The Yeast Copper Response Is Regulated by DNA Damage

Abstract

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.

A Conserved KIN17 Curved DNA-Binding Domain Protein Assembles with SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE7 to Adapt Arabidopsis Growth and Development to Limiting Copper Availability

“…Indeed, assuming a conserved role of KIN17, one could hypothesize that Cu is required to face conditions impairing DNA replication and genome integrity. Interestingly, a recent study provided evidence in favor of the activation of the Cu-import system in Saccharomyces cerevisiae in response to treatments with DNA-damaging agents (Dong et al, 2013). In this regard, our data supporting the KIN17-SPL7 interaction would reinforce the requirement of Cu in DNA metabolism and provide a first indication of how this coupling is achieved in plants.…”

Cellular sensing and transport of metal ions: implications in micronutrient homeostasis

“…Copper binding to this domain promotes an interaction between the transactivation domain and DNA binding domain, which in turn prevents Mac1 from binding to DNA and activating gene expression [55]. While this copper-induced allosteric switch explains how Mac1 activity can be regulated by copper, new studies have revealed that activation of gene expression under copper-limiting conditions requires a functional Cu-Zn superoxide dismutase (Sod1), and that Mac1 activity can be affected by the DNA damaging agent MMS [56, 57]. MMS is thought to trigger changes in the redox status of the regulatory cysteine residues within Mac1, which in turn correlates with alterations in Mac1 activity [57].…”

“…While this copper-induced allosteric switch explains how Mac1 activity can be regulated by copper, new studies have revealed that activation of gene expression under copper-limiting conditions requires a functional Cu-Zn superoxide dismutase (Sod1), and that Mac1 activity can be affected by the DNA damaging agent MMS [56, 57]. MMS is thought to trigger changes in the redox status of the regulatory cysteine residues within Mac1, which in turn correlates with alterations in Mac1 activity [57]. These newer studies suggest that other environmental factors alter, or may be critical to, copper sensing.…”

TheAspergillus fumigatustranscription factor AceA is involved not only in Cu but also in Zn detoxification through regulating transporters CrpA and ZrcA

“…Most knowledge of the intricacies of Cu-mediated metal detoxification is obtained from observations in the yeast Saccharomyces cerevisiae. Under conditions of high Cu, S. cerevisiae can trigger Cu detoxification and inactivate Cu uptake systems to protect cells from Cu toxicity (Ballou & Wilson, 2016;Dong, Addinall, Lydall, & Rutherford, 2013). In S. cerevisiae, Cu responsive transcription factor, Ace1, regulates the expression of Cu detoxification-related genes, including those encoding the metallothioneins (MTs) Cup1 and Crs5, and Cu/ Zn SOD1, to adapt to the stress of excess environmental Cu (Beaudoin & Labbe, 2001).…”