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Transition metal tolerance and the Saccharomyces cerevisiae genome

University of British Columbia

Transition metal ions are essential nutrients to all forms of life. Iron, copper, zinc, manganese, cobalt and nickel all have unique chemical and physical properties that make them attractive molecules for use in biological systems. Many of these same properties that allow these metals to provide essential biochemical activities and structural motifs to a multitude of proteins including enzymes and other cellular constituents also leads to a potential for cytotoxicity. Organisms have been required to evolve a number of systems for the efficient uptake, intracellular transport, protein loading and storage of metal ions to ensure that the needs of the cells can be met while minimizing the associated toxic effects. The yeast Saccharomyces cerevisiae has been used as model organism for the investigation of these systems and a majority of the genes and biological systems that function in yeast metal homeostasis are conserved throughout eukaryotes to humans. Traditionally, genomic studies in metal homeostasis focus on the response to one, or in some cases two, metals. Here, I have used high density yeast arrays of a S. cerevisiae deletion collection to study the genes required for tolerance to six transition metals in parallel and I have used this data to examine the role of genes not only in the homeostasis of individual metals but to also gain insight into cellular transition metal homeostasis as a whole. Genes and pathways with novel function in the homeostasis of a particular metal have been identified along with the systems that function with broad spectrum metal specificity. Data generated in this screen has also be combined with previously published data sets that examine different aspects of yeast biology in an attempt to delve deeper in to the cellular machinery that allows yeast, and potentially the cells of other organisms, to maintain the balance between metal ions as essential nutrients as opposed to toxic moieties. Metallochaperones represent a relatively recent emerging class of proteins that play a central role in maintaining this balance. As part of the analysis of the high density array screens, putative chaperones have been identified. Additionally a yeast 2 hybrid screen using a cytoplasmic domain of the S. cerevisiae high affinity iron transporter Ftr1p has been performed to with the goal of discovering candidate iron chaperones. As a whole, the research discussed in this thesis has shed light on a number of new features of the homeostatic mechanisms that function in S. cerevisiae and will provide the basis for further investigation into the interactions between cells and metal ions eventually leading to implications in human health and disease.

Text

2011-01-25

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/30821

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/