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Current Protein & Peptide Science


ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Review Article

Using Yeast to Define the Regulatory Role of Protein Lysine Methylation

Author(s): Yogita Jethmalani and Erin M. Green*

Volume 21, Issue 7, 2020

Page: [690 - 698] Pages: 9

DOI: 10.2174/1389203720666191023150727

Price: $65


The post-translational modifications (PTM) of proteins are crucial for cells to survive under diverse environmental conditions and to respond to stimuli. PTMs are known to govern a broad array of cellular processes including signal transduction and chromatin regulation. The PTM lysine methylation has been extensively studied within the context of chromatin and the epigenetic regulation of the genome. However, it has also emerged as a critical regulator of non-histone proteins important for signal transduction pathways. While the number of known non-histone protein methylation events is increasing, the molecular functions of many of these modifications are not yet known. Proteomic studies of the model system Saccharomyces cerevisiae suggest lysine methylation may regulate a diversity of pathways including transcription, RNA processing, translation, and signal transduction cascades. However, there has still been relatively little investigation of lysine methylation as a broad cellular regulator beyond chromatin and transcription. Here, we outline our current state of understanding of non-histone protein methylation in yeast and propose ways in which the yeast system can be leveraged to develop a much more complete picture of molecular mechanisms through which lysine methylation regulates cellular functions.

Keywords: Post-translational modification, methylation, yeast, signaling, transcription, translation.

Graphical Abstract
Ali, A.; Veeranki, S.N.; Chinchole, A.; Tyagi, S. MLL/WDR5 Complex Regulates Kif2A Localization to Ensure Chromosome Congression and Proper Spindle Assembly during Mitosis. Dev. Cell, 2017, 41(6), 605-622.e7.
[] [PMID: 28633016]
Beilharz, T.H.; Harrison, P.F.; Miles, D.M.; See, M.M.; Le, U.M.; Kalanon, M.; Curtis, M.J.; Hasan, Q.; Saksouk, J.; Margaritis, T.; Holstege, F.; Geli, V.; Dichtl, B. Coordination of Cell Cycle Progression and Mitotic Spindle Assembly Involves Histone H3 Lysine 4 Methylation by Set1/COMPASS. Genetics, 2017, 205(1), 185-199.
[] [PMID: 28049706]
Black, J.C.; Van Rechem, C.; Whetstine, J.R. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell, 2012, 48(4), 491-507.
[] [PMID: 23200123]
Blobel, G.A.; Kadauke, S.; Wang, E.; Lau, A.W.; Zuber, J.; Chou, M.M.; Vakoc, C.R. A reconfigured pattern of MLL occupancy within mitotic chromatin promotes rapid transcriptional reactivation following mitotic exit. Mol. Cell, 2009, 36(6), 970-983.
[] [PMID: 20064463]
Briggs, S.D.; Bryk, M.; Strahl, B.D.; Cheung, W.L.; Davie, J.K.; Dent, S.Y.; Winston, F.; Allis, C.D. Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev., 2001, 15(24), 3286-3295.
[] [PMID: 11751634]
Calpena, E.; Palau, F.; Espinós, C.; Galindo, M.I. Evolutionary History of the Smyd Gene Family in Metazoans: A Framework to Identify the Orthologs of Human Smyd Genes in Drosophila and Other Animal Species. PLoS One, 2015, 10(7)e0134106
[] [PMID: 26230726]
Cao, X.J.; Arnaudo, A.M.; Garcia, B.A. Large-scale global identification of protein lysine methylation in vivo. Epigenetics, 2013, 8(5), 477-485.
[] [PMID: 23644510]
Carlson, S.M.; Moore, K.E.; Green, E.M.; Martín, G.M.; Gozani, O. Proteome-wide enrichment of proteins modified by lysine methylation. Nat. Protoc., 2014, 9(1), 37-50.
[] [PMID: 24309976]
Caslavka Zempel, K.E.; Vashisht, A.A.; Barshop, W.D.; Wohlschlegel, J.A.; Clarke, S.G. Determining the Mitochondrial Methyl Proteome in Saccharomyces cerevisiae using Heavy Methyl SILAC. J. Proteome Res., 2016, 15(12), 4436-4451.
[] [PMID: 27696855]
Cessay, K.J.; Bergman, L.W.; Tuck, M.T. Further investigations regarding the role of trimethyllysine for cytochrome c uptake into mitochondria. Int. J. Biochem., 1991, 23(7-8), 761-768.
[] [PMID: 1650724]
Cheeseman, I.M.; Anderson, S.; Jwa, M.; Green, E.M.; Kang, Js.; Yates, J.R., III; Chan, C.S.; Drubin, D.G.; Barnes, G. Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p. Cell, 2002, 111(2), 163-172.
[] [PMID: 12408861]
Clarke, S.G. Protein methylation at the surface and buried deep: thinking outside the histone box. Trends Biochem. Sci., 2013, 38(5), 243-252.
[] [PMID: 23490039]
Cornett, E.M.; Dickson, B.M.; Krajewski, K.; Spellmon, N.; Umstead, A.; Vaughan, R.M.; Shaw, K.M.; Versluis, P.P.; Cowles, M.W.; Brunzelle, J.; Yang, Z.; Vega, I.E.; Sun, Z.W.; Rothbart, S.B. A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity. Sci. Adv., 2018, 4(11)eaav2623
[] [PMID: 30498785]
Couttas, T.A.; Raftery, M.J.; Padula, M.P.; Herbert, B.R.; Wilkins, M.R. Methylation of translation-associated proteins in Saccharomyces cerevisiae: Identification of methylated lysines and their methyltransferases. Proteomics, 2012, 12(7), 960-972.
[] [PMID: 22522802]
Davydova, E.; Ho, A.Y.; Malecki, J.; Moen, A.; Enserink, J.M.; Jakobsson, M.E.; Loenarz, C.; Falnes, P.Ø. Identification and characterization of a novel evolutionarily conserved lysine-specific methyltransferase targeting eukaryotic translation elongation factor 2 (eEF2). J. Biol. Chem., 2014, 289(44), 30499-30510.
[] [PMID: 25231979]
DiMaria, P.; Polastro, E.; DeLange, R.J.; Kim, S.; Paik, W.K. Studies on cytochrome c methylation in yeast. J. Biol. Chem., 1979, 254(11), 4645-4652.
[PMID: 220257]
Dzialo, M.C.; Travaglini, K.J.; Shen, S.; Loo, J.A.; Clarke, S.G. A new type of protein lysine methyltransferase trimethylates Lys-79 of elongation factor 1A. Biochem. Biophys. Res. Commun., 2014, 455(3-4), 382-389.
[] [PMID: 25446118]
Dzialo, M.C.; Travaglini, K.J.; Shen, S.; Roy, K.; Chanfreau, G.F.; Loo, J.A.; Clarke, S.G. Translational roles of elongation factor 2 protein lysine methylation. J. Biol. Chem., 2014, 289(44), 30511-30524.
[] [PMID: 25231983]
Green, E.M.; Morrison, A.J.; Gozani, O. New marks on the block: Set5 methylates H4 lysines 5, 8 and 12. Nucleus, 2012, 3(4), 335-339.
[] [PMID: 22688645]
Guo, A.; Gu, H.; Zhou, J.; Mulhern, D.; Wang, Y.; Lee, K.A.; Yang, V.; Aguiar, M.; Kornhauser, J.; Jia, X.; Ren, J.; Beausoleil, S.A.; Silva, J.C.; Vemulapalli, V.; Bedford, M.T.; Comb, M.J. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics, 2014, 13(1), 372-387.
[] [PMID: 24129315]
Hamey, J.J.; Separovich, R.J.; Wilkins, M.R. MT-MAMS: Protein Methyltransferase Motif Analysis by Mass Spectrometry. J. Proteome Res., 2018, 17(10), 3485-3491.
[] [PMID: 30156103]
Hamey, J.J.; Wilkins, M.R. Methylation of Elongation Factor 1A: Where, Who, and Why? Trends Biochem. Sci., 2018, 43(3), 211-223.
[] [PMID: 29398204]
Hamey, J.J.; Winter, D.L.; Yagoub, D.; Overall, C.M.; Hart-Smith, G.; Wilkins, M.R. Novel N-terminal and Lysine Methyltransferases That Target Translation Elongation Factor 1A in Yeast and Human. Mol. Cell. Proteomics, 2016, 15(1), 164-176.
[] [PMID: 26545399]
Hart-Smith, G.; Chia, S.Z.; Low, J.K.; McKay, M.J.; Molloy, M.P.; Wilkins, M.R. Stoichiometry of Saccharomyces cerevisiae lysine methylation: insights into non-histone protein lysine methyltransferase activity. J. Proteome Res., 2014, 13(3), 1744-1756.
[] [PMID: 24517342]
Huh, W.K.; Falvo, J.V.; Gerke, L.C.; Carroll, A.S.; Howson, R.W.; Weissman, J.S.; O’Shea, E.K. Global analysis of protein localization in budding yeast. Nature, 2003, 425(6959), 686-691.
[] [PMID: 14562095]
Jaiswal, D.; Jezek, M.; Quijote, J.; Lum, J.; Choi, G.; Kulkarni, R.; Park, D.; Green, E.M. Repression of Middle Sporulation Genes in Saccharomyces cerevisiae by the Sum1-Rfm1-Hst1 Complex Is Maintained by Set1 and H3K4 Methylation. G3 (Bethesda), 2017, 7(12), 3971-3982.
[] [PMID: 29066473]
Jaiswal, D.; Turniansky, R.; Green, E.M. Choose Your Own Adventure: The Role of Histone Modifications in Yeast Cell Fate. J. Mol. Biol., 2017, 429(13), 1946-1957.
[] [PMID: 27769718]
Jakobsson, M.E.; Davydova, E.; Małecki, J.; Moen, A.; Falnes, P.Ø. Saccharomyces cerevisiae Eukaryotic Elongation Factor 1A (eEF1A) Is Methylated at Lys-390 by a METTL21-Like Methyltransferase. PLoS One, 2015, 10(6)e0131426
[] [PMID: 26115316]
Jakobsson, M.E.; Małecki, J.; Falnes, P.Ø. Regulation of eukaryotic elongation factor 1 alpha (eEF1A) by dynamic lysine methylation. RNA Biol., 2018, 15(3), 314-319.
[] [PMID: 29447067]
Kalpage, H.A.; Bazylianska, V.; Recanati, M.A.; Fite, A.; Liu, J.; Wan, J.; Mantena, N.; Malek, M.H.; Podgorski, I.; Heath, E.I.; Vaishnav, A.; Edwards, B.F.; Grossman, L.I.; Sanderson, T.H.; Lee, I.; Hüttemann, M. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J., 2019, 33(2), 1540-1553.
[] [PMID: 30222078]
Kawai, S.; Murao, S.; Mochizuki, M.; Shibuya, I.; Yano, K.; Takagi, M. Drastic alteration of cycloheximide sensitivity by substitution of one amino acid in the L41 ribosomal protein of yeasts. J. Bacteriol., 1992, 174(1), 254-262.
[] [PMID: 1729213]
Kim, T.; Buratowski, S. Dimethylation of H3K4 by Set1 recruits the Set3 histone deacetylase complex to 5′ transcribed regions. Cell, 2009, 137(2), 259-272.
[] [PMID: 19379692]
Kim, T.; Xu, Z.; Clauder-Münster, S.; Steinmetz, L.M.; Buratowski, S. Set3 HDAC mediates effects of overlapping noncoding transcription on gene induction kinetics. Cell, 2012, 150(6), 1158-1169.
[] [PMID: 22959268]
Latham, J.A.; Chosed, R.J.; Wang, S.; Dent, S.Y. Chromatin signaling to kinetochores: transregulation of Dam1 methylation by histone H2B ubiquitination. Cell, 2011, 146(5), 709-719.
[] [PMID: 21884933]
Lee, S.W.; Berger, S.J.; Martinović, S.; Pasa-Tolić, L.; Anderson, G.A.; Shen, Y.; Zhao, R.; Smith, R.D. Direct mass spectrometric analysis of intact proteins of the yeast large ribosomal subunit using capillary LC/FTICR. Proc. Natl. Acad. Sci. USA, 2002, 99(9), 5942-5947.
[] [PMID: 11983894]
Levy, D. Lysine methylation signaling of non-histone proteins in the nucleus. Cell. Mol. Life Sci., 2019, 76(15), 2873-2883.
[] [PMID: 31123776]
Li, Z.; Gonzalez, P.A.; Sasvari, Z.; Kinzy, T.G.; Nagy, P.D. Methylation of translation elongation factor 1A by the METTL10-like See1 methyltransferase facilitates tombusvirus replication in yeast and plants. Virology, 2014, 448, 43-54.
[] [PMID: 24314635]
Lipson, R.S.; Webb, K.J.; Clarke, S.G. Two novel methyltransferases acting upon eukaryotic elongation factor 1A in Saccharomyces cerevisiae. Arch. Biochem. Biophys., 2010, 500(2), 137-143.
[] [PMID: 20510667]
Liu, H.; Galka, M.; Mori, E.; Liu, X.; Lin, Y.F.; Wei, R.; Pittock, P.; Voss, C.; Dhami, G.; Li, X.; Miyaji, M.; Lajoie, G.; Chen, B.; Li, S.S. A method for systematic mapping of protein lysine methylation identifies functions for HP1β in DNA damage response. Mol. Cell, 2013, 50(5), 723-735.
[] [PMID: 23707759]
Martin, J.L.; McMillan, F.M. SAM (dependent) I AM: the S-adenosylmethionine-dependent methyltransferase fold. Curr. Opin. Struct. Biol., 2002, 12(6), 783-793.
[] [PMID: 12504684]
Martín-Granados, C.; Riechers, S.P.; Stahl, U.; Lang, C. Absence of See1p, a widely conserved Saccharomyces cerevisiae protein, confers both deficient heterologous protein production and endocytosis. Yeast, 2008, 25(12), 871-877.
[] [PMID: 19160456]
Moore, K.E.; Carlson, S.M.; Camp, N.D.; Cheung, P.; James, R.G.; Chua, K.F.; Wolf-Yadlin, A.; Gozani, O. A general molecular affinity strategy for global detection and proteomic analysis of lysine methylation. Mol. Cell, 2013, 50(3), 444-456.
[] [PMID: 23583077]
Ng, H.H.; Feng, Q.; Wang, H.; Erdjument-Bromage, H.; Tempst, P.; Zhang, Y.; Struhl, K. Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev., 2002, 16(12), 1518-1527.
[] [PMID: 12080090]
Nislow, C.; Ray, E.; Pillus, L. SET1, a yeast member of the trithorax family, functions in transcriptional silencing and diverse cellular processes. Mol. Biol. Cell, 1997, 8(12), 2421-2436.
[] [PMID: 9398665]
Ong, S.E.; Mittler, G.; Mann, M. Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nat. Methods, 2004, 1(2), 119-126.
[] [PMID: 15782174]
Paik, W.K.; Park, K.S.; Frost, B.F.; Kim, S. Effect of enzymatic methylation on the import of in vitro synthesized apocytochrome C into mitochondria. Adv. Exp. Med. Biol., 1988, 231, 317-325.
[] [PMID: 2843008]
Park, K.S.; Frost, B.; Tuck, M.; Ho, L.L.; Kim, S.; Paik, W.K. Enzymatic methylation of in vitro synthesized apocytochrome c enhances its transport into mitochondria. J. Biol. Chem., 1987, 262(30), 14702-14708.
[PMID: 2822698]
Petrossian, T.; Clarke, S. Bioinformatic Identification of Novel Methyltransferases. Epigenomics, 2009, 1(1), 163-175.
[] [PMID: 20582239]
Petrossian, T.C.; Clarke, S.G. Multiple Motif Scanning to identify methyltransferases from the yeast proteome. Mol. Cell. Proteomics, 2009, 8(7), 1516-1526.
[] [PMID: 19351663]
Pijnappel, W.W.; Schaft, D.; Roguev, A.; Shevchenko, A.; Tekotte, H.; Wilm, M.; Rigaut, G.; Séraphin, B.; Aasland, R.; Stewart, A.F. The S. cerevisiae SET3 complex includes two histone deacetylases, Hos2 and Hst1, and is a meiotic-specific repressor of the sporulation gene program. Genes Dev., 2001, 15(22), 2991-3004.
[] [PMID: 11711434]
Polevoda, B.; Martzen, M.R.; Das, B.; Phizicky, E.M.; Sherman, F. Cytochrome c methyltransferase, Ctm1p, of yeast. J. Biol. Chem., 2000, 275(27), 20508-20513.
[] [PMID: 10791961]
Porras-Yakushi, T.R.; Whitelegge, J.P.; Clarke, S. A novel SET domain methyltransferase in yeast: Rkm2-dependent trimethylation of ribosomal protein L12ab at lysine 10. J. Biol. Chem., 2006, 281(47), 35835-35845.
[] [PMID: 17005568]
Porras-Yakushi, T.R.; Whitelegge, J.P.; Clarke, S. Yeast ribosomal/cytochrome c SET domain methyltransferase subfamily: identification of Rpl23ab methylation sites and recognition motifs. J. Biol. Chem., 2007, 282(17), 12368-12376.
[] [PMID: 17327221]
Porras-Yakushi, T.R.; Whitelegge, J.P.; Miranda, T.B.; Clarke, S. A novel SET domain methyltransferase modifies ribosomal protein Rpl23ab in yeast. J. Biol. Chem., 2005, 280(41), 34590-34598.
[] [PMID: 16096273]
Rathert, P.; Dhayalan, A.; Ma, H.; Jeltsch, A. Specificity of protein lysine methyltransferases and methods for detection of lysine methylation of non-histone proteins. Mol. Biosyst., 2008, 4(12), 1186-1190.
[] [PMID: 19396382]
Rathert, P.; Dhayalan, A.; Murakami, M.; Zhang, X.; Tamas, R.; Jurkowska, R.; Komatsu, Y.; Shinkai, Y.; Cheng, X.; Jeltsch, A. Protein lysine methyltransferase G9a acts on non-histone targets. Nat. Chem. Biol., 2008, 4(6), 344-346.
[] [PMID: 18438403]
Rathert, P.; Zhang, X.; Freund, C.; Cheng, X.; Jeltsch, A. Analysis of the substrate specificity of the Dim-5 histone lysine methyltransferase using peptide arrays. Chem. Biol., 2008, 15(1), 5-11.
[] [PMID: 18215768]
Sasikumar, A.N.; Perez, W.B.; Kinzy, T.G. The many roles of the eukaryotic elongation factor 1 complex. Wiley Interdiscip. Rev. RNA, 2012, 3(4), 543-555.
[] [PMID: 22555874]
Schubert, H.L.; Blumenthal, R.M.; Cheng, X. Many paths to methyltransfer: a chronicle of convergence. Trends Biochem. Sci., 2003, 28(6), 329-335.
[] [PMID: 12826405]
Shimazu, T.; Barjau, J.; Sohtome, Y.; Sodeoka, M.; Shinkai, Y. Selenium-based S-adenosylmethionine analog reveals the mammalian seven-beta-strand methyltransferase METTL10 to be an EF1A1 lysine methyltransferase. PLoS One, 2014, 9(8)e105394
[] [PMID: 25144183]
Spahn, C.M.; Beckmann, R.; Eswar, N.; Penczek, P.A.; Sali, A.; Blobel, G.; Frank, J. Structure of the 80S ribosome from Saccharomyces cerevisiae--tRNA-ribosome and subunit-subunit interactions. Cell, 2001, 107(3), 373-386.
[] [PMID: 11701127]
Spahn, C.M.; Gomez-Lorenzo, M.G.; Grassucci, R.A.; Jørgensen, R.; Andersen, G.R.; Beckmann, R.; Penczek, P.A.; Ballesta, J.P.; Frank, J. Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation. EMBO J., 2004, 23(5), 1008-1019.
[] [PMID: 14976550]
Strahl, B.D.; Grant, P.A.; Briggs, S.D.; Sun, Z.W.; Bone, J.R.; Caldwell, J.A.; Mollah, S.; Cook, R.G.; Shabanowitz, J.; Hunt, D.F.; Allis, C.D. Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol. Cell. Biol., 2002, 22(5), 1298-1306.
[] [PMID: 11839797]
Tran, K.; Green, E.M. SET domains and stress: uncovering new functions for yeast Set4. Curr. Genet., 2018.
[PMID: 30523388]
Tran, K.; Jethmalani, Y.; Jaiswal, D.; Green, E.M. Set4 is a chromatin-associated protein, promotes survival during oxidative stress, and regulates stress response genes in yeast. J. Biol. Chem., 2018, 293(37), 14429-14443.
[] [PMID: 30082318]
van Leeuwen, F.; Gafken, P.R.; Gottschling, D.E. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell, 2002, 109(6), 745-756.
[] [PMID: 12086673]
Wang, K.; Zhou, Y.J.; Liu, H.; Cheng, K.; Mao, J.; Wang, F.; Liu, W.; Ye, M.; Zhao, Z.K.; Zou, H. Proteomic analysis of protein methylation in the yeast Saccharomyces cerevisiae. J. Proteomics, 2015, 114, 226-233.
[] [PMID: 25109467]
Webb, K.J.; Al-Hadid, Q.; Zurita-Lopez, C.I.; Young, B.D.; Lipson, R.S.; Clarke, S.G. The ribosomal l1 protuberance in yeast is methylated on a lysine residue catalyzed by a seven-beta-strand methyltransferase. J. Biol. Chem., 2011, 286(21), 18405-18413.
[] [PMID: 21460220]
Webb, K.J.; Laganowsky, A.; Whitelegge, J.P.; Clarke, S.G. Identification of two SET domain proteins required for methylation of lysine residues in yeast ribosomal protein Rpl42ab. J. Biol. Chem., 2008, 283(51), 35561-35568.
[] [PMID: 18957409]
Winter, D.L.; Abeygunawardena, D.; Hart-Smith, G.; Erce, M.A.; Wilkins, M.R. Lysine methylation modulates the protein-protein interactions of yeast cytochrome C Cyc1p. Proteomics, 2015, 15(13), 2166-2176.
[] [PMID: 25755154]
Winter, D.L.; Hart-Smith, G.; Wilkins, M.R. Characterization of Protein Methyltransferases Rkm1, Rkm4, Efm4, Efm7, Set5 and Hmt1 Reveals Extensive Post-Translational Modification. J. Mol. Biol., 2018, 430(1), 102-118.
[] [PMID: 29183786]
Zhang, K.; Lin, W.; Latham, J.A.; Riefler, G.M.; Schumacher, J.M.; Chan, C.; Tatchell, K.; Hawke, D.H.; Kobayashi, R.; Dent, S.Y. The Set1 methyltransferase opposes Ipl1 aurora kinase functions in chromosome segregation. Cell, 2005, 122(5), 723-734.
[] [PMID: 16143104]
Zhang, M.; Xu, J.Y.; Hu, H.; Ye, B.C.; Tan, M. Systematic Proteomic Analysis of Protein Methylation in Prokaryotes and Eukaryotes Revealed Distinct Substrate Specificity. Proteomics, 2018, 18(1)
[] [PMID: 29150981]
Zhang, X.; Huang, Y.; Shi, X. Emerging roles of lysine methylation on non-histone proteins. Cell. Mol. Life Sci., 2015, 72(22), 4257-4272.
[] [PMID: 26227335 ]

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