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A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae

Foster, Andrew W.; Dainty, Samantha J.; Patterson, Carl J.; Pohl, Ehmke; Blackburn, Hannah; Wilson, Clare; Hess, Corinna R.; Rutherford, Julian C.; Quaranta, Laura; Corran, Andy; Robinson, Nigel J.

A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae Thumbnail


Authors

Andrew W. Foster

Samantha J. Dainty

Carl J. Patterson

Ehmke Pohl

Hannah Blackburn

Clare Wilson

Corinna R. Hess

Julian C. Rutherford

Laura Quaranta

Andy Corran



Abstract

The extreme resistance of Saccharomyces cerevisiae to copper is overcome by 2-(6-benzyl-2-pyridyl)quinazoline (BPQ), providing a chemical-biology tool which has been exploited in two lines of discovery. First, BPQ is shown to form a red (BPQ)2Cu(I) complex and promote Ctr1-independent copper-accumulation in whole cells and in mitochondria isolated from treated cells. Multiple phenotypes, including loss of aconitase activity, are consistent with copper-BPQ mediated damage to mitochondrial iron-sulphur clusters. Thus, a biochemical basis of copper-toxicity in S. cerevisiae is analogous to other organisms. Second, iron regulons controlled by Aft1/2, Cth2 and Yap5 that respond to mitochondrial iron-sulphur cluster status are modulated by copper-BPQ causing iron hyper-accumulation via up-regulated iron-import. Comparison of copper-BPQ treated, untreated and copper-only treated wild-type and fra2Δ by RNAseq has uncovered a new candidate Aft1 target-gene (LSO1) and paralogous non-target (LSO2), plus nine putative Cth2 target-transcripts. Two lines of evidence confirm that Fra2 dominates basal repression of the Aft1/2 regulons in iron-replete cultures. Fra2-independent control of these regulons is also observed but cth2 itself appears to be atypically Fra2-dependent. However, control of Cth2-target transcripts which is independent of cth2 transcript abundance or of Fra2, is also quantified. Use of copper-BPQ supports a substantial contribution of metabolite repression to iron-regulation.

Citation

Foster, A. W., Dainty, S. J., Patterson, C. J., Pohl, E., Blackburn, H., Wilson, C., …Robinson, N. J. (2014). A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae. Molecular Microbiology, 93(2), 317-330. https://doi.org/10.1111/mmi.12661

Journal Article Type Article
Acceptance Date May 29, 2014
Online Publication Date Jun 15, 2014
Publication Date Jul 1, 2014
Deposit Date Jun 5, 2014
Publicly Available Date Jul 4, 2014
Journal Molecular Microbiology
Print ISSN 0950-382X
Electronic ISSN 1365-2958
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 93
Issue 2
Pages 317-330
DOI https://doi.org/10.1111/mmi.12661

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Published Journal Article (Advance online version) (3.9 Mb)
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Advance online version © 2014 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.






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