The long-term goal of the research proposed here is to understand the molecular mechanism of homologous genetic recombination. This objective is approached by a combination of genetic analysis of mutants and biochemical analysis of DNA and purified enzymes. This research is focused on meiotic recombination in the fission yeast Schizosaccharomyces pombe, a widely studied model organism with features similar to those of multicellular eukaryotes, including humans.
Specific aims are to (1) determine the enzymatic activities that process meiotic DNA double- strand break (DSB) ends to prepare them for joint molecule formation, (2) determine the molecular basis of repression of recombination in and around centromeres, and (3) determine the mechanisms by which recombination is globally regulated by sister chromatid cohesins and linear element proteins over large (megabase) regions, and by the meiotic bouquet's restriction of ectopic recombination.
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 purified proteins. The results of these studies will elucidate the molecular mechanism of recombination as well as the controls on recombination that ensure its occurrence at the proper place along chromosomes and thereby promoting faithful segregation of homologs at the first meiotic division. Recombination is important for generating diversity at both the organismal and cellular levels, for faithful segregation of chromosomes during meiosis, and for repair of DNA double-strand breaks. Aberrancies of recombination can generate chromosomal rearrangements, such as translocations, duplications, and deletions. These rearrangements 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 C Study Section (MGC)
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Janes, Daniel E
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Fred Hutchinson Cancer Research Center
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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
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
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
Fowler, Kyle R; Gutierrez-Velasco, Susana; Martin-Castellanos, Cristina et al. (2013) Protein determinants of meiotic DNA break hot spots. Mol Cell 49:983-96
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Ellermeier, Chad; Higuchi, Emily C; Phadnis, Naina et al. (2010) RNAi and heterochromatin repress centromeric meiotic recombination. Proc Natl Acad Sci U S A 107:8701-5
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Farah, Joseph A; Cromie, Gareth A; Smith, Gerald R (2009) Ctp1 and Exonuclease 1, alternative nucleases regulated by the MRN complex, are required for efficient meiotic recombination. Proc Natl Acad Sci U S A 106:9356-61

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