Gene expression profiling and phenotype analyses ofS. cerevisiaein response to changing copper reveals six genes with new roles in copper and iron metabolism

Abstract

Aside from identifying targets of established copperand 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, hsp12-⌬ and arn1-⌬ display increased sensitivity to copper, cyc1-⌬ and crr1-⌬ show resistance to high copper, vma13-⌬ exhibits increased sensitivity to iron deprivation, and pep12-⌬ 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 downregulation of respiratory function to preserve iron and copper for other cellular processes.

La-motif–dependent mRNA association with Slf1 promotes copper detoxification in yeast

“…Along with the finding that Slf1p stabilizes target transcripts and confers hyper-resistance to toxic copper concentrations upon overexpression, these observations support a model in which Slf1p specifically stabilizes mRNAs coding for proteins important in response to copper stress, facilitating the synthesis of proteins engaged in copper detoxification. Indeed, elevated mRNA levels of the Slf1p targets CUP1 is well known to confer increased resistance against high copper concentrations (Jeyaprakash et al 1991), and deletion of either ACE1 or HSP12 leads to copper-hypersensitivity (Thiele 1988;van Bakel et al 2005).…”

“…CUP1 encodes a copper metallothionein, which confers high resistance to copper and cadmium (Winge et al 1985;Jeyaprakash et al 1991). HSP12 codes for a copper-induced heat shock protein increasing membrane stability under a variety of stress conditions (van Bakel et al 2005;Welker et al 2010), and knock-out cells show hypersensitivity to elevated copper concentrations (van Bakel et al 2005). TRR2, URM1, and LOT6 have not been directly linked to copper homeostasis but play roles in the oxidative stress response (Pedrajas et al 1999;Goehring et al 2003;Sollner et al 2007).…”

“…TRR2, URM1, and LOT6 have not been directly linked to copper homeostasis but play roles in the oxidative stress response (Pedrajas et al 1999;Goehring et al 2003;Sollner et al 2007). Among the nine copper and oxidative stress-related targets that were commonly associated with Slf1p and Sro9p were CTR2, involved in mobilization of vacuolar copper stores (Rees et al 2004); ACE1 coding for a copper binding transcription factor that activates CUP1 expression (Thiele 1988;Welch et al 1989); and SOL4, which encodes the second enzyme of the PPP (Godon et al 1998;Grant 2008) and gets downregulated upon copper deprivation (van Bakel et al 2005).…”

Molecular characterization of the copper transport system in Staphylococcus aureus

“…The capacity to transport diverse metals by CPX-ATPase has been shown in Archaeoglobus fulgidus, B. subtilis and other micro-organisms (Arguello et al, 2003;Gaballa & Helmann, 2003). In addition, association between genes for copper transport and genes for iron transport has been found in Saccharomyces cerevisiae (van Bakel et al, 2004(van Bakel et al, , 2005. Since both lead and iron can induce the transcription of the copA, this further suggests that copA may function as a co-transporter for these ions.…”

Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper

“…The cellular and molecular mechanisms underlying copperregulated gene expression and toxicity have been investigated in yeast, mouse fibroblasts, and rodent strains with mutations in Atp7b (5,28,33,69). Atp7b Ϫ/Ϫ mice demonstrate intracellular copper accumulation, low serum oxidase activity, and increased copper excretion in the urine and liver pathology, similar to Wilson's disease patients (12,32).…”