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Safe-guarding genome integrity during mammalian cell division


Sir William Dunn School of Pathology

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Dr U Gruneberg No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

The key goal of cell division is the correct segregation of the genetic material over multiple generations. Failure of this process can result in cell death or trigger tumorigenesis. An important prerequisite for correct chromosome segregation and maintenance of genomic integrity in eukaryotes is the tight attachment of the chromosomes to microtubules during cell division, making faithful partitioning of the chromosomes possible. 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 ensure the formation of stable microtubule-kinetochore attachments. Our aim is to understand how these mechanisms secure accurate segregation of the chromosomes in mammalian cells, and what aspects of these processes go wrong in cancer cells. We have recently discovered distinct roles for specific mitotic kinase-phosphatase modules in the regulation of chromosome segregation, the spindle assembly checkpoint and the metaphase-to-anaphase transition1-5 and will now aim to further understand their actions and interplay by using a combination of biochemical and cell biological techniques, including cutting edge fixed and live cell imaging, CRISPR/Cas9-mediated genetic manipulation of cell lines, in vitro protein assays, immunoprecipitations and mass spectrometry.

Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£17,285 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See https://www.path.ox.ac.uk/content/prospective-graduate-students for full details and to apply.

References

1. 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. doi: 10.1091/mbc.E20-04-0252

2. Hayward, D., Alfonso-Perez, T., and Gruneberg, U. (2019). Orchestration of the spindle assembly checkpoint by CDK1-cyclin B1. FEBS Lett. 10.1002/1873-3468.13591.

3. 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. 10.1083/jcb.201905026.

4. 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. 10.1083/jcb.201808015. PMC6446853

5. 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. 10.1083/jcb.201808014. PMC6446832


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