Lithium toxicity in yeast is due to the inhibition of RNA processing enzymes

EMBO J. 1997 Dec 1;16(23):7184-95. doi: 10.1093/emboj/16.23.7184.


Hal2p is an enzyme that converts pAp (adenosine 3',5' bisphosphate), a product of sulfate assimilation, into 5' AMP and Pi. Overexpression of Hal2p confers lithium resistance in yeast, and its activity is inhibited by submillimolar amounts of Li+ in vitro. Here we report that pAp accumulation in HAL2 mutants inhibits the 5'-->3' exoribonucleases Xrn1p and Rat1p. Li+ treatment of a wild-type yeast strain also inhibits the exonucleases, as a result of pAp accumulation due to inhibition of Hal2p; 5' processing of the 5.8S rRNA and snoRNAs, degradation of pre-rRNA spacer fragments and mRNA turnover are inhibited. Lithium also inhibits the activity of RNase MRP by a mechanism which is not mediated by pAp. A mutation in the RNase MRP RNA confers Li+ hypersensitivity and is synthetically lethal with mutations in either HAL2 or XRN1. We propose that Li+ toxicity in yeast is due to synthetic lethality evoked between Xrn1p and RNase MRP. Similar mechanisms may contribute to the effects of Li+ on development and in human neurobiology.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Cloning, Molecular
  • DNA, Ribosomal
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Exoribonucleases / antagonists & inhibitors
  • Exoribonucleases / metabolism
  • Lithium / toxicity*
  • Mutagenesis
  • Nucleotidases / genetics*
  • RNA Processing, Post-Transcriptional / drug effects*
  • RNA, Ribosomal / metabolism
  • Saccharomyces cerevisiae Proteins*
  • Tranquilizing Agents / toxicity*
  • Yeasts / genetics


  • DNA, Ribosomal
  • RNA, Ribosomal
  • Saccharomyces cerevisiae Proteins
  • Tranquilizing Agents
  • RAT1 protein, S cerevisiae
  • Adenosine Diphosphate
  • Lithium
  • adenosine 3'-phosphate-5'-phosphate
  • Endoribonucleases
  • Exoribonucleases
  • mitochondrial RNA-processing endoribonuclease
  • XRN1 protein, S cerevisiae
  • Nucleotidases
  • bisphosphoadenylate 3'-nucleotidase