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Role and regulation of the kinetochore protein Spc7 in fission yeast mitosis
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Shepperd, Lindsey A. (2013) Role and regulation of the kinetochore protein Spc7 in fission yeast mitosis. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2686684~S1
Abstract
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.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QK Botany |
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Library of Congress Subject Headings (LCSH): | Mitosis, Fission (Biology), Schizosaccharomyces pombe, Proteins | ||||
Official Date: | March 2013 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Miller, Jonathan | ||||
Sponsors: | Medical Research Council (Great Britain) (MRC) | ||||
Extent: | 1 volume (various pagings) : illustrations. | ||||
Language: | eng |
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