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Molecular mechanisms safe-guarding genome stability during mammalian cell division


   Sir William Dunn School of Pathology

  Prof Ulrike Gruneberg  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

Faithful cell division ensures the correct segregation of the genetic material over multiple generations. Failure of this process may result in cell death or trigger tumorigenesis. An important prerequisite for successful chromosome segregation and maintenance of genomic integrity is the correct attachment of the chromosomes to microtubules, enabling faithful partitioning of the genetic material. The fidelity of this process is achieved through the combined actions of the so-called error correction process and the spindle assembly checkpoint, crucial molecular safe-guarding mechanisms that jointly eliminate erroneous microtubule-kinetochore attachments and promote bipolar chromosome orientation critical for faithful cell division. We aim to understand the molecular mechanisms underpinning the accurate segregation of the chromosomes in mammalian cells, and what aspects of these processes are changed in cancer cells which often have higher, aneuploid, numbers of chromosomes than their non-transformed counterparts. Dynamic phosphorylation is a particularly important control mechanism for the cell division process. We have recently discovered distinct roles for specific mitotic kinase-phosphatase modules in the regulation of microtubule-kinetochore attachment formation, the spindle assembly checkpoint and the metaphase-to-anaphase transition1-6, and now seek to further understand their actions and interplay with microtubules and kinetochores by using a combination of biochemical and cell biological techniques, including quantitative fixed and live cell imaging, CRISPR/Cas9-mediated genetic manipulation of cells, in vitro reconstitution assays and protein-protein interaction analysis by mass spectrometry. 


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£20,168 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

Hayward, D., Roberts, E. and Gruneberg, U. (2022) MPS1 localizes to microtubule-attached kinetochores and actively promotes microtubule release.
bioRxiv 2022.05.23.493048; https://doi.org/10.1101/2022.05.23.493048
2. Bancroft, J., Holder, J., Geraghty, Z., Alfonso-Perez, Murphy, D., Barr, F.A. and U. Gruneberg. (2020) PP1 promotes cyclin B destruction and the metaphase-anaphase transition by dephosphorylating CDC20. Mol. Cell Biol. https://www.molbiolcell.org/doi/10.1091/mbc.E20-04-0252
3. Hayward, D., Alfonso-Perez, T., and Gruneberg, U. (2019). Orchestration of the spindle assembly checkpoint by CDK1-cyclin B1. FEBS Lett. https://doi.org/10.1002/1873-3468.13591
4. Hayward, D., Bancroft, J., Mangat, D., Alfonso-Perez, T., Dugdale, S., McCarthy, J., Barr, F.A., and Gruneberg, U. (2019). Checkpoint signalling and error correction require regulation of the MPS1 T-loop by PP2A-B56. J Cell Biol 218. https://doi.org/10.1083/jcb.201905026
5. Alfonso-Perez, T., Hayward, D., Holder, J., Gruneberg, U., and Barr, F.A. (2019). MAD1-dependent recruitment of CDK1-CCNB1 to kinetochores promotes spindle checkpoint signaling. J Cell Biol 218, 1108-1117. https://doi.org/10.1083/jcb.201808015
6. Hayward, D., Alfonso-Perez, T., Cundell, M.J., Hopkins, M., Holder, J., Bancroft, J., Hutter, L.H., Novak, B., Barr, F.A., and Gruneberg, U. (2019). CDK1-CCNB1 creates a spindle checkpoint-permissive state by enabling MPS1 kinetochore localization. J Cell Biol 218, 1182-1199. https://doi.org/10.1083/jcb.201808014

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