Meiosis is a specialized cell division used by sexually reproducing organisms to produce haploid gametes from diploid cells. This reduction in chromosome number is accomplished by having two rounds of chromosome segregation follow a single round of chromosome duplication. Failures in meiotic chromosome segregation in humans lead to infertility and birth defects such as Trisomy 21, the leading cause of mental retardation in the United States. In addition, meiotic chromosome segregation requires the repair of programmed double strand breaks (DSBs). DSB repair in mitotically dividing cells is critical for genome integrity and the prevention of cancer. Budding yeast is an excellent model system for studying meiosis. Mice and yeast mutated for orthologous meiotic genes are phenotypically similar, demonstrating that studies of meiosis in yeast are likely to be illuminating with regard to meiosis in humans. The first meiotic division (MI) is unique in that sister chromatids segregate to the same pole (called reductional segregation). Proper MI segregation requires that homologous chromosomes be connected to each other by crossovers between non-sister chromatids in combination with sister chromatid cohesion. Recent work has shown that crossing over between non-sister chromatids during meiosis is promoted in part by active suppression of DSB repair between sister chromatids. This suppression is mediated by Mek1, a meiosis-specific serine/threonine kinase. Understanding the molecular mechanism by which Mek1 inhibits meiotic sister chromatid repair requires identification of the substrates phosphorylated by this kinase. We will use novel biochemical and genetic strategies to identify Mek1 targets and characterize phosphorylation- defective versions of these proteins elucidate this process. In addition we will test a specific model for how cohesins may be involved in suppressing meiotic intersister DSB repair. Repair of meiotic DSBs utilizes two recombinases for strand invasion: Dmc1, which is meiosis-specific and Rad51, the major recombinase in vegetative cells. How the action of these two strand exchange proteins is coordinated during meiotic recombination not yet understood. Recent biochemical experiments have suggested a novel mechanism for regulating Rad51 activity mediated by Mek1 phosphorylation of an accessory protein, Rad54. One goal is to determine whether this mechanism functions in meiotic cells.

Public Health Relevance

Failures in the evolutionarily conserved cell division of meiosis result in infertility and birth defects such as Down syndrome. Proper meiotic chromosome segregation requires double strand break repair-a process also required to maintain genome integrity and prevent cancer. This grant is focused on understanding the molecular basis for proper chromosome behavior during meiosis-knowledge that may ultimately lead to the diagnosis and/or prevention of certain types of infertility, birth defects and even cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050717-15
Application #
7772272
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Hagan, Ann A
Project Start
1995-01-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
15
Fiscal Year
2010
Total Cost
$437,963
Indirect Cost
Name
State University New York Stony Brook
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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
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
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
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
Lo, Hsiao-Chi; Kunz, Ryan C; Chen, Xiangyu et al. (2012) Cdc7-Dbf4 is a gene-specific regulator of meiotic transcription in yeast. Mol Cell Biol 32:541-57

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