title: Application of the comprehensive set of heterozygous yeast deletion mutants to elucidate the molecular basis of cellular chromium toxicity.
abstract: BACKGROUND
  The serious biological consequences of metal toxicity are well documented, but the key modes of action of most metals are unknown. To help unravel molecular mechanisms underlying the action of chromium, a metal of major toxicological importance, we grew over 6,000 heterozygous yeast mutants in competition in the presence of chromium. Microarray-based screens of these heterozygotes are truly genome-wide as they include both essential and non-essential genes.
  
  
  RESULTS
  The screening data indicated that proteasomal (protein degradation) activity is crucial for cellular chromium (Cr) resistance. Further investigations showed that Cr causes the accumulation of insoluble and toxic protein aggregates, which predominantly arise from proteins synthesised during Cr exposure. A protein-synthesis defect provoked by Cr was identified as mRNA mistranslation, which was oxygen-dependent. Moreover, Cr exhibited synergistic toxicity with a ribosome-targeting drug (paromomycin) that is known to act via mistranslation, while manipulation of translational accuracy modulated Cr toxicity.
  
  
  CONCLUSIONS
  The datasets from the heterozygote screen represent an important public resource that may be exploited to discover the toxic mechanisms of chromium. That potential was validated here with the demonstration that mRNA mistranslation is a primary cause of cellular Cr toxicity.
authors: School of Biology, Institute of Genetics, The University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors: Sara
authors: S
authors: Holland
authors: Emma
authors: E
authors: Lodwig
authors: Theodora
authors: T
authors: Sideri
authors: Tom
authors: T
authors: Reader
authors: Ian
authors: I
authors: Clarke
authors: Konstantinos
authors: K
authors: Gkargkas
authors: David C
authors: DC
authors: Hoyle
authors: Daniela
authors: D
authors: Delneri
authors: Stephen G
authors: SG
authors: Oliver
authors: Simon V
authors: SV
authors: Avery
mesh_terms: D002857:Chromium / Q000494:pharmacology*; D017353:Gene Deletion; D006579:Heterozygote; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis / Q000187:drug effects; D012331:RNA, Fungal / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: D012331:RNA, Fungal; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D002857:Chromium