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Title: Role and regulation of the kinetochore protein Spc7 in fission yeast mitosis
Author: Shepperd, Lindsey A.
ISNI:       0000 0004 2749 1823
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2013
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To maintain genetic integrity, eukaryotic cells must faithfully segregate their chromosomes to daughter cells during mitosis. Errors during bi-orientation lead to aneuploidy, a hallmark of human cancers. A highly conserved mechanism termed the Spindle Assembly Checkpoint (SAC) delays the onset of anaphase until all chromosomes have correctly aligned on the metaphase plate. The proteins responsible for the SAC signal include Mad1, Mad2, BubR1 (Mad3 in fission yeast), Bub1, Bub3 and Mph1 kinase. The SAC monitors tension across the spindle and the attachment status of kinetochores; large, proteinaceous structures that assemble on centromeres during mitosis, and is maintained until all kinetochores are properly attached to microtubules. Phosphorylation and dephosphorylation at the kinetochore also regulate chromosome biorientation. Although the SAC has been intensively studied, the exact kinetochore binding site of some SAC components and regulatory mechanisms surrounding the SAC are poorly understood. I have shown, subsequent to previous work which implicated Protein Phosphatase 1 (PP1) in SAC silencing, that two PP1-binding motifs within the N-terminus of kinetochore protein Spc7 (KNL-1 in human cells) bind Dis2, a fission yeast homologue of PP1, in vitro. This interaction is essential for viability and efficient SAC silencing. I also present data implicating kinesin motor proteins Klp5 and Klp6 in PP1-binding and SAC silencing. Furthermore, I have established a role for the Spc7 MELT motifs in recruiting Bub1, Bub3 and Mad3 to the kinetochores using phospho-null (spc7-9TA) and phosphomimetic (spc7-9TE) mutants, and present evidence that this interaction is required for the recruitment of other SAC components. Additionally, the MELT motifs have a role in SAC maintenance and chromosome segregation, and spc7-9TE cells are able to silence the SAC more efficiently than wild type cells. Results presented in this thesis highlight KNL-1 as a major platform for SAC silencing at the kinetochore and will likely form the basis of future studies within the field of mitosis.
Supervisor: Not available Sponsor: Medical Research Council (Great Britain) (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology ; QK Botany