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Author

Anna YeFollow

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2017

Month Degree Awarded

September

First Advisor

Thomas J Maresca

Subject Categories

Biochemistry | Biophysics | Cell Biology | Molecular Biology

Abstract

Equal segregation of the genome is a prerequisite for cell survival. During cell division the duplicated DNA is compacted into chromosomes and a multi-protein macrostructure, known as the kinetochore (Kt), is assembled on each copy of compacted DNA. Simultaneously, the mitotic spindle, which is made up of microtubules (MTs), is built to facilitate the equal distribution of the chromosomes between the resulting daughter cells. Kinetochores mediate the interaction between the MTs and the chromosomes, properly positioning them for segregation. To ensure that the DNA is equally divided in every cell division, cells have built a surveillance system to detect any errors that may occur. An important checkpoint during mitosis is the spindle assembly checkpoint (SAC), which ensures that all chromosomes are forming the appropriate attachments with MTs.

In cases of erroneous attachment, mitotic progression is halted and an error correction pathway is activated to give chromosomes a second change to establish proper attachment. When all the chromosomes have achieved biorientation, cells progress into anaphase, where each copy of the DNA is pulled toward opposite axis of the cell. It is critical that chromosome are properly attached and aligned to ensure equal segregation, as misegragation is the leading cause of cell death or cancer. Finally, a cleavage furrow is formed at the cell equator that constricts and severs the cell, giving rise to two daughters.

It is remarkable how cells are able to go through many rounds of division without any errors. Although a lot of work has been done to further understand the mechanisms in which cells detect and correct potential catastrophic error, many more mystery remains to be uncovered. In the last six years, I tried to make my contribution to field by exploring how a previously classified as a non-motile kinesin generates force to move chromosomes, how much force is being exerted on a bioriented kinetochore, the roles aurora kinases play to ensure proper kinetochore-microtubule attachment and proper cytokinesis.

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