Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Dec 1;16(23):7184–7195. doi: 10.1093/emboj/16.23.7184

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

B Dichtl 1, A Stevens 1, D Tollervey 1
PMCID: PMC1170319  PMID: 9384595

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.

Full Text

The Full Text of this article is available as a PDF (573.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amberg D. C., Goldstein A. L., Cole C. N. Isolation and characterization of RAT1: an essential gene of Saccharomyces cerevisiae required for the efficient nucleocytoplasmic trafficking of mRNA. Genes Dev. 1992 Jul;6(7):1173–1189. doi: 10.1101/gad.6.7.1173. [DOI] [PubMed] [Google Scholar]
  2. Bashkirov V. I., Scherthan H., Solinger J. A., Buerstedde J. M., Heyer W. D. A mouse cytoplasmic exoribonuclease (mXRN1p) with preference for G4 tetraplex substrates. J Cell Biol. 1997 Feb 24;136(4):761–773. doi: 10.1083/jcb.136.4.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baudin A., Ozier-Kalogeropoulos O., Denouel A., Lacroute F., Cullin C. A simple and efficient method for direct gene deletion in Saccharomyces cerevisiae. Nucleic Acids Res. 1993 Jul 11;21(14):3329–3330. doi: 10.1093/nar/21.14.3329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beltrame M., Tollervey D. Identification and functional analysis of two U3 binding sites on yeast pre-ribosomal RNA. EMBO J. 1992 Apr;11(4):1531–1542. doi: 10.1002/j.1460-2075.1992.tb05198.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bergès T., Petfalski E., Tollervey D., Hurt E. C. Synthetic lethality with fibrillarin identifies NOP77p, a nucleolar protein required for pre-rRNA processing and modification. EMBO J. 1994 Jul 1;13(13):3136–3148. doi: 10.1002/j.1460-2075.1994.tb06612.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berridge M. J., Downes C. P., Hanley M. R. Neural and developmental actions of lithium: a unifying hypothesis. Cell. 1989 Nov 3;59(3):411–419. doi: 10.1016/0092-8674(89)90026-3. [DOI] [PubMed] [Google Scholar]
  7. Chang D. D., Clayton D. A. A novel endoribonuclease cleaves at a priming site of mouse mitochondrial DNA replication. EMBO J. 1987 Feb;6(2):409–417. doi: 10.1002/j.1460-2075.1987.tb04770.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cherest H., Surdin-Kerjan Y., Robichon-Szulmajster H. Methionine-mediated repression in Saccharomyces cerevisiae: a pleiotropic regulatory system involving methionyl transfer ribonucleic acid and the product of gene eth2. J Bacteriol. 1971 Jun;106(3):758–772. doi: 10.1128/jb.106.3.758-772.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chu S., Archer R. H., Zengel J. M., Lindahl L. The RNA of RNase MRP is required for normal processing of ribosomal RNA. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):659–663. doi: 10.1073/pnas.91.2.659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dichtl B., Tollervey D. Pop3p is essential for the activity of the RNase MRP and RNase P ribonucleoproteins in vivo. EMBO J. 1997 Jan 15;16(2):417–429. doi: 10.1093/emboj/16.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Doye V., Wepf R., Hurt E. C. A novel nuclear pore protein Nup133p with distinct roles in poly(A)+ RNA transport and nuclear pore distribution. EMBO J. 1994 Dec 15;13(24):6062–6075. doi: 10.1002/j.1460-2075.1994.tb06953.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Falany C. N. Sulfation and sulfotransferases. Introduction: changing view of sulfation and the cytosolic sulfotransferases. FASEB J. 1997 Jan;11(1):1–2. doi: 10.1096/fasebj.11.1.9034159. [DOI] [PubMed] [Google Scholar]
  13. Gietz D., St Jean A., Woods R. A., Schiestl R. H. Improved method for high efficiency transformation of intact yeast cells. Nucleic Acids Res. 1992 Mar 25;20(6):1425–1425. doi: 10.1093/nar/20.6.1425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gläser H. U., Thomas D., Gaxiola R., Montrichard F., Surdin-Kerjan Y., Serrano R. Salt tolerance and methionine biosynthesis in Saccharomyces cerevisiae involve a putative phosphatase gene. EMBO J. 1993 Aug;12(8):3105–3110. doi: 10.1002/j.1460-2075.1993.tb05979.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Grignon S., Bruguerolle B. Cerebellar lithium toxicity: a review of recent literature and tentative pathophysiology. Therapie. 1996 Mar-Apr;51(2):101–106. [PubMed] [Google Scholar]
  16. Henry Y., Wood H., Morrissey J. P., Petfalski E., Kearsey S., Tollervey D. The 5' end of yeast 5.8S rRNA is generated by exonucleases from an upstream cleavage site. EMBO J. 1994 May 15;13(10):2452–2463. doi: 10.1002/j.1460-2075.1994.tb06530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Jerka-Dziadosz M., Frankel J. The effects of lithium chloride on pattern formation in Tetrahymena thermophila. Dev Biol. 1995 Oct;171(2):497–506. doi: 10.1006/dbio.1995.1299. [DOI] [PubMed] [Google Scholar]
  18. Johnson A. W., Kolodner R. D. Strand exchange protein 1 from Saccharomyces cerevisiae. A novel multifunctional protein that contains DNA strand exchange and exonuclease activities. J Biol Chem. 1991 Jul 25;266(21):14046–14054. [PubMed] [Google Scholar]
  19. Kearsey S., Kipling D. Recombination and RNA processing: a common strand? Trends Cell Biol. 1991 Nov;1(5):110–112. doi: 10.1016/0962-8924(91)90101-e. [DOI] [PubMed] [Google Scholar]
  20. Klein P. S., Melton D. A. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8455–8459. doi: 10.1073/pnas.93.16.8455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lindahl L., Archer R. H., Zengel J. M. A new rRNA processing mutant of Saccharomyces cerevisiae. Nucleic Acids Res. 1992 Jan 25;20(2):295–301. doi: 10.1093/nar/20.2.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Livingston B. T., Wilt F. H. Lithium evokes expression of vegetal-specific molecules in the animal blastomeres of sea urchin embryos. Proc Natl Acad Sci U S A. 1989 May;86(10):3669–3673. doi: 10.1073/pnas.86.10.3669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lygerou Z., Allmang C., Tollervey D., Séraphin B. Accurate processing of a eukaryotic precursor ribosomal RNA by ribonuclease MRP in vitro. Science. 1996 Apr 12;272(5259):268–270. doi: 10.1126/science.272.5259.268. [DOI] [PubMed] [Google Scholar]
  24. Lygerou Z., Mitchell P., Petfalski E., Séraphin B., Tollervey D. The POP1 gene encodes a protein component common to the RNase MRP and RNase P ribonucleoproteins. Genes Dev. 1994 Jun 15;8(12):1423–1433. doi: 10.1101/gad.8.12.1423. [DOI] [PubMed] [Google Scholar]
  25. Manji H. K., Potter W. Z., Lenox R. H. Signal transduction pathways. Molecular targets for lithium's actions. Arch Gen Psychiatry. 1995 Jul;52(7):531–543. doi: 10.1001/archpsyc.1995.03950190013003. [DOI] [PubMed] [Google Scholar]
  26. Masselot M., De Robichon-Szulmajster H. Methionine biosynthesis in Saccharomyces cerevisiae. I. Genetical analysis of auxotrophic mutants. Mol Gen Genet. 1975 Aug 5;139(2):121–132. doi: 10.1007/BF00264692. [DOI] [PubMed] [Google Scholar]
  27. Michaelis S., Herskowitz I. The a-factor pheromone of Saccharomyces cerevisiae is essential for mating. Mol Cell Biol. 1988 Mar;8(3):1309–1318. doi: 10.1128/mcb.8.3.1309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Muhlrad D., Decker C. J., Parker R. Deadenylation of the unstable mRNA encoded by the yeast MFA2 gene leads to decapping followed by 5'-->3' digestion of the transcript. Genes Dev. 1994 Apr 1;8(7):855–866. doi: 10.1101/gad.8.7.855. [DOI] [PubMed] [Google Scholar]
  29. Murguía J. R., Bellés J. M., Serrano R. A salt-sensitive 3'(2'),5'-bisphosphate nucleotidase involved in sulfate activation. Science. 1995 Jan 13;267(5195):232–234. doi: 10.1126/science.7809627. [DOI] [PubMed] [Google Scholar]
  30. Murguía J. R., Bellés J. M., Serrano R. The yeast HAL2 nucleotidase is an in vivo target of salt toxicity. J Biol Chem. 1996 Nov 15;271(46):29029–29033. doi: 10.1074/jbc.271.46.29029. [DOI] [PubMed] [Google Scholar]
  31. Neuwald A. F., Krishnan B. R., Brikun I., Kulakauskas S., Suziedelis K., Tomcsanyi T., Leyh T. S., Berg D. E. cysQ, a gene needed for cysteine synthesis in Escherichia coli K-12 only during aerobic growth. J Bacteriol. 1992 Jan;174(2):415–425. doi: 10.1128/jb.174.2.415-425.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Peng Z., Verma D. P. A rice HAL2-like gene encodes a Ca(2+)-sensitive 3'(2'),5'-diphosphonucleoside 3'(2')-phosphohydrolase and complements yeast met22 and Escherichia coli cysQ mutations. J Biol Chem. 1995 Dec 8;270(49):29105–29110. doi: 10.1074/jbc.270.49.29105. [DOI] [PubMed] [Google Scholar]
  33. Peters D. J., Van Lookeren Campagne M. M., Van Haastert P. J., Spek W., Schaap P. Lithium ions induce prestalk-associated gene expression and inhibit prespore gene expression in Dictyostelium discoideum. J Cell Sci. 1989 May;93(Pt 1):205–210. doi: 10.1242/jcs.93.1.205. [DOI] [PubMed] [Google Scholar]
  34. Quintero F. J., Garciadeblás B., Rodríguez-Navarro A. The SAL1 gene of Arabidopsis, encoding an enzyme with 3'(2'),5'-bisphosphate nucleotidase and inositol polyphosphate 1-phosphatase activities, increases salt tolerance in yeast. Plant Cell. 1996 Mar;8(3):529–537. doi: 10.1105/tpc.8.3.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ramaswamy S. G., Jakoby W. B. (2')3',5'-Bisphosphate nucleotidase. J Biol Chem. 1987 Jul 25;262(21):10044–10047. [PubMed] [Google Scholar]
  36. Robzyk K., Kassir Y. A simple and highly efficient procedure for rescuing autonomous plasmids from yeast. Nucleic Acids Res. 1992 Jul 25;20(14):3790–3790. doi: 10.1093/nar/20.14.3790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rodriguez-Navarro A., Asensio J. An efflux mechanism determines the low net entry of lithium in yeasts. FEBS Lett. 1977 Mar 15;75(1):169–172. doi: 10.1016/0014-5793(77)80078-1. [DOI] [PubMed] [Google Scholar]
  38. Rosenthal N. E., Goodwin F. K. The role of the lithium ion in medicine. Annu Rev Med. 1982;33:555–568. doi: 10.1146/annurev.me.33.020182.003011. [DOI] [PubMed] [Google Scholar]
  39. Schmitt M. E., Clayton D. A. Characterization of a unique protein component of yeast RNase MRP: an RNA-binding protein with a zinc-cluster domain. Genes Dev. 1994 Nov 1;8(21):2617–2628. doi: 10.1101/gad.8.21.2617. [DOI] [PubMed] [Google Scholar]
  40. Sherman F. Getting started with yeast. Methods Enzymol. 1991;194:3–21. doi: 10.1016/0076-6879(91)94004-v. [DOI] [PubMed] [Google Scholar]
  41. Shuai K., Warner J. R. A temperature sensitive mutant of Saccharomyces cerevisiae defective in pre-rRNA processing. Nucleic Acids Res. 1991 Sep 25;19(18):5059–5064. doi: 10.1093/nar/19.18.5059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Stevens A., Hsu C. L., Isham K. R., Larimer F. W. Fragments of the internal transcribed spacer 1 of pre-rRNA accumulate in Saccharomyces cerevisiae lacking 5'----3' exoribonuclease 1. J Bacteriol. 1991 Nov;173(21):7024–7028. doi: 10.1128/jb.173.21.7024-7028.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Stevens A., Poole T. L. 5'-exonuclease-2 of Saccharomyces cerevisiae. Purification and features of ribonuclease activity with comparison to 5'-exonuclease-1. J Biol Chem. 1995 Jul 7;270(27):16063–16069. doi: 10.1074/jbc.270.27.16063. [DOI] [PubMed] [Google Scholar]
  44. Thomas D., Barbey R., Henry D., Surdin-Kerjan Y. Physiological analysis of mutants of Saccharomyces cerevisiae impaired in sulphate assimilation. J Gen Microbiol. 1992 Oct;138(10):2021–2028. doi: 10.1099/00221287-138-10-2021. [DOI] [PubMed] [Google Scholar]
  45. Thomas D., Cherest H., Surdin-Kerjan Y. Elements involved in S-adenosylmethionine-mediated regulation of the Saccharomyces cerevisiae MET25 gene. Mol Cell Biol. 1989 Aug;9(8):3292–3298. doi: 10.1128/mcb.9.8.3292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tollervey D. A yeast small nuclear RNA is required for normal processing of pre-ribosomal RNA. EMBO J. 1987 Dec 20;6(13):4169–4175. doi: 10.1002/j.1460-2075.1987.tb02763.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tollervey D., Mattaj I. W. Fungal small nuclear ribonucleoproteins share properties with plant and vertebrate U-snRNPs. EMBO J. 1987 Feb;6(2):469–476. doi: 10.1002/j.1460-2075.1987.tb04777.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Venema J., Henry Y., Tollervey D. Two distinct recognition signals define the site of endonucleolytic cleavage at the 5'-end of yeast 18S rRNA. EMBO J. 1995 Oct 2;14(19):4883–4892. doi: 10.1002/j.1460-2075.1995.tb00169.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Weinshilboum R. M., Otterness D. M., Aksoy I. A., Wood T. C., Her C., Raftogianis R. B. Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes. FASEB J. 1997 Jan;11(1):3–14. [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES