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The Role of CAF-1 in Epigenetic Conversions at the Telomeres of Saccharomyces cerevisiae and its Control by Protein Kinases

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Title: The Role of CAF-1 in Epigenetic Conversions at the Telomeres of Saccharomyces cerevisiae and its Control by Protein Kinases
Author: Jeffery, Daniel Charles Barrie
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Yankulov, Krassimir
Abstract: Epigenetics is the study of heritable changes in gene expression that are not caused by changes in the DNA sequence. The expression profile of a given cell is regulated by the complex interactions of histone post-translational modifications, DNA methylation, nuclear organization and ATP-dependent histone exchange, as well as a multitude of interacting factors that come along with them. The inheritance of these epigenetic marks that are associated with silenced or active DNA are regulated by multiple mechanisms to ensure that they are faithfully copied after DNA replication. CAF-1 is a central figure in this process that reassembles nucleosomes at the replication fork. However, a mechanism for epigenetic conversions is necessary for cells to undergo differentiation and alter the epigenetic states of certain genes. This mechanism is currently unknown. In this thesis, I use the telomeres of S. cerevisiae as a model to study the mechanism of epigenetic conversions. I developed an assay for the quantitative assessment of the frequency of epigenetic conversions in telomere position effect (TPE) variegation. Then, using this assay, I demonstrated that the deletion of CAC1, the largest subunit of the CAF-1 complex, causes a major reduction in the frequency of telomeric epigenetic conversions, indicating that CAC1 is a key factor in this process. I also present evidence that the cell cycle regulator CDK (Cdc28p) is a major regulator of CAF-1. I showed that CDK phosphorylates Cac1p at the S94 and S515 residues to recruit it to chromatin. Finally, I demonstrated the role of sub-telomeric elements in the control of TPE, showing that Core X and Y’ elements suppress extreme variations in gene silencing at telomeres. With these data, I propose a model for the control of epigenetic conversions at regions of position effect variegation (PEV). This research represents the first comprehensive analysis of epigenetic conversions in a model organism and links epigenetic maintenance and conversions to cell cycle.
Date: 2014-04
Rights: Attribution-NonCommercial-NoDerivs 2.5 Canada
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Attribution-NonCommercial-NoDerivs 2.5 Canada Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 2.5 Canada