Functional Genomics Analysis of the Saccharomyces Cerevisiae Iron Responsive Transcription Factor Aft1 Reveals Iron-Independent Functions

By Berthelet, Sharon; Usher, Jane et al. | Genetics, July 2010 | Go to article overview

Functional Genomics Analysis of the Saccharomyces Cerevisiae Iron Responsive Transcription Factor Aft1 Reveals Iron-Independent Functions


Berthelet, Sharon, Usher, Jane, Shulist, Kristian, Hamza, Akil, Maltez, Nancy, Johnston, Anne, Fong, Ying, Harris, Linda J., Baetz, Kristin, Genetics


ABSTRACT

The Saccharomyces cerevisiae transcription factor Aft1 is activated in iron-deficient cells to induce the expression of iron regulon genes, which coordinate the increase of iron uptake and remodel cellular metabolism to survive low-iron conditions. In addition, Aft1 has been implicated in numerous cellular processes including cell-cycle progression and chromosome stability; however, it is unclear if all cellular effects of Aft1 are mediated through iron homeostasis. To further investigate the cellular processes affected by Aft1, we identified >70 deletion mutants that are sensitive to perturbations in AFT1 levels using genome-wide synthetic lethal and synthetic dosage lethal screens. Our genetic network reveals that Aft1 affects a diverse range of cellular processes, including the RIM101 pH pathway, cell-wall stability, DNA damage, protein transport, chromosome stability, and mitochondrial function. Surprisingly, only a subset of mutants identified are sensitive to extracellular iron fluctuations or display genetic interactions with mutants of iron regulon genes AFT2 or FET3. We demonstrate that Aft1 works in parallel with the RIM101 pH pathway and the role of Aft1 in DNA damage repair is mediated by iron. In contrast, through both directed studies and microarray transcriptional profiling, we show that the role of Aft1 in chromosome maintenance and benomyl resistance is independent of its iron regulatory role, potentially through a nontranscriptional mechanism.

LIKE all organisms, the yeast Saccharomyces cerevisiae maintains tight regulation of cellular iron uptake and utilization to prevent toxicity caused by iron overload (reviewed in Kaplan et al. 2006). S. cerevisiae responds to iron depletion through transcriptional remodeling governed primarily by the iron-responsive transcription factor Aft1 (reviewed in Rutherford and Bird 2004). Aft1 is routinely shuttled between the nucleus and the cytoplasm where the export of Aft1 from the nucleus is promoted in the presence of iron-sulfur clusters (ISC) in the cell (Yamaguchi-Iwai et al. 2002; Chen et al. 2004; Rutherford et al. 2005; Ueta et al. 2007).Uponiron depletion and decreased levels of ISCs, Aft1 accumulates in the nucleus where it activates the transcription of 25 genes, referred to as the "iron regulon," that are required for increasing cellular iron content (Yamaguchi-Iwai et al. 1996; Rutherford et al. 2001; Rutherford et al. 2003; Shakoury-Elizeh et al. 2004; Courel et al. 2005).

The iron regulon genes can be grouped into three categories (extensively reviewed in Kaplan et al. 2006; Philpott and Protchenko 2008). The majority of the genes encode proteins that increase iron uptake from the environment, including genes that encode siderophore transporters (ARN1, ARN2, ARN3, ARN4), cellwall siderophore binding/uptake proteins (FIT1, FIT2, FIT3), iron-reducing metalloreductase proteins (FRE1- FRE5),andthe high-affinity iron transportcomplex composed of a ferroxidase (FET3) and a permease (FTR1). As copper is required for the activity of Fet3, the iron regulon also includes the copper chaperone ATX1 and copper transporter CCC2. A second class of genes encode proteins that allow the cell to mobilize the significant amounts of iron the cell stores in the vacuole (SMF3, FET5, FRE6, FTH1, COT1) or in the mitochondria as heme or ISC(HMX1,MRS4).Athirdclass of genesencode proteins that allow the cell to remodel its metabolic activities to decrease the use of iron-dependent enzymes/ pathways in favor of iron-independent processes. This includes the upregulation of the biotin transporter VTH1, which allows the cell to obtain essential biotin from the environment instead of utilizing the irondependent biotin biosynthesis pathway and CTH2/ TIS11, which encodes a mRNA binding protein that destabilizes mRNAs that encode enzymes that require iron cofactors.

In the absence of Aft1, its paralog Aft2 can compensate and regulate transcription of many iron regulon genes (Blaiseau et al. …

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