Our long-term goal is to understand the mechanisms of meiotic and mitotic recombination. A knowledge of the mechanisms by which cells create double-stranded DNA breaks (the DNA lesions that initiate recombination) and repair these breaks is essential for understanding the genomic instability associated with cancer. Although most of our proposed experiments will be done with the yeast Saccharomyces cerevisiae, we will examine DNA mismatch repair (MMR) in both yeast and C. elegans. The first Specific Aim is to examine the properties of DNA sequence and chromatin structure that affect the frequency of meiotic recombination. For most of these experiments, we will use DNA microarrays to monitor meiotic recombination activity at every locus in the genome. The second Specific Aim is to study the mechanism of reciprocal mitotic recombination. Using a system that allows selection of reciprocal mitotic crossovers, we will determine whether there are hotspots for mitotic exchanges. We will also investigate the genetic regulation of mitotic recombination using mutations that affect various pathways of recombination and DNA repair. Our third Specific Aim is to examine various aspects of DNA mismatch repair in yeast and in C. elegans. We will analyze the roles of the yeast MMR proteins Msh3p, Msh6p, MIh2p, and MIh3p, as well as the possible involvement of the DNA replication proteins DNA polymerase delta and PCNA, in the repair of mismatches generated during meiotic recombination. The proposed C. elegans studies will concentrate on determining phenotypes associated with msh-2 and msh-6 mutant worms, and on the isolation of new MMR worm mutants.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetics Study Section (GEN)
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Anderson, Richard A
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Duke University
Schools of Medicine
United States
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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
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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
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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
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
Yin, Yi; Petes, Thomas D (2015) Recombination between homologous chromosomes induced by unrepaired UV-generated DNA damage requires Mus81p and is suppressed by Mms2p. PLoS Genet 11:e1005026

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