The fidelity of chromosome segregation is essential to ensure genome stability. Failure to exit mitosis and complete cell division results in tetraploidy and extra centrosomes which is a path to tumour development and drug resistance. About 30% of the proteome is phosphorylated at some point in mitosis. Phosphorylation enables a rapid tuning of protein activity and dephosphorylation at the metaphase/anaphase transition enables progression through mitosis. Understanding the coordination of the final stages by kinase-phosphatase networks and physical completion of cell division is essential. However this stage is transient, thus difficult to study. In this project, the student will use proteomic approaches to define the regulation of the mitotic spindle apparatus throughout mitosis and define the role of mitotic kinases and phosphatases in regulating the central spindle and midbody, a region of high mechanical activity from molecular motors to organize the region. The student will select and enrich for cells in late mitosis to perform phosphoproteomics analysis with and without the phosphatases and kinases of interest. These results will identify phosphorylations regulated during mitotic exit.
The microtubule midzone is a highly organized region, shaped by multiple motors and Aurora B kinase activity balanced by counteracting phosphatases. Using 3D high resolution fluorescent imaging, the student will use image analysis and classification to obtain 3D structural information of the microtubule midzone and midbody in situ.
Combining state-of-the-art proteomics and super resolution imaging with high temporal and spatial resolution, the student will develop a model for the structural assembly and regulation of the midzone. This model will be tested using a candidate approach with cutting edge tools in cell biology and biochemistry. Overall, this work will define the regulatory and molecular players that orchestrate the successful completion of cell division.
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