| During the cell cycle, replicated chromosomes must remain paired until cell division in mitosis. This pairing is mediated by the conserved cohesin complex. During mitosis, a bipolar spindle facilitates the equal transmission of genetic material to two daughter cells. This fidelity in chromosome segregation protects cells against chromosomal instability and aneuploidy, which can contribute to development and progression of a variety of diseases, including cancer and Down syndrome. In this thesis, I present an RNA interference screen for novel regulators of bipolar spindle assembly, which led to the finding that the deubiquitinase USP37 regulates chromosome segregation during mitosis. Although the role of ubiquitin ligases (e.g. APC/C, SCF complex) in cell cycle regulation is known, the role of deubiquitinases is less well characterized. Accordingly, my thesis focuses on understanding the molecular mechanisms by which USP37 regulates chromosome segregation. In Chapter 3, I present evidence that USP37 regulates the NDC80 (HEC1) complex in kinetochore-microtubule attachment during chromosome segregation in mitosis. In Chapter 4, I present evidence that USP37 regulates chromatid cohesion. Specifically, USP37 regulates the deubiquitylation and stability of chromatin-associated WAPL, a protein required for removal of cohesin from chromosome arms in early mitosis. Collectively, the data presented in this thesis provide new insights into the regulation of mitotic chromosome segregation and cohesion by the ubiquitin proteasome system. |
