Control of chromosome biorientation by a feedback loop involving the Ska complex and Aurora B kinase.
PhD Thesis, University of Basel,
Faculty of Science.
Restricted to Repository staff only until 8 March 2018.
Available under License CC BY-NC-ND (Attribution-NonCommercial-NoDerivatives).
Official URL: http://edoc.unibas.ch/diss/DissB_11724
Proper chromosome attachment to opposite spindle poles (biorientation) and error-free chromosome segregation relies on the plasticity of kinetochore-microtubule attachments; these must remain flexible enough to allow the release of erroneously attached spindle microtubules, yet become sufficiently stable to harness forces for chromosome movements and silence the spindle assembly checkpoint. Aurora B kinase fosters chromosome biorientation by facilitating the dynamics of kinetochore-microtubule attachments through phosphorylation of kinetochore proteins that bind microtubules. Prominent among the substrates, whose microtubule and kinetochore binding is curtailed by Aurora B, is the Ska complex, a key factor for kinetochore-fiber stability. Here, we show that Ska is not only a substrate of Aurora B, but is also required, in turn, for Aurora B activity. Ska-deficient cells fail to biorient and display lagging chromosomes and micronuclei as a result of suppressed kinetochore-microtubule turnover. These defects coincide with diminished kinetochore localization of the Aurora B effectors MCAK and CENP-E, as well as reduced Aurora B substrate phosphorylation. We further show that Ska requires its microtubule binding capability to promote Aurora B activity in cells and directly stimulates Aurora B catalytic activity in vitro. Finally, we demonstrate that PP1 counters Aurora B activity to enable Ska kinetochore accumulation once biorientation is achieved, which allows Ska to exert its kinetochore-fiber stabilizing function. Together, we propose that the Ska complex enhances Aurora B activity to limit its own microtubule and kinetochore association and ensure that the dynamics and stability of kinetochore-microtubules fall within an optimal balance for chromosome biorientation and faithful chromosome segregation.
|Advisors:||Nigg, Erich A. and Meraldi, Patrick|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Growth & Development > Cell Biology (Nigg)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource (124 Seiten)|
|Last Modified:||02 Sep 2016 08:18|
|Deposited On:||02 Sep 2016 08:17|
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