Lithium toxicity in yeast is due to the inhibition of RNA processing enzymes.
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.
Dichtl
B
B
EMBL, Gene Expression Programme, Postfach 10.2209, 69012 Heidelberg, Germany.
Stevens
A
A
Tollervey
D
D
D000244:Adenosine Diphosphate / Q000378:metabolism; D003001:Cloning, Molecular; D004275:DNA, Ribosomal; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005095:Exoribonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008094:Lithium / Q000633:toxicity*; D016296:Mutagenesis; D009708:Nucleotidases / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012335:RNA, Ribosomal / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014149:Tranquilizing Agents / Q000633:toxicity*; D015003:Yeasts / Q000235:genetics
D004275:DNA, Ribosomal; D012335:RNA, Ribosomal; D029701:Saccharomyces cerevisiae Proteins; D014149:Tranquilizing Agents; C075577:RAT1 protein, S cerevisiae; D000244:Adenosine Diphosphate; D008094:Lithium; C010840:adenosine 3'-phosphate-5'-phosphate; D004722:Endoribonucleases; D005095:Exoribonucleases; C058330:mitochondrial RNA-processing endoribonuclease; C068398:XRN1 protein, S cerevisiae; D009708:Nucleotidases; C053354:bisphosphoadenylate 3'-nucleotidase