PhD project

Supervisor: Ulrike Gruneberg

Faithful cell division ensures the correct segregation of the genetic material over multiple generations. Failure of this process may result in cell death or lay the foundation for 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. In my research group, 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 chromosome segregation 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 transition^1-6, 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.

Keywords:

• Biochemistry, Cancer/Oncology, Cell Biology/Development, Molecular Biology

Publications:

• Hayward, D., Roberts, E. and Gruneberg, U. (2022) MPS1 localizes to microtubule-attached kinetochores and actively promotes microtubule release. Curr. Biol. https://www.cell.com/current-biology/fulltext/S0960-9822(22)01695-5
• 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
• 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
• 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
• 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
• 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