Molecular control of iron-sensing in yeast.

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Title. Molecular control of iron-sensing in yeast. All eukaryotes require iron (Fe) for survival. The ability of this transition metal to exist in two redox states makes it essential at the active center of many enzymes and electron transporters. Paradoxically, the properties that make Fe essential in these reactions can also make it toxic under certain conditions. Excess Fe has the ability to unleash toxic oxygen radicals that can damage cellular components. Consequently, organisms must tightly regulate their internal Fe load, and respond appropriately by controlling Fe acquisition and compartmentalization to maintain homeostasis. The yeast Schizosaccharomyces pombe is an outstanding model system for understanding many aspects of eukaryotic cell growth, metabolism, and signal transduction. Studies of S. pombe have identified novel genes that function in the regulation of Fe transport and have revealed their existence and importance in other organisms. In response to high Fe, the Fep1 transcription factor represses the expression of a set of genes involved in the acquisition of Fe. Under Fe-limiting conditions, optimization of cellular Fe utilization is coordinated by the Php4 protein, which acts as a negative regulatory subunit of the CCAAT-binding factor and fosters repression of genes encoding Fe-using proteins. Despite these recent findings, little is known about the mechanisms by which Fep1 and Php4 respond to low or high Fe availability. Furthermore, we know little about the functional roles of the products of many Fep1/Php4 target genes (>40 unexplored genes). Overall, the proposed research will provide a better understanding of the molecular circuitry of Fe-dependent cellular processes, including Fe-sensing by Fep1 and Php4, and Fe-trafficking that relies on the vacuolar Fe transporter Abc3. The long-term objective of this program is to use this knowledge to better understand the molecular basis of Fe homeostasis and use the results to draw parallels with other living systems. The proposed work also promises an exceptional opportunity for the training of highly qualified personnel, making them highly valuable to the Canadian biotech sector and/or academic research community.