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 P-i. Overexpression of Hal2p confers lithium resistance in yeast, and its activity is inhi bited by submillimolar amounts of Li+ in vitro. Here we report that pA p accumulation in HAL2 mutants inhibits the 5'-->3' exoribonucleases X rn1p and Rat1p. Li+ treatment of a wild-type yeast strain also inhibit s the exonucleases, as a result of pAp accumulation due to inhibition of Hal2p; 5' processing of the 5.8S rRNA and snoRNAs, degradation of p re-rRNA spacer fragments and mRNA turnover are inhibited, Lithium also inhibits the activity of RNase MRP by a mechanism which is not mediat ed by pAp, A mutation in the RNase MRP RNA confers Li+ hypersensitivit y and is synthetically lethal with mutations in either HAL2 or XRN1. W e propose that Li+ toxicity in yeast is due to synthetic lethality evo ked between Xrn1p and RNase MRP. Similar mechanisms may contribute to the effects of Li+ on development and in human neurobiology.