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- Title
A chemical potentiator of copper-accumulation used to investigate the iron-regulons of S accharomyces cerevisiae.
- Authors
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.
- Abstract
The extreme resistance of S accharomyces 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)2 Cu(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 upregulated iron-import. Comparison of copper- BPQ treated, untreated and copper-only treated wild-type and fra2Δ by RNA-seq 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.
- Subjects
DRUG synergism; REGULONS; SACCHAROMYCES cerevisiae; REPRESSION (Psychology); BIOACCUMULATION; IRON-sulfur proteins
- Publication
Molecular Microbiology, 2014, Vol 93, Issue 2, p317
- ISSN
0950-382X
- Publication type
Article
- DOI
10.1111/mmi.12661