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EASTBIO Modification of the kinetochore for spatial regulation of meiotic recombination


School of Biological Sciences

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Prof A Marston , Dr O Davies No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Meiosis produces gametes and is a key source of genetic diversity in sexually reproducing organisms. Diversity arises from the random distribution of maternal and paternal chromosomes at the first meiotic division and as a result of genetic exchanges arising from meiotic recombination. However, meiotic recombination does not occur uniformly along the length of chromosomes. Instead, exchanges which result in crossover recombination are actively suppressed close to telomeres and centromeres. This suppression is critical for accurate chromosome segregation and genome integrity during meiosis, but how it is achieved remains unknown.
Using budding yeast as a model system, we found that the kinetochore plays a critical role in preventing crossover recombination close to centromeres [1]. 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 [2]. 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.

http://marston.bio.ed.ac.uk/

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Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership http://www.eastscotbiodtp.ac.uk/how-apply-0. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition fees. The fee difference will be covered by the University of Edinburgh for successful international applicants. Please refer to UKRI website (https://www.ukri.org/our-work/developing-people-and-skills/find-studentships-and-doctoral-training/get-a-studentship-to-fund-your-doctorate/) and Annex B of the UKRI Training Grant Terms and Conditions (https://www.ukri.org/wp-content/uploads/2020/10/UKRI-291020-guidance-to-training-grant-terms-and-conditions.pdf) for full eligibility criteria.

References

1. Vincenten, N., Kuhl, L.M., Lam, I., Oke, A., Kerr, A.R.W., Hochwagen, A., Fung, J., Keeney, S., Vader, G., and Marston, A.L. (2015). The kinetochore prevents centromere-proximal crossover recombination during meiosis. Elife 4.
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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