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Title: The role of the kinetochore-associated Dam1 complex during fission yeast mitosis
Author: Griffiths, K.
Awarding Body: (UCL) University College London
Current Institution: University College London (University of London)
Date of Award: 2007
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Bipolar attachment of the kinetochore to the spindle is crucial for sister chromatid separation during mitosis. The kinetochore, a specialised proteinaceous structure formed on centromeres is required for tethering the spindle. It consists of many sub complexes including core platform proteins and outer proteins. In budding yeast the Dam1/DASH complex is essential, constituting 10 components and plays a vital role in chromosome segregation. All 10 homologues of the Dam1 complex have been identified in the fission yeast, an organism that contains a more complex centromere structure. This thesis describes the study of the fission yeast Dam1 complex and its role during mitosis in ensuring proper chromosome segregation. In this thesis we describe the localisation of this complex to the kinetochore and its dependence on both microtubules and functional Mis6 complex. We show that Dam1 complex genes are not essential but deletion shows monopolar chromosome segregation defects and spindle collapse indicative of an importance for proper microtubule dynamics and chromosome bi-orientation. We show that despite being non-essential, deletion mutants are synthetic lethal when combined with deletion of the kinesins Klp5/6, which play a role in promoting chromosome biorientation. To understand this further, we isolated a dam1 temperature-sensitive mutant in a klp5 null background, termed dam1-A8. This is a 'gain of function' mutant that shows resistance to the spindle drug TBZ unlike dam1 deletion, which is sensitive. We have shown in the double dam1-A8klp5 mutant massive chromosome mis-segregation, congression defects and monopolar attachment of the kinetochore to one SPB. Indeed dam1-A8 alone shows sister chromatid congression defects, thus indicating that the Dam1 complex despite its non-essentiality is required in concert with the mitotic kinesins Klp5/6 to promote proper bipolar attachment and spindle microtubule dynamics and either loss or gain of function dam1 mutants leads to defects in chromosome bi-orientation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available