Transcriptional Activation in Yeast in Response to Copper Deficiency Involves Copper-Zinc Superoxide Dismutase

Wood, L. Kent; Thiele, Dennis J.

doi:10.1074/jbc.m807027200

Cited by 48 publications

(45 citation statements)

References 75 publications

(74 reference statements)

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“…Transcription of the yeast CTR1 gene is induced in response to low-copper conditions by a mechanism that requires the transcription factor Mac1 and the copper chaperone Ccs1 (31). To determine whether the same proteins are required for the response of CTR1 to MMS, CTR1 transcript levels were analyzed in wild-type, mac1 Δ, and ccs1 Δ cells that had been treated with MMS (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1). However, Mac1 has never been isolated from yeast in a copper-bound form, and a recent study established that Mac1 is transcriptionally inactive in mutants that lack Sod1 or its copper chaperone Ccs1 (31). This suggested a potential role for Sod1 in the regulation of Mac1 and raised the question of what constitutes the low-copper-sensing mechanism in yeast.…”

Section: Introductionmentioning

confidence: 99%

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The Yeast Copper Response Is Regulated by DNA Damage

Dong

Addinall

Lydall

et al. 2013

Molecular and Cellular Biology

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Copper is an essential but potentially toxic redox-active metal, so the levels and distribution of this metal are carefully regulated to ensure that it binds to the correct proteins. Previous studies of copper-dependent transcription in the yeast Saccharomyces cerevisiae have focused on the response of genes to changes in the exogenous levels of copper. We now report that yeast copper genes are regulated in response to the DNA-damaging agents methyl methanesulfonate (MMS) and hydroxyurea by a mechanism(s) that requires the copper-responsive transcription factors Mac1 and AceI, copper superoxide dismutase (Sod1) activity, and the Rad53 checkpoint kinase. Furthermore, in copper-starved yeast, the response of the Rad53 pathway to MMS is compromised due to a loss of Sod1 activity, consistent with the model that yeast imports copper to ensure Sod1 activity and Rad53 signaling. Crucially, the Mac1 transcription factor undergoes changes in its redox state in response to changing levels of copper or MMS. This study has therefore identified a novel regulatory relationship between cellular redox, copper homeostasis, and the DNA damage response in yeast.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Yeast Copper Response Is Regulated by DNA Damage

Dong

Addinall

Lydall

et al. 2013

Molecular and Cellular Biology

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“…Previously, we have shown that in S . cerevisiae , cytosolic SOD1 functions in glucose sensing and signaling [53], and the laboratories of Thiele and Zheng have shown a role for nuclear SOD1 in gene regulation and the response to DNA damage [54, 55]. C .…”

Section: Discussionmentioning

confidence: 99%

An Adaptation to Low Copper in Candida albicans Involving SOD Enzymes and the Alternative Oxidase

Broxton

Culotta

2016

PLoS ONE

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In eukaryotes, the Cu/Zn superoxide dismutase (SOD1) is a major cytosolic cuproprotein with a small fraction residing in the mitochondrial intermembrane space (IMS) to protect against respiratory superoxide. Curiously, the opportunistic human fungal pathogen Candida albicans is predicted to express two cytosolic SODs including Cu/Zn containing SOD1 and manganese containing SOD3. As part of a copper starvation response, C. albicans represses SOD1 and induces the non-copper alternative SOD3. While both SOD1 and SOD3 are predicted to exist in the same cytosolic compartment, their potential role in mitochondrial oxidative stress had yet to be investigated. We show here that under copper replete conditions, a fraction of the Cu/Zn containing SOD1 localizes to the mitochondrial IMS to guard against mitochondrial superoxide. However in copper starved cells, localization of the manganese containing SOD3 is restricted to the cytosol leaving the mitochondrial IMS devoid of SOD. We observe that during copper starvation, an alternative oxidase (AOX) form of respiration is induced that is not coupled to ATP synthesis but maintains mitochondrial superoxide at low levels even in the absence of IMS SOD. Surprisingly, the copper-dependent cytochrome c oxidase (COX) form of respiration remains high with copper starvation. We provide evidence that repression of SOD1 during copper limitation serves to spare copper for COX and maintain COX respiration. Overall, the complex copper starvation response of C. albicans involving SOD1, SOD3 and AOX minimizes mitochondrial oxidative damage whilst maximizing COX respiration essential for fungal pathogenesis.

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“…Increased expression under conditions of copper excess may offer cells additional protection against oxidative damage in the presence of this redox-active metal. Sod1 and its chaperone, Ccs1, are primarily located in the cytosol, but a small amount of both are also located in the mitochondrial intermembrane space (Sturtz et al 2001) and in the nucleus (Wood and Thiele 2009). Surprisingly, both the nuclear localization and enzymatic activity of Sod1 are required for the Mac1 response to low copper.…”

Section: Copper Detoxification and Utilizationmentioning

confidence: 99%

Regulation of Cation Balance inSaccharomyces cerevisiae

2013

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All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish the electrochemical gradients across membranes that drive cellular processes such as transport and ATP synthesis. Metal ions serve as essential enzyme cofactors and perform both structural and signaling roles within cells. However, because these ions can also be toxic, cells have developed sophisticated homeostatic mechanisms to regulate their levels and avoid toxicity. Studies in Saccharomyces cerevisiae have characterized many of the gene products and processes responsible for acquiring, utilizing, storing, and regulating levels of these ions. Findings in this model organism have often allowed the corresponding machinery in humans to be identified and have provided insights into diseases that result from defects in ion homeostasis. This review summarizes our current understanding of how cation balance is achieved and modulated in baker's yeast. Control of intracellular pH is discussed, as well as uptake, storage, and efflux mechanisms for the alkali metal cations, Na + and K + , the divalent cations, Ca 2+ and Mg 2+ , and the trace metal ions, Fe 2+ , Zn 2+ , Cu 2+ , and Mn 2+ . Signal transduction pathways that are regulated by pH and Ca 2+ are reviewed, as well as the mechanisms that allow cells to maintain appropriate intracellular cation concentrations when challenged by extreme conditions, i.e., either limited availability or toxic levels in the environment. TABLE OF CONTENTS Abstract 677Introduction 678

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Transcriptional Activation in Yeast in Response to Copper Deficiency Involves Copper-Zinc Superoxide Dismutase

Cited by 48 publications

References 75 publications

The Yeast Copper Response Is Regulated by DNA Damage

The Yeast Copper Response Is Regulated by DNA Damage

An Adaptation to Low Copper in Candida albicans Involving SOD Enzymes and the Alternative Oxidase

Regulation of Cation Balance inSaccharomyces cerevisiae

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