeast, mutations in DNA mismatch repair genes result in microsatellite instability and some human tumors with unstable microsatellites have mutations in human homologues of the yeast DNA mismatch repair genes. Some microsatellite unstable tumors, however, lack such mutations. In the current proposal, mutant screens designed to identify new genes affecting microsatellite instability in yeast are proposed. If new genes are identified, human homologues of these genes will be isolated. DNA isolated from tumors with unstable microsatellites that do not have mutations in known DNA mismatch repair genes will be examined to determine whether these tumors have mutations in human homologues of the newly-discovered yeast genes. Three other types of experiments concerning microsatellite instability are proposed. Since mistakes made during DNA replication are likely to contribute to microsatellite instability, a search for mutations in yeast DNA polymerase delta that result in unstable microsatellites will be performed. Second, the genetic regulation of microsatellite in mitochondrial DNA in yeast will be studied. Third, a transgenic mouse line will be constructed to allow the measurement of microsatellite instability in vivo.
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