Abstract

The long-term objective of the research proposed here is to understand the molecular mechanisms of homologous genetic recombination. These objectives are approached genetically by studying mutants altered in recombination and physically by analyzing DNA from cells undergoing recombination. The research is focused on meiotic recombination in the fission yeast Schizosaccharomyces pombe, a widely studied model organism with molecular similarities to multicellular eukaryotes, including humans.
Specific aims of the research are to 1) determine the genetic regulation of meiotic DNA breakage and repair during meiosis, 2) isolate and analyze new 5. pombe mutants altered in the early and late steps of recombination, and 3) elucidate the mechanism of a novel pathway of meiotic recombination active in the apparent absence of DNA double-strand breaks. Recombination is important for generating diversity at both the organismal and cellular levels, for proper segregation of chromosomes during meiosis, and for repair of DNA double-strand breaks. Aberrancies of recombination generate chromosomal rearrangements, such as translocations, duplications, and deficiencies. These rearrangements are associated with, and in some cases are 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM032194-23
Application #
6924089
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Portnoy, Matthew
Project Start
1983-03-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
23
Fiscal Year
2005
Total Cost
$376,389
Indirect Cost

  Institution

Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109

  Publications

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

Showing the most recent 10 out of 73 publications