About the Project
Using budding yeast as a model system, we found that the kinetochore plays a critical role in preventing crossover recombination close to centromeres . How the kinetochore achieves crossover suppression is unclear, but a network of regulators of meiotic recombination which associate with the kinetochore during meiotic prophase are likely to be involved . In this project, you will determine how meiotic recombination proteins are recruited to the kinetochore to spatially regulate crossover formation.
Aim 1. Requirements for assembly of the prophase kinetochore “cap”
The requirements for recruitment of meiotic recombination proteins to kinetochores will be determined by live-cell imaging and chromatin immunoprecipitation. This will reveal the hierarchy of protein assembly at meiotic prophase kinetochores.
Aim 2. Functional analysis in yeast
The importance of factors found to localize to the kinetochore in suppression of meiotic recombination and chromosome segregation will be determined by microscopy-based and next-generation sequencing-based assays [1,3].
Aim 3. Reconstitution of regulators of recombination at the kinetochore
Biophysical (MALS, SAXS, SPR) and structural methods (X-ray crystallography and cryo-EM) will be used to determine key interactions between kinetochore proteins and kinetochore-localized recombination regulators. Where appropriate, this will be complemented by purification of complexes from yeast under conditions where recombination is prevented. These experiments will guide the generation of in vivo mutations that will inform the analysis in Aim 2.
Overall, this project will review how a network of recombination regulators that are specifically recruited to kinetochores in meiotic prophase spatially control crossover recombination.
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2. Borek, W.E., Vincenten, N., Duro, E., Makrantoni, V., Spanos, C., Sarangapani, K.K., Alves, F. de L., Kelly, D.A., Asbury, C.L., Rappsilber, J., et al. (2020). The proteomic landscape of centromeric chromatin reveals an essential role for the Ctf19 complex in meiotic kinetochore assembly. bioRxiv, 2020.06.23.167395.
3. Thacker, D., Lam, I., Knop, M., and Keeney, S. (2011). Exploiting spore-autonomous fluorescent protein expression to quantify meiotic chromosome behaviors in Saccharomyces cerevisiae. Genetics 189, 423–439.
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