Molecular Biology

, Volume 52, Issue 6, pp 846–853 | Cite as

The Common Partner of Several Methyltransferases Modifying the Components of The Eukaryotic Translation Apparatus

  • E. N. VasilievaEmail author
  • I. G. Laptev
  • P. V. Sergiev
  • O. A. Dontsova


TRM112 is necessary for the activation and stability of several methyltransferases involved in the modification of various components of the translation apparatus. This unique protein is a partner for enzymes that methylate tRNA, rRNA, and the translation termination factor. Here we review the structural and functional features of the TRM112 complexes with methyltransferases and provide, where possible, information on their significance.


methylation translation methyltransferase tRNA rRNA translation termination factor ribosome assembly 



  1. 1.
    Bourgeois G., Létoquart J., van Tran N., Graille M. 2017. Trm112, a protein activator of methyltransferases modifying actors of the eukaryotic translational apparatus. Biomolecules. 7, 7.CrossRefGoogle Scholar
  2. 2.
    Heurgué-Hamard V., Graille M., Scrima N., Ulryck N., Champ S., van Tilbeurgh H., Buckingham R.H. 2006. The zinc finger protein Ynr046w is plurifunctional and a component of the eRF1 methyltransferase in yeast. J. Biol. Chem. 281, 36140–36148.CrossRefPubMedGoogle Scholar
  3. 3.
    Létoquart J., Huvelle E., Wacheul L., Bourgeois G., Zorbas C., Graille M., Heurgué-Hamard V., Lafontaine D.L.J. 2014. Structural and functional studies of Bud23–Trm112 reveal 18S rRNA N 7-G1575 methylation occurs on late 40S precursor ribosomes. Proc. Natl. Acad. Sci. U. S. A. 111, E5518–E5526.CrossRefPubMedGoogle Scholar
  4. 4.
    Letoquart J., van Tran N., Caroline V., Aleksandrov A., Lazar N., Van Tilbeurgh H., Liger D., Graille M. 2015. Insights into molecular plasticity in protein complexes from Trm9-Trm112 tRNA modifying enzyme crystal structure. Nucleic Acids Res. 42, 10989–11002.CrossRefGoogle Scholar
  5. 5.
    Liger D., Mora L., Lazar N., Figaro S., Henri J., Scrima N., Buckingham R.H., van Tilbeurgh H., Heurgué-Hamard V., Graille M. 2011. Mechanism of activation of methyltransferases involved in translation by the Trm112 ‘hub’ protein. Nucleic Acids Res. 39, 6249–6259.CrossRefPubMedGoogle Scholar
  6. 6.
    Mazauric M.-H., Dirick L., Purushothaman S.K., Björk G.R., Lapeyre B. 2010. Trm112p is a 15-kDa zinc finger protein essential for the activity of two tRNA and one protein methyltransferases in yeast. J. Biol. Chem. 285, 18505–18515.CrossRefPubMedGoogle Scholar
  7. 7.
    Chen C., Huang B., Anderson J.T., Byström A.S. 2011. Unexpected accumulation of ncm5U and ncm5s2U in a trm9 mutant suggests an additional step in the synthesis of mcm5U and mcm5s2U. PLoS One. 6, e20783.CrossRefPubMedGoogle Scholar
  8. 8.
    Figaro S., Wacheul L., Schillewaert S., Graille M., Huvelle E., Mongeard R., Zorbas C., Lafontaine D.L.J., Heurgue-Hamard V. 2012. Trm112 is required for Bud23-mediated methylation of the 18S rRNA at position G1575. Mol. Cell. Biol. 32, 2254–2267.CrossRefPubMedGoogle Scholar
  9. 9.
    Hu Z., Zhang X., Qin Z., Hu Y. 2010. Arabidopsis SMO2 regulates seed germination and ABA response. Plant Signaling Behavior. 5, 325–327.CrossRefPubMedGoogle Scholar
  10. 10.
    Gu T., He H., Zhang Y., Han Z., Hou G., Zeng T., Liu Q., Wu Q. 2012. Trmt112 gene expression in mouse embryonic development. Acta Histochem. Cytochem. 45 (2), 113–119.CrossRefPubMedGoogle Scholar
  11. 11.
    Towns W.L., Begley T.J. 2012. Transfer RNA methyltransferases and their corresponding modifications in budding yeast and humans: Activities, predications, and potential roles in human health. DNA Cell Biol. 31, 434–454.CrossRefPubMedGoogle Scholar
  12. 12.
    Zorbas C., Nicolas E., Wacheul L., Huvelle E., Heurgue-Hamard V., Lafontaine D.L.J. 2015. The human 18S rRNA base methyltransferases DIMT1L and WBSCR22-TRMT112 but not rRNA modification are required for ribosome biogenesis. Mol. Biol. Cell. 26, 2080–2095.CrossRefPubMedGoogle Scholar
  13. 13.
    Guy M.P., Phizicky E.M. 2014. Two-subunit enzymes involved in eukaryotic post-transcriptional tRNA modification. RNA Biol. 11, 1608–1618.CrossRefPubMedGoogle Scholar
  14. 14.
    Bourgeois G., Marcoux J., Saliou J.-M., Cianférani S., Graille M. 2016. Activation mode of the eukaryotic m2G10 tRNA methyltransferase Trm11 by its partner protein Trm112. Nucleic Acids Res. 45, 1971–1982.Google Scholar
  15. 15.
    Begley U., Sosa M.S., Avivar-Valderas A., Patil A., Endres L., Estrada Y., Chan C.T.Y., Su D., Dedon P.C., Aguirre-Ghiso J.A., Begley T. 2013. A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α: hTRM9L suppresses tumour growth. EMBO Mol. Med. 5, 366–383.CrossRefPubMedGoogle Scholar
  16. 16.
    Sardana R., Johnson A.W. 2012. The methyltransferase adaptor protein Trm112 is involved in biogenesis of both ribosomal subunits. Mol. Biol. Cell. 23, 4313–4322.CrossRefPubMedGoogle Scholar
  17. 17.
    Purushothaman S.K., Bujnicki J.M., Grosjean H., Lapeyre B. 2005. Trm11p and Trm112p are both required for the formation of 2-methylguanosine at position 10 in yeast tRNA. Mol. Cell. Biol. 25, 4359–4370.CrossRefPubMedGoogle Scholar
  18. 18.
    Sharma S., Yang J., Watzinger P., Kötter P., Entian K.-D. 2013. Yeast Nop2 and Rcm1 methylate C2870 and C2278 of the 25S rRNA, respectively. Nucleic Acids Res. 41, 9062–9076.CrossRefPubMedGoogle Scholar
  19. 19.
    Kalhor H.R., Clarke S. 2003. Novel methyltransferase for modified uridine residues at the wobble position of tRNA. Mol. Cell. Biol. 23, 9283–9292.CrossRefPubMedGoogle Scholar
  20. 20.
    Glatt S., Létoquart J., Faux C., Taylor N.M.I., Séraphin B., Müller C.W. 2012. The elongator subcomplex Elp456 is a hexameric RecA-like ATPase. Nat. Struct. Mol. Biol. 19, 314–320.CrossRefPubMedGoogle Scholar
  21. 21.
    Glatt S., Zabel R., Kolaj-Robin O., Onuma O.F., Baudin F., Graziadei A., Taverniti V., Lin T.-Y., Baymann F., Séraphin B., Breunig K.D., Müller C.W. 2016. Structural basis for tRNA modification by Elp3 from Dehalococcoides mccartyi. Nat. Struct. Mol. Biol. 23, 794–802.CrossRefPubMedGoogle Scholar
  22. 22.
    Huang B., Lu J., Bystrom A.S. 2008. A genome-wide screen identifies genes required for formation of the wobble nucleoside 5-methoxycarbonylmethyl-2-thiouridine in Saccharomyces cerevisiae. RNA. 14, 2183–2194.CrossRefPubMedGoogle Scholar
  23. 23.
    Noma A., Sakaguchi Y., Suzuki T. 2009. Mechanistic characterization of the sulfur-relay system for eukaryotic 2-thiouridine biogenesis at tRNA wobble positions. Nucleic Acids Res. 37, 1335–1352.CrossRefPubMedGoogle Scholar
  24. 24.
    Begley U., Dyavaiah M., Patil A., Rooney J.P., DiRenzo D., Young C.M., Conklin D.S., Zitomer R.S., Begley T.J. 2007. Trm9-catalyzed tRNA modifications link translation to the DNA damage response. Mol. Cell. 28, 860–870.CrossRefPubMedGoogle Scholar
  25. 25.
    Chan C.T.Y., Dyavaiah M., DeMott M.S., Taghizadeh K., Dedon P.C., Begley T.J. 2010. A quantitative systems approach reveals dynamic control of tRNA modifications during cellular stress. PLoS Genet. 6, e1001247.CrossRefPubMedGoogle Scholar
  26. 26.
    Deng W., Babu I.R., Su D., Yin S., Begley T.J., Dedon P.C. 2015. Trm9-catalyzed tRNA modifications regulate global protein expression by codon-biased translation. PLoS Genet. 11, e1005706.CrossRefPubMedGoogle Scholar
  27. 27.
    Lu J., Huang B., Esberg A., Johansson M.J. 2005. The Kluyveromyces lactis γ-toxin targets tRNA anticodons. RNA. 11, 1648–1654.Google Scholar
  28. 28.
    Studte P., Zink S., Jablonowski D., Bär C., von der Haar T., Tuite M.F., Schaffrath R. 2008. tRNA and protein methylase complexes mediate zymocin toxicity in yeast. Mol. Microbiol. 69, 1266–1277.CrossRefPubMedGoogle Scholar
  29. 29.
    Songe-Moller L., van den Born E., Leihne V., Vagbo C.B., Kristoffersen T., Krokan H.E., Kirpekar F., Falnes P.O., Klungland A. 2010. Mammalian ALKBH8 possesses tRNA methyltransferase activity required for the biogenesis of multiple wobble uridine modifications implicated in translational decoding. Mol. Cell. Biol. 30, 1814–1827.CrossRefPubMedGoogle Scholar
  30. 30.
    Fu D., Brophy J.A.N., Chan C.T.Y., Atmore K.A., Begley U., Paules R.S., Dedon P.C., Begley T.J., Samson L.D. 2010. Human AlkB homolog ABH8 is a tRNA methyltransferase required for wobble uridine modification and DNA damage survival. Mol. Cell. Biol. 30, 2449–2459.CrossRefPubMedGoogle Scholar
  31. 31.
    Fu Y., Dai Q., Zhang W., Ren J., Pan T., He C. 2010. The AlkB domain of mammalian ABH8 catalyzes hydroxylation of 5-methoxycarbonylmethyluridine at the wobble position of tRNA. Angew. Chem. Int. Ed. 49, 8885–8888.CrossRefGoogle Scholar
  32. 32.
    van den Born E., Vågbø C.B., Songe-Møller L., Leihne V., Lien G.F., Leszczynska G., Malkiewicz A., Krokan H.E., Kirpekar F., Klungland A., Falnes P.Ø. 2011. ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA. Nat. Commun. 2, 172.CrossRefPubMedGoogle Scholar
  33. 33.
    Zdżalik D., Vågbø C.B., Kirpekar F., Davydova E., Puścian A., Maciejewska A.M., Krokan H.E., Klungland A., Tudek B., van den Born E., Falnes P.Ø. 2014. Protozoan ALKBH8 oxygenases display both DNA repair and tRNA modification activities. PLoS One. 9, e98729.CrossRefPubMedGoogle Scholar
  34. 34.
    Cantara W.A., Crain P.F., Rozenski J., McCloskey J.A., Harris K.A., Zhang X., Vendeix F.A.P., Fabris D., Agris P.F. 2011. The RNA modification database, RNAMDB: 2011 update. Nucleic Acids Res. 39, D195–D201.CrossRefPubMedGoogle Scholar
  35. 35.
    Armengaud J., Urbonavicius J., Fernandez B. 2004. N2-methylation of guanosine at position 10 in tRNA is catalyzed by a THUMP domain-containing, S-adenosylmethionine-dependent methyltransferase, conserved in Archaea and Eukaryota. J. Am. Chem. Soc. 27, 1574–1574.Google Scholar
  36. 36.
    Neumann P., Lakomek K., Naumann P.-T., Erwin W.M., Lauhon C.T., Ficner R. 2014. Crystal structure of a 4‑thiouridine synthetase–RNA complex reveals specificity of tRNA U8 modification. Nucleic Acids Res. 42, 6673–6685.CrossRefPubMedGoogle Scholar
  37. 37.
    Kohli M., Riska S.M., Mahoney D.W., Chai H.S., Hillman D.W., Rider D.N., Costello B.A., Qin R., Lamba J., Sahasrabudhe D.M., Cerhan J.R. 2012. Germline predictors of androgen deprivation therapy response in advanced prostate cancer. Mayo Clin. Proc. 87, 240–246.CrossRefPubMedGoogle Scholar
  38. 38.
    Yu Y.P., Ding Y., Chen Z., Liu S., Michalopoulos A., Chen R., Gulzar Z.G., Yang B., Cieply K.M., Luvison A., Ren B.-G., Brooks J.D., Jarrard D., Nelson J.B., Michalopoulos G.K., et al. 2014. Novel fusion transcripts associate with progressive prostate cancer. Am. J. Pathol. 184, 2840–2849.CrossRefPubMedGoogle Scholar
  39. 39.
    Lunardi A., Di Minin G., Provero P., Dal Ferro M., Carotti M., Del Sal G., Collavin L. 2010. A genome-scale protein interaction profile of Drosophila p53 uncovers additional nodes of the human p53 network. Proc. Natl. Acad. Sci. U. S. A. 107, 6322–6327.CrossRefPubMedGoogle Scholar
  40. 40.
    White J., Li Z., Sardana R., Bujnicki J.M., Marcotte E.M., Johnson A.W. 2008. Bud23 methylates G1575 of 18S rRNA and is required for efficient nuclear export of pre-40S subunits. Mol. Cell. Biol. 28, 3151–3161.CrossRefPubMedGoogle Scholar
  41. 41.
    McCarthy A.A., McCarthy J.G. 2007. The structure of two N-methyltransferases from the caffeine biosynthetic pathway. Plant Physiol. 144, 879–889.CrossRefPubMedGoogle Scholar
  42. 42.
    Sardana R., Zhu J., Gill M., Johnson A.W. 2014. Physical and functional interaction between the methyltransferase Bud23 and the essential DEAH-box RNhHelicase Ecm16. Mol. Cell. Biol. 34, 2208–2220.CrossRefPubMedGoogle Scholar
  43. 43.
    Sardana R., Liu X., Granneman S., Zhu J., Gill M., Papoulas O., Marcotte E.M., Tollervey D., Correll C.C., Johnson A.W. 2015. The DEAH-box helicase Dhr1 dissociates U3 from the pre-rRNA to promote formation of the central pseudoknot. PLoS Biol. 13, e1002083.CrossRefPubMedGoogle Scholar
  44. 44.
    Õunap K., Käsper L., Kurg A., Kurg R. 2013. The human WBSCR22 protein is involved in the biogenesis of the 40S ribosomal subunits in mammalian cells. PLoS One. 8, e75686.CrossRefPubMedGoogle Scholar
  45. 45.
    Õunap K., Leetsi L., Matsoo M., Kurg R. 2015. The stability of ribosome biogenesis factor WBSCR22 is regulated by interaction with TRMT112 via ubiquitin-proteasome pathway. PLoS One. 10, e0133841.CrossRefPubMedGoogle Scholar
  46. 46.
    Doll A., Grzeschik K.-H. 2001. Characterization of two novel genes, WBSCR20 and WBSCR22,deleted in Williams–Beuren syndrome. Cytogenet. Genome Res. 95, 20–27.CrossRefGoogle Scholar
  47. 47.
    Merla G., Ucla C., Guipponi M., Reymond A. 2002. Identification of additional transcripts in the Williams-Beuren syndrome critical region. Hum. Genet. 110, 429–438.CrossRefPubMedGoogle Scholar
  48. 48.
    Nakazawa Y., Arai H., Fujita N. 2011. The novel metastasis promoter Merm1/Wbscr22 enhances tumor cell survival in the vasculature by suppressing Zac1/p53-dependent apoptosis. Cancer Res. 71, 1146–1155.CrossRefPubMedGoogle Scholar
  49. 49.
    Tiedemann R.E., Zhu Y.X., Schmidt J., Shi C.X., Sereduk C., Yin H., Mousses S., Stewart A.K. 2012. Identification of molecular vulnerabilities in human multiple myeloma cells by RNA interference lethality screening of the druggable genome. Cancer Res. 72, 757–768.CrossRefPubMedGoogle Scholar
  50. 50.
    Stefanska B., Cheishvili D., Suderman M., Arakelian A., Huang J., Hallett M., Han Z.-G., Al-Mahtab M., Akbar S.M.F., Khan W.A., Raqib R., Tanvir I., Khan H.A., Rabbani S.A., Szyf M. 2014. Genome-wide study of hypomethylated and induced genes in patients with liver cancer unravels novel anticancer targets. Clin. Cancer Res. 20, 3118–3132.CrossRefPubMedGoogle Scholar
  51. 51.
    Jangani M., Poolman T.M., Matthews L., Yang N., Farrow S.N., Berry A., Hanley N., Williamson A.J.K., Whetton A.D., Donn R., Ray D.W. 2014. The methyltransferase WBSCR22/Merm1 enhances glucocorticoid receptor function and is regulated in lung inflammation and cancer. J. Biol. Chem. 289, 8931–8946.CrossRefPubMedGoogle Scholar
  52. 52.
    Petry S., Brodersen D.E., Murphy F.V., Dunham C.M., Selmer M., Tarry M.J., Kelley A.C., Ramakrishnan V. 2005. Crystal structures of the ribosome in complex with release factors RF1 and RF2 bound to a cognate stop codon. Cell. 123, 1255–1266.CrossRefPubMedGoogle Scholar
  53. 53.
    Mora L., Heurgué-Hamard V., de Zamaroczy M., Kervestin S., Buckingham R.H. 2007. Methylation of bacterial release factors RF1 and RF2 is required for normal translation termination in vivo. J. Biol. Chem. 282, 35638–35645.CrossRefPubMedGoogle Scholar
  54. 54.
    Graille M., Heurgué-Hamard V., Champ S., Mora L., Scrima N., Ulryck N., van Tilbeurgh H., Buckingham R.H. 2005. Molecular basis for bacterial class I release factor methylation by PrmC. Mol. Cell. 20, 917–927.CrossRefPubMedGoogle Scholar
  55. 55.
    Heurgué-Hamard V., Champ S., Mora L., Merkoulova-Rainon T., Kisselev L.L., Buckingham R.H. 2005. The glutamine residue of the conserved GGQ motif in Saccharomyces cerevisiae release factor eRF1 is methylated by the product of the YDR140w gene. J. Biol. Chem. 280, 2439–2445.CrossRefPubMedGoogle Scholar
  56. 56.
    Figaro S., Scrima N., Buckingham R.H., Heurgué-Hamard V. 2008. HemK2 protein, encoded on human chromosome 21, methylates translation termination factor eRF1. FEBS Lett. 582, 2352–2356.CrossRefPubMedGoogle Scholar
  57. 57.
    Kusevic D., Kudithipudi S., Jeltsch A. 2016. Substrate specificity of the HEMK2 protein glutamine methyltransferase and identification of novel substrates. J. Biol. Chem. 291, 6124–6133.CrossRefPubMedGoogle Scholar
  58. 58.
    Nie D.-S., Liu Y.-B., Lu G.-X. 2009. Cloning and primarily function study of two novel putative N 5-glutamine methyltransferase (Hemk) splice variants from mouse stem cells. Mol. Biol. Repts. 36, 2221–2228.CrossRefGoogle Scholar
  59. 59.
    Liu P., Nie S., Li B., Yang Z.-Q., Xu Z.-M., Fei J., Lin C., Zeng R., Xu G.-L. 2010. Deficiency in a glutamine-specific methyltransferase for release factor causes mouse embryonic lethality. Mol. Cell. Biol. 30, 4245–4253.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • E. N. Vasilieva
    • 1
    Email author
  • I. G. Laptev
    • 2
    • 3
  • P. V. Sergiev
    • 2
    • 3
  • O. A. Dontsova
    • 2
    • 3
    • 4
  1. 1.Faculty of Bioengineering and Bioinformatics, Moscow State UniversityMoscowRussia
  2. 2.Faculty of Chemistry, Moscow State UniversityMoscowRussia
  3. 3.Skolkovo Institute of Science and TechnologySkolkovoRussia
  4. 4.Shemyakin–Ovchinnikov Institute of Bioorganic ChemistryMoscowRussia

Personalised recommendations