The long-term goal of the research proposed here is to determine the molecular mechanism of homologous genetic recombination. This objective is approached by a combination of genetic analysis of mutants altered in recombination and biochemical analysis of DNA from cells. This research uses the fission yeast Schizosaccharomyces pombe, a widely studied, highly tractable model organism with features similar to those of multicellular eukaryotes, including humans. The studies are focused on meiotic recombination, whose high rates of recombination facilitate both genetic and biochemical analyses.
Specific aims are to (1) determine how meiotic DNA double-strand break (DSB) formation is differentially regulated along chromosome arms by sister chromatid cohesins, linear element proteins, and protein kinases, (2) determine how meiotic DSB formation is repressed specifically in heterochromatic centromeres, and (3) determine how the Mus81-Eme1 Holliday junction resolvase is regulated in meiosis.
These aims will be attacked by a combination of genetic analysis of mutants, fluorescence microscopy of intracellular proteins, physical analysis of DNA intermediates from meiotic cells, and enzymology of isolated proteins. The results of these studies will elucidate the molecular mechanism of recombination as well as the controls on recombination that ensure that it occurs at the proper place along chromosomes to promote faithful segregation of homologs at the first meiotic division. Recombination is important for faithful meiotic chromosome segregation, for repair of DNA double-strand breaks, and for generating diversity at both the organismal and cellular levels. Aberrancies of recombination can generate chromosomal rearrangements, such as translocations, duplications, and deletions, which are often associated with or the cause of birth defects and cancers. Understanding the molecular mechanism of recombination is important in determining the causes of these diseases and possibly preventing them.

Public Health Relevance

Genetic recombination is important for the accurate repair of broken DNA, for formation of viable sex cells (eggs and sperm), and for enhancing diversity among cells and organisms. Failure of recombination can lead to birth defects and cancer, and understanding the molecular mechanism of recombination is important to prevent or possibly cure such diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Janes, Daniel E
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Fred Hutchinson Cancer Research Center
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Fowler, Kyle R; Hyppa, Randy W; Cromie, Gareth A et al. (2018) Physical basis for long-distance communication along meiotic chromosomes. Proc Natl Acad Sci U S A 115:E9333-E9342
Nambiar, Mridula; Smith, Gerald R (2018) Pericentromere-Specific Cohesin Complex Prevents Meiotic Pericentric DNA Double-Strand Breaks and Lethal Crossovers. Mol Cell 71:540-553.e4
Ma, Lijuan; Fowler, Kyle R; Martín-Castellanos, Cristina et al. (2017) Functional organization of protein determinants of meiotic DNA break hotspots. Sci Rep 7:1393
Nambiar, Mridula; Smith, Gerald R (2016) Repression of harmful meiotic recombination in centromeric regions. Semin Cell Dev Biol 54:188-97
Polakova, Silvia; Molnarova, Lucia; Hyppa, Randy W et al. (2016) Dbl2 Regulates Rad51 and DNA Joint Molecule Metabolism to Ensure Proper Meiotic Chromosome Segregation. PLoS Genet 12:e1006102
Ma, Lijuan; Milman, Neta; Nambiar, Mridula et al. (2015) Two separable functions of Ctp1 in the early steps of meiotic DNA double-strand break repair. Nucleic Acids Res 43:7349-59
Phadnis, Naina; Cipak, Lubos; Polakova, Silvia et al. (2015) Casein Kinase 1 and Phosphorylation of Cohesin Subunit Rec11 (SA3) Promote Meiotic Recombination through Linear Element Formation. PLoS Genet 11:e1005225
Cipak, Lubos; Polakova, Silvia; Hyppa, Randy W et al. (2014) Synchronized fission yeast meiosis using an ATP analog-sensitive Pat1 protein kinase. Nat Protoc 9:223-31
Fowler, Kyle R; Sasaki, Mariko; Milman, Neta et al. (2014) Evolutionarily diverse determinants of meiotic DNA break and recombination landscapes across the genome. Genome Res 24:1650-64
Hyppa, Randy W; Fowler, Kyle R; Cipak, Lubos et al. (2014) DNA intermediates of meiotic recombination in synchronous S. pombe at optimal temperature. Nucleic Acids Res 42:359-69

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