Date of Award

2014

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Hudson, John W.

Keywords

Biological sciences, Cancer, Epigenetics, HCC, Polo-like kinases, Tumourigenesis

Rights

CC BY-NC-ND 4.0

Abstract

Many highly conserved proteins have evolved specific niches in the cell cycle. For the Polo-like kinases (PLKs), these roles include centrosome duplication and maturation, the interaction with key DNA damage response proteins, cytokinesis, and chromosome separation. The PLKs deliver their effects via phosphorylation of their substrates at serine and threonine residues. Due to their importance in the cell cycle, expression of the PLKs is strictly governed. PLK deregulation is ubiquitously associated with malignancy. Elucidating how these proteins are regulated is key to understanding how their proper function can be restored in tumourigenesis. In recent years, the study of epigenetics as an additional mechanism controlling gene expression has come to the forefront. Epigenetic mechanisms include the addition or removal of methyl groups at the DNA and histone levels. My studies describe the regulation of PLK expression at the DNA level through the epigenetic mechanism of DNA methylation, the microenvironmental alteration of PLK epigenetic marks, and how these modifications translate in vivo in the context of carcinogenesis. Furthermore, I describe a novel interaction between PLK4, the most structurally divergent of the PLKs, and PRMT5, another evolutionarily conserved protein that is responsible for the methylation of arginine residues. Here I propose that the DNA hypermethylation of PLK4 promoter, and its subsequent reduction at the protein level, contributes to a tumourigenic state. As a signalling protein, the significant decrease in PLK4 creates a domino effect destabilizing global epigenetic marks, inhibiting the expression of the guardian of the genome, p53, and potentially contributing to the upregulation of the pro-mitotic protein, PLK1, the original member of the PLKs.

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