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Title: Investigating the mechanism of Aurora B transport by the kinesin motor MKlp2
Author: Baron, R. D.
ISNI:       0000 0004 7428 4982
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Previous work has demonstrated that MKlp2 is essential for the movement of Aurora Kinase B from chromatin to the mid-zone of the central spindle. The aim of this thesis was to identify the key steps in the mechanism underlying this observation. The results showed how MKlp2 accumulates in the nucleus during S-phase until release into the cytoplasm at nuclear envelope breakdown. In the cytoplasm MKlp2 remains inactive as a result of inhibitory C-terminal CDK1 phosphorylation of p.T857, p.S867 and p.S878. Satisfaction of the spindle assembly checkpoint inactivates the cyclin B1- CDK1 complex with resultant dephosphorylation of these residues. This promotes rapid enrichment of MKlp2 at the pericentromeric chromatin, with the terminal 40 amino acids of MKlp2 binding to the histone H3 tail. MKlp2 then interacts with the CPC, with amino acids 650-750 essential for binding. The MKlp2-Aurora B complex then transitions from the chromatin to the nucleating central spindle microtubules with the chromatin defining an origin of microtubule loading. MKlp2 traverses the microtubule network through dynamic movement of the kinesin motor heads carrying its cargo to the spindle midzone. This relocation is a single one-way trip for both MKlp2 and Aurora B, and both remain stably associated with the central spindle following relocalisation. This novel mechanism of MKlp2 interaction with the histone H3 tail and its specific enrichment immediately prior to the metaphase-to-anaphase transition is critical for maintaining the fidelity of cytokinesis and MKlp2 mutants that cannot enrich on chromatin have a four-fold increased failure of cytokinesis. Targeting this mechanism by MKlp2 knockdown results in delayed apoptosis. The mechanism identified in this thesis could be exploited to target cancer cells.
Supervisor: Barr, Francis ; Neoptolemos, John ; Greenhalf, William Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral