Differential control of Zap1-regulated genes in response to zinc deficiency in Saccharomyces cerevisiae

Wu, Chang Yi; Bird, Amanda J.; Chung, Lisa; Newton, Michael A.; Winge, Dennis R.; Eide, David J.

doi:10.1186/1471-2164-9-370

Cited by 78 publications

(123 citation statements)

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“…Several candidate Zap1 target genes encode proteins with roles in protein homeostasis, including a molecular chaperone (HSP26), and proteins involved in autophagy (ATG19, ATG41, and UTH1) and vacuolar proteolysis (PRB1, PRC1, and PEP4) (11). By functional genomics analysis, we also identified genes that were important for survival in low zinc but were not known Zap1 targets (23).…”

Section: Fet4mentioning

confidence: 93%

“…Analysis of the Zap1 regulon revealed that zinc-regulated genes can be sorted into two basic classes: "homeostatic" genes induced to maintain intracellular zinc supply and "adaptive" genes that may aid the survival of deficient cells without altering zinc status (11). Homeostatic genes include those required for zinc uptake across the plasma membrane (ZRT1, ZRT2, and * This work was supported by National Institutes of Health Grant GM056285.…”

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Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth

MacDiarmid

Taggart

Jeong

et al. 2016

Journal of Biological Chemistry

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Stability of many proteins requires zinc. Zinc deficiency disrupts their folding, and the ubiquitin-proteasome system may help manage this stress. In Saccharomyces cerevisiae, UBI4 encodes five tandem ubiquitin monomers and is essential for growth in zinc-deficient conditions. Although UBI4 is only one of four ubiquitin-encoding genes in the genome, a dramatic decrease in ubiquitin was observed in zinc-deficient ubi4⌬ cells. The three other ubiquitin genes were strongly repressed under these conditions, contributing to the decline in ubiquitin. In a screen for ubi4⌬ suppressors, a hypomorphic allele of the RPT2 proteasome regulatory subunit gene (rpt2 E301K ) suppressed the ubi4⌬ growth defect. The rpt2 E301K mutation also increased ubiquitin accumulation in zinc-deficient cells, and by using a ubiquitin-independent proteasome substrate we found that proteasome activity was reduced. These results suggested that increased ubiquitin supply in suppressed ubi4⌬ cells was a consequence of more efficient ubiquitin release and recycling during proteasome degradation. Degradation of a ubiquitin-dependent substrate was restored by the rpt2 E301K mutation, indicating that ubiquitination is rate-limiting in this process. The UBI4 gene was induced ϳ5-fold in low zinc and is regulated by the zinc-responsive Zap1 transcription factor. Surprisingly, Zap1 controls UBI4 by inducing transcription from an intragenic promoter, and the resulting truncated mRNA encodes only two of the five ubiquitin repeats. Expression of a short transcript alone complemented the ubi4⌬ mutation, indicating that it is efficiently translated. Loss of Zap1-dependent UBI4 expression caused a growth defect in zinc-deficient conditions. Thus, the intragenic UBI4 promoter is critical to preventing ubiquitin deficiency in zinc-deficient cells.Zinc is an essential element with diverse roles in biology. Unlike transition metals, such as iron and copper, zinc ions (Zn 2ϩ ) are not redox-active under physiological conditions and do not play a direct role in redox reactions. Zn 2ϩ strongly interacts with ligands, such as cysteine, histidine, and acidic amino acids in proteins (1). When bound by three or fewer ligands, Zn 2ϩ can act as a Lewis acid to facilitate catalysis by diverse classes of enzymes, including oxidoreductases, transferases, and hydrolases (2). In contrast, binding of Zn 2ϩ by four ligands produces a relatively inert, structurally rigid tetrahedral complex, which provides stability to many classes of protein domains (1-3). Because of its catalytic and structural roles, Zn 2ϩ has been estimated to be required for the folding and function of ϳ10% of proteins encoded by eukaryotic genomes and ϳ5% of proteins in prokaryotes (4, 5). One abundant example is the enzyme alcohol dehydrogenase, which contains two Zn 2ϩ atoms per subunit, one serving in catalysis and the other playing a structural role (1, 6, 7). Consistent with the importance of zinc to Adh 2 folding, mutants of Adh lacking structural zinc site ligands are unstable and quickly degraded in ...

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Section: Fet4mentioning

confidence: 93%

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confidence: 99%

Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth

MacDiarmid

Taggart

Jeong

et al. 2016

Journal of Biological Chemistry

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“…In fission yeast Schizosaccharomyces pombe, responses to low and high levels of peroxide are modulated by Pap1 and Atf1, respectively (33). Differential activation of target genes by a single regulator (Zap1) in response to zinc deficiency has been reported in Saccharomyces cerevisiae (34), where the elucidation of an underlying mechanism is awaited. Activity modulation through two regulatory metal-binding sites in Zur extends the versatility of this regulator to allow graded expression of target genes in response to expanded concentration ranges of zinc.…”

Section: Graded Expression Of Metal-sensitive Genes In Accordance Withmentioning

confidence: 99%

Graded expression of zinc-responsive genes through two regulatory zinc-binding sites in Zur

Shin

Jung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

110

189

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Zinc is one of the essential transition metals in cells. Excess or lack of zinc is detrimental, and cells exploit highly sensitive zinc-binding regulators to achieve homeostasis. In this article, we present a crystal structure of active Zur from Streptomyces coelicolor with three zinc-binding sites (C-, M-, and D-sites). Mutations of the three sites differentially affected sporulation and transcription of target genes, such that C- and M-site mutations inhibited sporulation and derepressed all target genes examined, whereas D-site mutations did not affect sporulation and derepressed only a sensitive gene. Biochemical and spectroscopic analyses of representative metal site mutants revealed that the C-site serves a structural role, whereas the M- and D-sites regulate DNA-binding activity as an on-off switch and a fine-tuner, respectively. Consistent with differential effect of mutations on target genes, zinc chelation by TPEN derepressed some genes ( znuA, rpmF2 ) more sensitively than others ( rpmG2 , SCO7682) in vivo. Similar pattern of TPEN-sensitivity was observed for Zur-DNA complexes formed on different promoters in vitro. The sensitive promoters bound Zur with lower affinity than the less sensitive ones. EDTA-treated apo-Zur gained its DNA binding activity at different concentrations of added zinc for the two promoter groups, corresponding to free zinc concentrations of 4.5 × 10 −16 M and 7.9 × 10 −16 M for the less sensitive and sensitive promoters, respectively. The graded expression of target genes is a clever outcome of subtly modulating Zur-DNA binding affinities in response to zinc availability. It enables bacteria to detect metal depletion with improved sensitivity and optimize gene-expression pattern.

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“…Zap1 plays a central role in the homeostatic regulation of this essential yet potentially toxic metal ion. Under conditions where zinc is limiting, Zap1 activates expression of ϳ80 target genes in the yeast genome (11,12). When cells are zinc-replete, Zap1 function is shut off (13).…”

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Roles of Two Activation Domains in Zap1 in the Response to Zinc Deficiency in Saccharomyces cerevisiae

Frey

Eide

2011

Journal of Biological Chemistry

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Previous studies suggested that the zinc-responsive Zap1 transcriptional activator directly regulates the expression of over 80 genes in Saccharomyces cerevisiae. Many of these genes play key roles to enhance the ability of yeast cells to grow under zinc-limiting conditions. Zap1 is unusual among transcriptional activators in that it contains two activation domains, designated AD1 and AD2, which are regulated independently by zinc. These two domains are evolutionarily conserved among Zap1 orthologs suggesting that they are both important for Zap1 function. In this study, we have examined the roles of AD1 and AD2 in low zinc growth and the regulation of Zap1 target gene expression. Using alleles that are specifically disrupted for either AD1 or AD2 function, we found that these domains are not redundant, and both are important for normal growth in low zinc. AD1 plays the primary role in zinc-responsive gene regulation, whereas AD2 is required for maximal expression of only a few target promoters. AD1 alone is capable of driving full expression of most Zap1 target genes and dictates the kinetics of Zap1 gene induction in response to zinc withdrawal. Surprisingly, we found that AD1 is less active in zinc-limited cells under heat stress and AD2 plays a more important role under those conditions. These results suggest that AD2 may contribute more to Zap1 function when zinc deficiency is combined with other environmental stresses. In the course of these studies, we also found that the heat shock response is induced under conditions of severe zinc deficiency.

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Differential control of Zap1-regulated genes in response to zinc deficiency in Saccharomyces cerevisiae

Cited by 78 publications

References 49 publications

Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth

Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth

Graded expression of zinc-responsive genes through two regulatory zinc-binding sites in Zur

Roles of Two Activation Domains in Zap1 in the Response to Zinc Deficiency in Saccharomyces cerevisiae

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