Dichtl B, Stevens A, Tollervey D
EMBL, Gene Expression Programme, Postfach 10.2209, 69012 Heidelberg, Germany.
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.
Hal2p是一种将硫酸同化产物pAp（腺苷3'，5' - 二磷酸）转化为5' - AMP和磷酸根离子的酶。Hal2p的过表达赋予酵母锂抗性，并且其活性在体外受到亚毫摩尔量的Li +抑制。在此我们报告，HAL2突变体中pAp的积累会抑制5'→3'外切核糖核酸酶Xrn1p和Rat1p。用Li +处理野生型酵母菌株也会抑制外切核酸酶，这是由于Hal2p受到抑制导致pAp积累所致；5.8S rRNA和snoRNAs的5'加工、前体rRNA间隔片段的降解以及mRNA周转均受到抑制。锂还通过一种不由pAp介导的机制抑制RNase MRP的活性。RNase MRP RNA中的突变赋予Li +超敏感性，并且与HAL2或XRN1中的突变具有合成致死性。我们提出酵母中Li +毒性是由于Xrn1p和RNase MRP之间引发的合成致死性。类似的机制可能导致Li +对发育和人类神经生物学的影响。
