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


RESULTS
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.


CONCLUSIONS
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.
Ulrich
U
Schlecht
Sundari
S
Suresh
Weihong
W
Xu
Ana Maria
AM
Aparicio
Angela
A
Chu
Michael J
MJ
Proctor
Ronald W
RW
Davis
Curt
C
Scharfe
Stanford Genome Technology Center, Department of Biochemistry, Stanford University, 855 S California Avenue, Palo Alto, CA 94304, USA. bstonge@stanford.edu.
Robert P
RP
St Onge
D019069:Cell Respiration; D016000:Cluster Analysis; D003300:Copper / Q000172:deficiency / Q000378:metabolism*; D003470:Culture Media; D004221:Disulfiram / Q000494:pharmacology; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D010641:Phenotype; D014617:Vacuoles / Q000235:genetics / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*
D003470:Culture Media; D006834:Hydrazines; C512195:elesclomol; D003300:Copper; D004221:Disulfiram