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Title page for ETD etd-03282016-121934


Type of Document Dissertation
Author Gayek, Anna Sophia
URN etd-03282016-121934
Title Not Just for Pulling Chromosomes: The Role of Kinetochore-Microtubules in Enforcing Bipolarity of the Human Mitotic Spindle
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Irina Kaverina Committee Chair
Chin Chiang Committee Member
Kathleen L. Gould Committee Member
Matthew J. Lang Committee Member
Ryoma Ohi Committee Member
Keywords
  • microtubule
  • kinetochore
  • mitosis
Date of Defense 2016-03-09
Availability unrestricted
Abstract
Two processes influence the success of mitosis, the process by which eukaryotic cells divide their replicated genome into two new daughter cells. First, the cell must build a bipolar array of microtubules called the mitotic spindle, which is accomplished by microtubule sliding by the Kinesin-5 Eg5; second, a subset of those microtubules, called kinetochore-microtubules (K-MTs), must attach correctly to each chromosome. The stability of these K-MT attachments to the chromosome influences whether chromosomes will segregate correctly in anaphase, but an influence of K-MT stability on the ability of cells to build or maintain bipolar spindles had not been recognized. Here we show that human cell lines with high K-MT stability are better able to maintain bipolar spindles when Eg5 is inhibited compared to cell lines with low K-MT stability. Artificially stabilizing K-MTs promoted bipolarity maintenance, while destabilizing K-MTs undermined the maintenance of bipolarity. In addition, inhibition of the mitotic master-regulator cyclin-dependent kinase-1 (CDK-1) in the G2 phase of the cell cycle stabilized K-MTs after CDK-1 inhibition was relieved, which promoted bipolar spindle maintenance without Eg5 but undermined mitotic fidelity. These results indicate that the dynamics of K-MTs play a previously unappreciated role in determining the overall geometry of the mitotic spindle.
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