Meiosis is a fundamental process that sexually reproducing organisms undergo in order to reduce by half the chromosome number in germ cells. When meiosis fails, chromosomally imbalanced gametes result. In mammals the zygotes generated by fertilization of such chromosomally imbalanced gametes are inviable and account for a large number of spontaneous abortions. In cases where viable offspring are produced, mental and morphological defects such as those seen for Trisomy 21 or Turner syndrome (XO) are observed. Understanding how the meiotic process works to accurately segregate homologous chromosomes may ultimately provide the knowledge needed to monitor and prevent failures of this process. Proper segregation of homologs at Meiosis I requires that they first become physically associated by formation of a multi-protein structure called the synaptonemal complex (SC). The SC is formed by condensation of replicated pairs of sister chromatids along protein cores called axial elements (AEs) that are then synapsed by the insertion of a central region. Genetic studies in yeast have demonstrated that AEs are important for generating and packaging crossovers so that they ensure proper disjunction. Three key meiosis-specific components of yeast AEs are HOP1, RED1 and MEK1. Genetic experiments suggest that a balance between Hop1p/Red1p complexes and Red1p homo-oligomers is important for AE function and that this stoichiometry is regulated by the Mek1p kinase. The focus of this grant is to understand how AEs function in yeast by defining the specific roles of HOP1, RED1, and MEK1 during meiosis. Towards this end, a novel screen designed to isolate separation of function mutants in RED1 has been developed. This screen has already been successful in discovering an allele of RED1 that is specifically defective in binding to Hop1p. This mutant provides a useful tool to determine which meiotic processes require Red1p/Hop1 heterooligomers. Similar separation of function mutants will be sought in HOP1 and complementary experiments performed. The hypothesis that Hop1p homo-oligomers have a RED1-independent function in binding near the ends of meiotic double strand breaks will be tested using the chromatin immunoprecipitation technique. To understand how AE assembly is regulated, genetic and biochemical approaches will be used to identify the kinase responsible for activating Mek1p by phosphorylation of a conserved threonine.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Genetics Study Section (GEN)
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Carter, Anthony D
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State University New York Stony Brook
Schools of Arts and Sciences
Stony Brook
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Kniewel, Ryan; Murakami, Hajime; Liu, Yan et al. (2017) Histone H3 Threonine 11 Phosphorylation Is Catalyzed Directly by the Meiosis-Specific Kinase Mek1 and Provides a Molecular Readout of Mek1 Activity in Vivo. Genetics 207:1313-1333
Prugar, Evelyn; Burnett, Cameron; Chen, Xiangyu et al. (2017) Coordination of Double Strand Break Repair and Meiotic Progression in Yeast by a Mek1-Ndt80 Negative Feedback Loop. Genetics 206:497-512
Callender, Tracy L; Laureau, Raphaelle; Wan, Lihong et al. (2016) Correction: Mek1 Down Regulates Rad51 Activity during Yeast Meiosis by Phosphorylation of Hed1. PLoS Genet 12:e1006283
Suhandynata, Raymond T; Wan, Lihong; Zhou, Huilin et al. (2016) Identification of Putative Mek1 Substrates during Meiosis in Saccharomyces cerevisiae Using Quantitative Phosphoproteomics. PLoS One 11:e0155931
Hollingsworth, Nancy M (2016) Mek1/Mre4 is a master regulator of meiotic recombination in budding yeast. Microb Cell 3:129-131
Callender, Tracy L; Laureau, Raphaelle; Wan, Lihong et al. (2016) Mek1 Down Regulates Rad51 Activity during Yeast Meiosis by Phosphorylation of Hed1. PLoS Genet 12:e1006226
Park, Jae-Sook; Thorsness, Mary K; Policastro, Robert et al. (2016) Yeast Vps13 promotes mitochondrial function and is localized at membrane contact sites. Mol Biol Cell 27:2435-49
Chen, Xiangyu; Suhandynata, Ray T; Sandhu, Rima et al. (2015) Phosphorylation of the Synaptonemal Complex Protein Zip1 Regulates the Crossover/Noncrossover Decision during Yeast Meiosis. PLoS Biol 13:e1002329
Suhandynata, Ray; Liang, Jason; Albuquerque, Claudio P et al. (2014) A method for sporulating budding yeast cells that allows for unbiased identification of kinase substrates using stable isotope labeling by amino acids in cell culture. G3 (Bethesda) 4:2125-35
Liu, Yan; Gaines, William A; Callender, Tracy et al. (2014) Down-regulation of Rad51 activity during meiosis in yeast prevents competition with Dmc1 for repair of double-strand breaks. PLoS Genet 10:e1004005

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