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PMID: 9384595 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S.

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

The EMBO journal ·Vol. 16 ·No. 23 ·1997-12-01 ·Pages 7184-95

Dichtl B, Stevens A, Tollervey D

Abstract

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.

MeSH Terms
Adenosine Diphosphate/metabolism Cloning, Molecular DNA, Ribosomal Endoribonucleases/genetics,metabolism Exoribonucleases/antagonists & inhibitors,metabolism Lithium/toxicity Mutagenesis Nucleotidases/genetics RNA Processing, Post-Transcriptional/drug effects RNA, Ribosomal/metabolism Saccharomyces cerevisiae Proteins Tranquilizing Agents/toxicity Yeasts/genetics
Chemicals
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
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Dichtl B
EMBL, Gene Expression Programme, Postfach 10.2209, 69012 Heidelberg, Germany.
Stevens A
Tollervey D
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/16.23.7184
Published
1997-12-01
Pages
7184-95
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1170319
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/16.23.7184 PMC Full Text View journal details
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