Iron, copper, and zinc are all essential nutrients. The electron transfer properties of iron and copper are fundamental to processes such as respiration and photosynthesis. Zinc forms the catalytic center in numerous enzymes and has an important structural role in a wide range of proteins. However, all these metals can be toxic if their levels and distribution are not carefully regulated, as their inappropriate binding may compromise cellular function. The uncontrolled redox activity of iron and copper can also lead to the generation of damaging oxygen radicals. Therefore, organisms maintain cytoplasmic metal concentrations at a nontoxic level that is sufficient for growth. A variety of homeostatic mechanisms have been identified, which include the control of translation and RNA stability by iron-regulatory proteins and the metal-dependent trafficking or degradation of metal transporters (39,109,138). This review focuses on the role that metal-responsive transcription factors have in regulating trace metal metabolism. These factors are able to sense changes in metal concentrations and coordinate the expression of genes that are involved in the acquisition, distribution, sequestration, and use of metals. Consequently, the ability to mediate metal-responsive gene expression is an important aspect of metal homeostasis in those organisms that contain these factors.

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The yeast Zap1 transcription factor controls the expression of genes involved in zinc accumulation and storage. Zap1 is active in zinc-limited cells and repressed in replete cells. Zap1 has two activation domains, AD1 and AD2, which are both regulated by zinc. AD2 function was mapped to a region containing two Cys2His2 zinc fingers, ZF1 and ZF2, that are not involved in DNA binding. More detailed mapping placed AD2 almost precisely within the endpoints of ZF2, suggesting a role for these fingers in regulating activation domain function. Consistent with this hypothesis, ZF1 and ZF2 bound zinc in vitro but less stably than did zinc fingers involved in DNA binding. Furthermore, mutations predicted to disrupt zinc binding to ZF1 and/or ZF2 rendered AD2 constitutively active. Our results also indicate that the repressed form of AD2 requires an intramolecular interaction between ZF1 and ZF2. These studies suggest that these zinc fingers play an unprecedented role as zinc sensors to control activation domain function.

Background: The Zap1 transcription factor is a central player in the response of yeast to changes in zinc status. We previously used transcriptome profiling with DNA microarrays to identify 46 potential Zap1 target genes in the yeast genome. In this new study, we used complementary methods to identify additional Zap1 target genes.

The transcriptional activator Zap1 induces target gene expression in response to zinc deficiency. We demonstrate that during zinc starvation, Zap1 is required for the repression of ADH1 expression. ADH1 encodes the major zinc-dependent alcohol dehydrogenase that is utilized during fermentation. During zinc starvation, Zap1 binds upstream of the activator Rap1 and induces an intergenic RNA transcript, ZRR1. ZRR1 expression leads to the transient displacement of Rap1 from the ADH1 promoter resulting in ADH1 repression. Using a microarray-based approach, we screened for additional genes repressed by Zap1 intergenic transcripts. We found that ADH3, the major mitochondrial alcohol dehydrogenase, is regulated in a manner similar to ADH1. Thus, during zinc deficiency, Zap1 mediates the repression of two of the most abundant zinc-requiring enzymes.