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A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

ABSTRACT: Copper is an essential component of cytochrome C oxidase (i.e. complex IV of the electron transport chain), and is thus critical for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. We found that addition of copper to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains using microarrays.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE47175 | GEO | 2013/05/23

SECONDARY ACCESSION(S): PRJNA204982

REPOSITORIES: GEO

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A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

Project description:Copper is an essential component of cytochrome C oxidase (i.e. complex IV of the electron transport chain), and is thus critical for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. We found that addition of copper to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains using microarrays. In the yeast homozygous gene deletion collection, both copies of every non-essential gene are deleted in a diploid strain. Each strain contains unique 20-bp M-bM-^@M-^\barcodeM-bM-^@M-^] sequences flanked by common priming sites, allowing the relative abundance of individual strains to be quantitatively monitored within a pool of competitively-grown strains. To identify genes that are important for Cu-dependent respiratory growth, we measured the fitness of 5050 homozygous deletion strains in parallel in rich media (i.e. Yeast Extract, Peptone) using either dextrose, ethanol, glycerol, or lactate as a carbon source, in the presence or absence of 500 M-BM-5M CuSO4 for 9 generations. Each condition was tested in triplicate. Please note that there is a large percentage of null-values (i.e. Not Available) in the respiration deficient-pool samples because the respiration deficient pool consists of only a small subset of the complete pool (represented by 331 barcodes instead of 9937). For our analysis we discarded the remaining barcodes by assigning the null-value to them.

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A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system.

Project description:Copper is essential for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health.We found that addition of copper (Cu) to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains. Cu's positive effect on respiratory growth was quantitatively reduced in deletion strains representing 73 different genes, the function of which identify increased iron uptake as a cause of the increase in growth rate. Conversely, these effects were enhanced in strains representing 93 genes. Many of these strains exhibited respiratory defects that were specifically rescued by supplementing the growth medium with Cu. Among the genes identified are known and direct regulators of copper homeostasis, genes required to maintain low vacuolar pH, and genes where evidence supporting a functional link with Cu has been heretofore lacking. Roughly half of the genes are conserved in man, and several of these are associated with Mendelian disorders, including the Cu-imbalance syndromes Menkes and Wilson's disease. We additionally demonstrate that pharmacological agents, including the approved drug disulfiram, can rescue Cu-deficiencies of both environmental and genetic origin.A functional screen in yeast has expanded the list of genes required for Cu-dependent fitness, revealing a complex cellular system with implications for human health. Respiratory fitness defects arising from perturbations in this system can be corrected with pharmacological agents that increase intracellular copper concentrations.

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