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Exploration of the budding yeast kinase Mck1 in cell cycle regulation

University of British Columbia

The study of essential cellular processes such as the regulation of the cell cycle and cellular responses to DNA replication stress in model organisms such as the budding yeast Saccharomyces cerevisiae (S. cerevisiae) benefits our understanding of these processes in human cells. The pathways that govern the response to the DNA replication checkpoint as well as those involved in accurate chromosome segregation are vital to prevent genomic instability, which is a cause of cancer. The yeast cell cycle is governed by one cyclindependent kinase, Cdk1, which controls cell cycle transitions by interacting with specific cyclins during G1, S and M phase. Using a combination of genetic and biochemical techniques, I have discovered that Mck1, a homologue of mammalian glycogen synthase kinase 3 (GSK-3), is a novel negative regulator of Cdk1 activity in budding yeast. My thesis also explores a role for Mck1 during the DNA replication checkpoint. Additionally, my work has contributed to the understanding of the mechanisms utilized to restrain spindle elongation during DNA replication stress. My thesis has three main conclusions; 1) The kinase activity of Mck1 is required to inhibit Clb2-Cdk1 activity post-nuclear division. 2) Mck1 kinase activity is required for survival during chronic exposure to DNA replication stress caused by HU in a process other than checkpoint activation. 3) Overexpression of MCK1 rescues the viability of a kinetochore mutant (spc24-9) that is defective in attachment of chromosomes to kinetochore microtubules. In particular, overexpression of Mck1 restrains the precocious spindle elongation that occurs in spc24-9 strains in response to DNA replication stress. Overall, my thesis demonstrates that the Mck1 kinase contributes to regulation of cell cycle progression in budding yeast. This is important as it demonstrates a conserved function with the mammalian homologue, which has been implicated in several diseases including cancer.

Text

2013-08-31

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/42927

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/