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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM052319-04
Application #
2636486
Study Section
Special Emphasis Panel (ZRG5-MBC-1 (01))
Project Start
1995-05-01
Project End
2002-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Moore, Anthony; Dominska, Margaret; Greenwell, Patricia et al. (2018) Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences. Genetics 209:425-438
Kiktev, Denis A; Sheng, Ziwei; Lobachev, Kirill S et al. (2018) GC content elevates mutation and recombination rates in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 115:E7109-E7118
Zhang, Ke; Wu, Xue-Chang; Zheng, Dao-Qiong et al. (2017) Effects of Temperature on the Meiotic Recombination Landscape of the Yeast Saccharomyces cerevisiae. MBio 8:
Zhao, Ying; Dominska, Margaret; Petrova, Aleksandra et al. (2017) Properties of Mitotic and Meiotic Recombination in the Tandemly-Repeated CUP1 Gene Cluster in the Yeast Saccharomyces cerevisiae. Genetics 206:785-800
Omer, Sumita; Lavi, Bar; Mieczkowski, Piotr A et al. (2017) Whole Genome Sequence Analysis of Mutations Accumulated in rad27? Yeast Strains with Defects in the Processing of Okazaki Fragments Indicates Template-Switching Events. G3 (Bethesda) 7:3775-3787
Yin, Yi; Dominska, Margaret; Yim, Eunice et al. (2017) High-resolution mapping of heteroduplex DNA formed during UV-induced and spontaneous mitotic recombination events in yeast. Elife 6:
Zheng, Dao-Qiong; Zhang, Ke; Wu, Xue-Chang et al. (2016) Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 113:E8114-E8121
Andersen, Sabrina L; Zhang, Aimee; Dominska, Margaret et al. (2016) High-Resolution Mapping of Homologous Recombination Events in rad3 Hyper-Recombination Mutants in Yeast. PLoS Genet 12:e1005938
Clausen, Anders R; Lujan, Scott A; Burkholder, Adam B et al. (2015) Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation. Nat Struct Mol Biol 22:185-91
O'Connell, Karen; Jinks-Robertson, Sue; Petes, Thomas D (2015) Elevated Genome-Wide Instability in Yeast Mutants Lacking RNase H Activity. Genetics 201:963-75

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