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.
Highlights
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
A major mechanism of metal sensing involves the binding of a metal ion to a relevant transcription factor, and the specificity of response is ensured by a combination of the affinity of the metal ion for its target site and the extent to which metal binding elicits a necessary allosteric change in the sensor [14]
A library of S. cerevisiae deletion mutants was grown on rich medium agar plates containing bathophenanthroline disulfonate (BPS)
Summary
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. Copper import and distribution are carefully regulated in all organisms by mechanisms that include the control of gene transcription, the compartmentalization of copper enzymes, the use of chaperones to deliver copper to relevant targets, and the localization and turnover of copper transporters [3,4,5,6] Crucial to these processes is the ability of a cell to sense both the availability and the need for copper. Mac has never been isolated from yeast in a copper-bound form, and a recent study established that Mac is transcriptionally inactive in mutants that lack Sod or its copper chaperone Ccs1 [31] This suggested a potential role for Sod in the regulation of Mac and raised the question of what constitutes the low-copper-sensing mechanism in yeast. Using the yeast deletion library, we have identified mutants that exhibit high levels of metal reductase activity on the cell sur-
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