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Thomas Jefferson University - Ya-ming Hou, PhD
Ya-ming Hou, PhD

Biochemistry & Molecular Biology
Thomas Jefferson University
Jefferson Medical College
Department of Biochemistry & Molecular Pharmacology
Professor
Ph.D., University of California, Berkeley, 1986

Mailing Address
233 South 10th Street, 220 BLSB
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-503-4480
Fax: 215-503-5393
Ya-Ming.Hou@jefferson.edu
Personal Web Site
Qualifications
B.S.,

M.A.,

Ph.D.
Expertise and Research Interests
We are interested in the specificity of translation of the genetic code, focusing on the questions of how tRNAs are synthesized, matured, modified, aminoacylated, and function on the ribosome.

The tRNA molecules are essential for the specificity of decoding, which is the key determinant in the speed and quality of cell growth. Elevated levels of tRNAs can lead to cancer, while deficiency in tRNAs can lead to cell toxicity.

How are tRNAs synthesized and matured? How are they selectively charged with amino acids? How do they enter the ribosome, and how does their dynamics affect the decoding specificity? These questions have direct implications on diseases and origins of life.

The central aim of our research is to investigate the above questions at the fundamental level: what does it take to achieve the specificity of tRNA at each step of decoding? To address this fundamental question, we focus on the following enzymes: (1) the m1G37 methyl transferase, which synthesizes the m1G37 modification that is essential for the specificity of decoding, (2) the CCA-adding enzyme, which adds the CCA sequence to the tRNA 3' end to synthesize the mature tRNA, (3) aminoacyl-tRNA synthetases, which catalyze addition of an amino acid to each tRNA to synthesize the charged aminoacyl-tRNAs, and (4) the ribosome, which uses the charged aminoacyl-tRNAs as the substrates for protein synthesis.

To address these fundamental questions at the mechanistic level, we have developed a variety of methods, including biochemical, structural, kinetic, and genetic approaches. We focus on one representative enzyme in each case and build a framework of information by examining the enzyme in the larger biological context. Because tRNAs are ancient and enzymes that interact and recognize tRNAs are also ancient, we have a large database to search for related and homologous enzymes in evolution.

Our research provides the basis to gain biochemical, structural, and bioinformatic insights into tRNAs in evolution. These insights are important for understanding the origins of the genetic code and for developing new strategies for drug targeting against diseases arising from errors of tRNA functions.




Laboratory Staff
Keywords
Biochemistry; Biophysics; Developmental Biology; Genetics; transfer RNA; RNA modification; RNA repair; RNA maturation; Ribosome; Protein Synthesis; Antibiotics; Aminoacyl-tRNA Synthetase; Gene Expression; Bacterial Pathogenesis; Suppressor Mutation; Nucleic Acid Structure/Function; Pseudo-Complementary Nucleic Acid; Genetic Code; Protein Design
Languages
English
Chinese
Publications
  • Liu, C, Sanders, JM, Pascal, JM, Hou, YM. (2011) Adaptation to tRNA acceptor stem structure by flexible adjustment in the catalytic domain of class I tRNA synthetases. RNA, in revision.
  • Frenkel-Morgenstern, M, Danon, T, Christian, T, Igarashi, I, Cohen, L, Hou, YM, Jensen, LJ. (2011) Genes adopt non-optimal codon usage to generate cell-cycle-dependent oscillations in protein levels. Molecular Systems Biology, in revision.
  • McLaughlin, HM, Sakaguchi, R, Giblin, W, Wilson, TE, Biesecker, L, Lupski, JR, Talbot, K, Vance, JM, Zuchner, S, Lee, YC, Kennerson, M, Hou, YM, Nicholson, G, Antonellis, A. (2011) A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with dominant axonal Charcot-Marie-Tooth disease. Human Mutations, in press.
  • Silver, HR, Nissley, JA, Reed, SH, Hou, YM, Johnson, ES. (2011) A role for SUMO in nucleotide excision repair. DNA repair, in press.
  • Igarashi, T, Liu, C, Morinaga, H, Kim, S, Hou, YM. (2011) Pyrophosphorolysis of CCA addition: Implication for fidelity. J. Mol. Biol., in press.
  • Ghosh, A, Sakaguchi, R, Liu, C, Vishveshwara S, Hou, YM. (2011) Allosteric communication in cysteinyl-tRNA synthetase: A network of direct and indirect readout. J. Biol. Chem 286, 37721-37731.
  • Lahoud, G, Goto-Ito, S, Yoshida, KI, Ito, T, Yokoyama, S, Hou, YM. (2011) Differentiating analogous tRNA methyltransferases by fragments of the methyl donor. RNA 17, 1236-1246.
  • Liu, C, Gamper, H, Liu, H, Cooperman, BS, Hou, YM. (2011) Potential for interdependent development of tRNA determinants for aminoacylation and ribosome decoding. Nat. Commun. 2:329 doi: 10.1038/ncomms1331.
  • Christian, T, Lahoud, G, Liu, C, Hoffmann, K, Perona, JJ, Hou, YM. (2010) Mechanism of N-methylation by the tRNA m1G37 methyltransferase Trm5. RNA. 16, 2484-2492.
  • Lahouds, G, Hou, YM. (2010) Biosynthesis: A new (old) way of hijacking tRNA. Nature Chem Biol. 6, 795-796.
  • McLaughlin, HM, Sakaguchi, R, Liu, C, Igarashi, T, Chu, K, Lyer, R, Cruz, P, Cherukuri, PF, Hansen, NF, Mullikin, JC, NISC Comparative Sequencing Program, Biesecker, LG, Wilson, TE, Ionasescu, V, Nicholson, G, Searby, C, Talbot, K, Vance, JM, Zuchner, S, Szigeti, K, Lupski, JR, Hou, YM, Green, ED, Antonellis, A. (2010) Compound heterozygosity for loss-of-function lysyl-tRNA synthetase (KARS) mutations in a patient with peripheral neuropathy. J.Am Hum Genetics 87, 560-566.
  • Mei, Y, Stonestrom, A, Hou, YM, Yang, X. (2010) Apoptotic regulation and transfer RNA. Protein & Cell, 1, 795-801.
  • Christian, T, Lahoud, G, Liu, C, Hou, YM. (2010) Control of catalytic cycle by a pair of analogous tRNA modification enzymes. J. Mol. Biol. 400, 204-217.
  • Hou, YM. (2010) CCA addition to tRNA: Implications for tRNA quality control. IUBMB Life 62, 251-260.
  • Hou, YM, Perona, JJ. (2010) Stereochmical mechanisms of tRNA methyltransferases. FEBS Lett 584, 278-286.
  • Liu, C, Betteridge, T, Hou, YM. (2009) Fluorophore labeling to monitor tRNA dynamics. Methods in Enzymology (Editor Herschlag, D, Academic Press) 469, 69-93.
  • Kim, S, Liu, CP, Halkidis, K, Gamper, H, Hou, YM. (2009) Distinct kinetic determinants for the stepwise CCA addition to tRNA. RNA 15, 1827-1836.
  • Liu, X, Silks, LA, Liu, C, Ollivault-Shiflett, M, Huang, X, Li, J, Wang, Y, Yu, H, Hou, YM, Liu, J, Shen, J. (2009) Incorporation of tellurocysteine into glutathione transferase installs high glutathione peroxidase efficiency. Angew Chem Int Ed Engl 48, 2020-2023.
  • Macauley, SR, Zimmerman, SA, Apolinario, EE, Evilia, C, Hou, YM, Ferry, JG, Sowers, KR. (2009) The archetype gamma-class carbonic anhydrase (Cam) contains iron when synthesized in vivo. Biochemistry 48, 817-819.
  • Lahoud, G, Timoshchuk, V, Levedev, A, Arar, K, Hou, YM, Gamper, H. (2008) Properties of pseudo-complementary DNA substituted with weakly pairing analogs of guanine or cytosine. Nucleic Acids Res 36, 6999-7008.
  • Lahoud, G, Arar, K, Hou, YM, Gamper, H. (2008) RecA mediated DNA strand invasion by pseudo-complementary oligonucleotides. Nucleic Acids Res 36, 6806-6815.
  • Zhang, CM, Liu, C, Christian, T, Gamper, H, Rosenski, J, Pan, D, Randolph, JB, Wickstrom, E, Cooperman, BS, Hou, YM. (2008) Pyrrolo-C as a molecular probe for monitoring conformations of the tRNA 3' end. RNA 44, 2245-2253.
  • Hauenstein, SI, Hou, YM, Perona, JJ. (2008) The homotetrameric phosphoseryl-tRNA synthetase from Methanosarcina mazei exhibits half-of-the-sites activity. J Biol Chem 283, 21997-22006.
  • Pan, D, Zhang, CM, Kirillov, S, Hou, YM, Cooperman, BS. (2008) The tRNA tertiary core differentially modulates specific steps of the elongation cycle. J. Biol. Chem. 283, 18431-18440.
  • Lahoud, G, Timoshchuk, V, Lebedev, A, de Vega M, Salas, M, Arar, K, Hou, YM, Gamper, H. (2008) Enzymatic synthesis of structure-free DNA with pseudo-complementary properties. Nucleic Acids Res, 36, 3409-3419.
  • Dupasquier, M, Kim, S, Halkidis, K, Gamper, H, Hou, YM. (2008) tRNA integrity is a prerequisite for rapid CCA addition: Implication for quality control. J. Mol. Biol. 379, 579-588.
  • Zhang, CM, Liu, C, Slater, S, Hou, YM. (2008) Aminoacylation of tRNA with phosphoserine for synthesis of cysteinyl-tRNACys. Nat Struc Mol Biol. 15, 507-514.
  • Francklyn, CS, First, EA, Perona, JJ, Hou, YM. (2008) Methods for kinetic and thermodynamic analysis of aminoacyl-tRNA synthetases. Methods 44, 100-118.
  • Perona, JJ, Hou, YM. (2007) Indirect readout of tRNA for aminoacylation. Biochemistry 46, 10419-10432, invited review. (Selected as a Hot Article by ACS.)
  • Christian, T, Hou, YM. (2007) Distinct determinants of tRNA recognition by the TrmD and Trm5 methyl transferases. J. Mol. Biol. 373, 623-632.
  • Betteridge, T, Liu, H, Gamper, H, Kirillov, S, Cooperman, BS, Hou, YM. (2007) Fluorescent labeling of tRNAs for dynamic experiments. RNA 13, 1594-1601.
  • Liu, C, Gamper, H, Shtivelband, S, Hauenstein, S, Perona, JJ, Hou, YM. (2007) Kinetic quality control of anticodon recognition by a eukaryotic aminoacyl-tRNA synthetase. J. Mol. Biol, 367, 1063-1078.
  • Zhang, CM, Perona, JJ, Ryu, K, Francklyn, C, Hou, YM. (2006) Distinct kinetic mechanisms of the two classes of aminoacyl-tRNA synthetases. J. Molecular Biology, 361, 300-311.
  • Christian T, Evilia, C, Hou, YM. (2006) Catalysis by the second class of tRNA (m1G37) methyl transferase requires a conserved proline. Biochemistry 45, 7463-7473.
  • Gamper, HB, Arar, K, Gewirtz, Hou, YM. (2006) Unrestricted hybridization of oligonucleotides to structure-free DNA. Biochemistry 45, 6978-6986.
  • Evilia, C, Hou, YM. (2006) Acquisition of an insertion peptide for efficient aminoacylation by a halophile tRNA synthetase. Biochemistry 45, 6835-6845.
  • Pan, D, Kirillov, S, Zhang, CM, Hou, YM, Cooperman, BS. (2006) Rapid ribosomal translocation depends on the conserved 18-55 base pair in P-site transfer RNA. Nature Structural and Molecular Biology 13, 354-359.
  • Hou, YM, Li, Z, Gamper, H. (2006) Isolation of a site-specifically modified RNA from an unmodified transcript. Nucleic Acids Res. 34, e21.
  • Hou, YM, Gu, SQ, Zhou, HP, Ingerman, L. (2005) Metal-ion dependent catalysis and specificity of CCA-adding enzyme: A comparison of two classes. Biochemistry 44, 12849-12859.
  • Gamper, HB, Arar, K, Gewirtz, A, Hou, YM. (2005) Unrestricted accessibility of short oligonucleotides to RNA, RNA 11, 1441-1447.
  • Shitivelband, S, Hou, YM. (2005) Breaking the stereo barrier of amino acid attachment to tRNA by a single nucleotide, J. Mol. Biol, 348, 513-521.
  • Zhang, CM, Hou, YM. (2005) Domain-domain communication for tRNA aminoacylation: The importance of covalent connectivity, Biochemistry 44, 7240-7249.
  • Hauenstein, S, Zhang, CM, Hou, YM,Perona, JJ. (2004) Shape-selective RNA recognition by cysteinyl-tRNA synthetase. Nature Structural and Molecular Biology 11, 1134-1141.
  • Ougland, R, Zhang, CM, Johansen, RF, Seeberg, E, Hou, YM, Remme, J, Falnes, PO. (2004) AlkB mediated repair restores the biological activity of chemically methylated mRNA and tRNA. Mol Cell 16, 107-116.
  • Gamper, HB, Gewirtz, A, Hou, YM. (2004) Modified bases in RNA reduce secondary structure and enhance hybridization. Biochemistry 43, 10224-10236.
  • Zhang, CM, Hou, YM. (2004) Synthesis of cysteinyl-tRNACys by a prolyl-tRNA synthetase, RNA Biology 1, 35-41.
  • Christian, T, Evilia, C, Williams, S, Hou, YM. (2004) Distinct origins of tRNA(m1G37) methyl transferase, J. Mol. Biol 339, 707-719.
  • Zhang, CM, Christian, T, Newberry, KJ, Perona, JJ, Hou, YM. (2003) Zinc mediated amino acid discrimination in cysteinyl-tRNA synthetase, J. Mol. Biol., 327, 911-917.
  • Evilia, C, Ming, XT, DasSarma, S, Hou, YM. (2003) Aminoacylation of an unusual tRNA from an extreme halophile, RNA 9, 794-801.
  • Lipman, RSA, Chen, J, Evilia, C, Vitseva, O, Hou, YM. (2003) Association of an aminoacyl-tRNA synthetase with a metabolic protein in archaea, Biochemistry 42, 7487-96.
  • Rajanna, C, Wang, J, Zhang, D, Xu, Z, Ali, A, Hou, YM, Karaolis, DKR. (2003) The Vibrio pathogenicity island forms precise extrachromosomal circular excision products, J. Bacteriology 185, 6893-6901.
  • Zhang, CM, Newberry, KJ, Perona, JJ, Hou, YM. (2003) Amino acid discrimination by a highly differentiated metal center of an aminoacyl-tRNA synthetase, Biochemistry 42, 10931-10937.
  • Ming, XT, Smith, K, Suga, H, Hou, YM. (2002) Recognition of tRNA backbone for aminoacylation with cysteine: Evolution from E. coli to human, J. Mol. Biol. 318, 1207-1220.
  • Francklyn, C, Perona, JJ, Putz, J, Hou, YM. (2002) Aminoacyl-tRNA synthetases: versatile players in the changing theater of translation, RNA 8, 1363-1372.
  • Lipman, RSA, Wang, JL, Sowers, KR, Hou, YM. (2002) Prevention of mis-aminoacylation of a dual-specificity aminoacyl-tRNA synthetase, J. Mol. Biol. 315, 943-949.
  • Lipman, RSA, Beuning, PJ, Musier-Forsyth, Hou, YM. (2002) Amino acid activation of a dual-specificity tRNA synthetase is independent of tRNA, J. Mol. Biol. 316, 421-427.
  • Seth, M, Thurlow, DL, Hou, YM. (2002) Poly(C) synthesis by class I and class II CCA-adding enzymes, Biochemistry 41, 4521-4532.
  • Newberry, KJ, Hou, YM, Perona, JJ. (2002) Structural origins of amino acid selection without editing by cysteinyl-tRNA synthetase, EMBO J. 21, 2778-2787.
  • Hou, YM. (2002) Base pairing in RNA: Unusual patterns, Encyclopedia of Life Sciences, http://www.els.net. London: Nature Publishing Group.
  • Hou, YM, Zhang, XL, Holland, JA, Davis, DR. (2001) An important 2-OH group for an RNA-protein interaction, Nucleic Acids Res 29, 976-985.
  • Davidson, E, Caffarella, J, Vitseva, O, Hou, YM, King, MP. (2001) Isolation of two cDNAs encoding functional human cytoplasmic cysteinyl-tRNA synthetase, Biological Chemistry 382, 399-406.
  • Burke, B, Lipman, RSA, Shiba, K, Musier-Forsyth, K, Hou, YM. (2001) Divergent adaptation of recognition of tRNAPro by Methanococcus jannaschii prolyl-tRNA synthetase, J. Biol. Chem. 276, 20286-20291.
  • Tardif, K, Liu, MS, Vitseva, O, Hou, YM, and Horowitz, J. (2001) Misacylation by E. coli valyl-tRNA synthetase: Evidence for two tRNA binding sites, Biochemistry 40, 8118-8125.
  • Hamann, CS, Hou, YM. (2000) Probing a tRNA core that contributes to aminoacylation, J. Mol. Biol. 295, 777-789.
  • Sherlin, LD, Bullock, TL, Newberry, KJ, Lipman, RSA, Hou, YM, Beijer, B, Sproat, BS, Perona, JJ. (2000) Influence of transfer RNA tertiary structure on aminoacylation efficiency by glutaminyl and cysteinyl-tRNA synthetases, J. Mol. Biol. 299, 431-446.
  • Madore, E, Lipman, RSA, Hou, YM, Lapointe J. (2000) Evidence for unfolding of the single-stranded GCCA 3'-end of a tRNA on its aminoacyl-tRNA synthetase from a stacked helical to a fold-back conformation, Biochemistry 39, 6791-6798.
  • Lipman, RSA, Sowers, KR, Hou, YM. (2000) Synthesis of cysteinyl-tRNACys by a genome that lacks the normal cysteine-tRNA synthetase, Biochemistry 39, 7792-7798.
  • Hou, YM, Sundaram, M, Zhang, XL, Holland, JA, Davis, DR. (2000) Recognition of functional groups in an RNA helix by a class I tRNA synthetase, RNA 6, 922-927.
  • Hou, YM. (2000) Unusual synthesis by the E. coli CCA-adding enzyme, RNA 6, 1031-1043.
  • Christian, T, Lipman, RSA, Evilia, C, Hou, YM. (2000) Alternative design of a tRNA core for aminoacylation, J. Mol. Biol. 303, 503-514.
  • Gamper, HB, Hou, YM, Kmiec. (2000) Evidence for a four-strand exchange catalyzed by the recA protein, Biochemistry 39, 15272-15281.
  • Newberry, KJ, Kohn, J, Hou, YM, Perona, JJ. (1999) Crystallization and preliminary diffraction analysis of Escherichia coli cysteinyl-tRNA synthetase, Acta Cryst. D. D55, 1046-1047.
  • Hou, YM. (1999) Transfer RNAs and pathogenicity islands, Trends in Biochemical Sciences 24, 295-298.
  • Hamann, CS, Sowers, KR, Lipman, RSA, Hou, YM. (1999) An archaeal aminoacyl-tRNA synthetase missing from genomic analysis, J. Bacteriology 181, 5880-5884.
  • Holland, JA, Hou, YM, Davis, DR. (1999) NMR structural studies of the tRNACys amino acceptor stem of Mycoplasma pneumonia, Nucleic Acids Sym Series 41, 101-103.
  • Hou, YM. (1999) Contribution of a tRNA core to aminoacylation: the role of a proposed adenosine base triple in aminoacylation with cysteine, Nucleic Acids Sym.Series 41, 208-210.
  • Hou, YM. (1999) Contribution of a tRNA core to aminoacylation: the role of a proposed adenosine base triple in aminoacylation with cysteine, Nucleic Acids Sym.Series 41, 208-210.
  • Gamper, HB, Hou, YM, Stamm, MR, Podyminogin, MA, Meyer, RB. (1998) Targeted D-loop formation in supercoiled DNA by chimeric oligonucleotides,J. Am. Chem. Society 120, 2128-2183.
  • Hou, YM, Lipman, RSA, Zarutskie, JA. (1998) A tRNA circularization assay: Evidence for the variation of the conformation of the CCA end, RNA 4, 733-738.
  • Lipman, RSA, Hou, YM. (1998) Aminoacylation of tRNA in the evolution of an aminoacyl-tRNA synthetase, Proc. Natl. Acad. Sci. USA. 95, 13495-13500.
  • Hou, YM. (1997) Discriminating among the discriminator bases of tRNAs, Chem& Biol 4, 93-96.
  • Hamann, CS, Hou, YM. (1997) An RNA structural determinant for tRNA recognition, Biochemistry, 36, 7967-7972.
  • Hamann, CS, Hou, YM. (1997) A strategy of tRNA recognition that includes determinants of RNA structure, Bioorganic & Medicinal Chemistry 5, 1011-1019.
  • Ohannesian, DW, Oh, J, Hou, YM. (1996) Mutational analysis of a leucine heptad repeat motif in a class I tRNA synthetase, Biochemistry 35, 14405-14412.
  • Hou, YM, Gamper, H. (1996) Inhibition of tRNA aminoacylation by 2'-O-methyl oligonucleotides, Biochemistry 35, 15340-15348.
  • Hou, YM, Sterner, T, Jansen, M. (1995) Permutation of a pair of tertiary nucleotides in a transfer RNA, Biochemistry 34, 2978-2984.
  • Hamann, CS, Hou, YM. (1995) Enzymatic aminoacylation of tRNA acceptor stem helices with cysteine is dependent on a single nucleotide, Biochemistry 34, 6527-6532.
  • Hou, YM. (1995) RNA recognition based on a pair of tertiary hydrogen interaction, Nucleic Acids Research Symposia Series 33, 172-175.
  • Hou, YM, Sterner, T, Bhalla, R. (1995) Evidence for a conserved relationship between an acceptor stem and a tRNA in aminoacylation, RNA 1, 707-713.
  • Sterner, T, Jansen, M, Hou, YM. (1995) Structural and functional accommodation of nucleotide variations at a conserved tRNA tertiary base pair, RNA 1, 841-851.
  • Hou, YM. (1994) Structural elements that contribute to an unusual tertiary interaction in a transfer RNA, Biochemistry 33, 4677-4683.
  • Hou, YM, Westhof, E, GiegĂ©, R. (1993) An unusual RNA tertiary interaction has a role for the specific aminoacylation of a transfer RNA, Proc. Natl. Acad. Sci. USA. 90, 6776-6780.
  • Hou, YM. (1993) The tertiary structure of tRNA and the development of the genetic code, Trends In Biochemistry Sciences. 18, 362-364.
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