Gene expression profiling and phenotype analysis of S. cerevisiae in response to changing copper reveals six genes with new roles in copper and iron metabolism

Exhaustive microarray time course analyses of Saccharomyces cerevisiae during copper starvation and copper excess reveal new aspects of metal-induced gene regulation. Aside from identifying targets of established copper-and iron-responsive transcription factors, we find that genes encoding mitochondrial proteins are downregulated and that copper-independent iron transport genes are preferentially upregulated, both during prolonged copper deprivation. The experiments also suggest the presence of a small regulatory iron pool that links copper and iron responses. One hundred twenty-eight genes with putative roles in metal metabolism were further investigated by several systematic phenotype screens. Of the novel phenotypes uncovered, hsp1!2-Δ and arn1-Δ display increased sensitivity to copper, cyc1-Δ and crr1-Δ show resistance to high copper, vma13-Δ exhibits increased sensitivity to iron deprivation, and pep12-Δ results in reduced growth in high copper and low iron. Besides revealing new components of eukaryotic metal trafficking pathways, the results underscore the previously determined intimate links between iron and copper metabolism and mitochondrial and vacuolar function in metal trafficking. The analyses further suggest that copper starvation can specifically lead to down-regulation of respiratory function to preserve iron and copper for other cellular processes.