Structure and Function of Nucleic Acid Binding Proteins
Chris received his Ph.D from the University of California at Santa Barbara in 1988. From 1989-1991, he carried out postdoctoral studies with Paul Schimmel, then at M.I.T. He joined the University of Vermont in 1991. He is currently Professor in the Department of Biochemistry, and Adjunct Professor in the Department of Microbiology and Molecular Genetics. Chris also serves as one of the three co-directors of the University of Vermont undergraduate program in Biochemistry.
The Role of Protein Synthesis Enzymes in Complex Human Diseases
Project Description: My research group has been investigating the biology of tRNA and aminoacyl-tRNA synthetases (ARSs) for over two decades. Among discoveries by the PI and the lab are: the first description of minimal tRNA substrates (mini- and microhelix); the characterization of identity elements in the tRNA acceptor stem; the discovery of mechanistic distinctions between class I and class II ARSs, including substrate assisted catalysis; the first characterizations of an aminoacyl-tRNA synthetase-like protein (HisZ) with a function distinct from aminoacylation; fundamental discoveries around ARS editing. In collaboration with investigators from Franklin and Marshall College, we are characterizing a mutant version of human histidyl-tRNA synthetase that is genetically linked to type IIIb Usher Syndrome. Secondly, in a collaborative project with Karen Lounsbury (Department of Pharmacology), we discovered a new function for threonyl-tRNA synthetase in angiogenesis and tumor metastasis. In additional to Dr. Lounsbury, we have recruited a broad team of researchers to investigate this problem, including experts in immunobiology (Matt Poynter, Department of Medicine), zebrafish (Alicia Ebert, Department of Biology), microRNAs (Jane Lian). Through these efforts, we will establish the role of TARS in tumor growth and metastasis, and explore its potential as a molecular biomarker for prostate cancer diagnosis.s.
Francklyn, C. & Schimmel, P. (1989) Aminoacylation of RNA Minihelices with Alanine. Nature 337: 478-481.
Francklyn, C. , Shi, J. P., & Schimmel, P. (1992) Overlapping Nucleotide Determinants for Specific Aminoacylation of RNA Microhelices with Three Different Amino Acids. Science. 255: 1121-1125.
Sankaranarayanan, R., Dock-Bregeon, A.-C, Rees, B., Bovee, M., Caillet, J., Romby, P., Francklyn, C. S., & Moras, D. (2000). Zinc mediated Amino Acid Discrimination by Threonyl-tRNA Synthetase. Nature Structural Biology. 7: 461-465.
Dock-Bregeon, A.-C., Sankaranarayan R., Romby, P., Caillet, J., Springer, M., Rees, B., Francklyn, C. S., Ehresmann, C., Moras, D. (2000) Transfer RNA mediated editing in the Class II Threonyl-tRNA Synthetase: The Class II Solution to the Double Discrimination Problem. Cell 103: 877-884.
Guth, E., Connolly, S.A, Bovee, M., & Francklyn, C.S. (2005) A substrate assisted concerted mechanism for aminoacylation of tRNAHis by histidyl-tRNA synthetase from Escherichia coli. Biochemistry. 44(10): 3785-3795.
Guth, E. & Francklyn, C.S. (2007) Kinetic Discrimination proofreading of tRNA identity by the conserved motif 2 loop of a class II aminoacyl-tRNA Synthetase. Molecular Cell 25:531-542.
Minajigi A, Francklyn CS. (2008) RNA-assisted catalysis in a protein enzyme: the 2´-hydroxyl of tRNA (Thr) promotes aminoacylation by threonyl-tRNA synthetase. Proc. Natl. Acad. Sci. U. S. A. 2008 Nov 18; 105 (46): 17748-53.
Minajigi A, Francklyn CS. (2010) Aminoacyl transfer rate dictates choice of editing pathway in threonyl-tRNA synthetase. J. Biol. Chem. Jul 30; 285(31): 23810-7.
Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, Cassidy RP, Fiorentini CJ, Heiken KF, Lawrence JJ, Mahoney MH, Miller CJ, Nair DT, Politi KA, Worcester KN, Setton RA, Dipiazza R, Sherman EA, Eastman JT, Francklyn C, Robey-Bond S, Rider NL, Gabriel S, Morton DH, Strauss KA (2012) Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. Epub 2012 Jan 17.
Williams TF, Mirando AC, Wilkinson, B, Francklyn C, Lounsbury KM. Secreted Threonyl-tRNA Synthetase Stimulates Endothelial Cell Migration and Angiogenesis. (2013) Scientific Reports. 3: 1317 DOI: 10.1.1038/srep01317.
Li L, Francklyn, C., Carter CW Jr. (2013) Aminoacylating Urzymes challenge the RNA world hypothesis. J. Biol. Chem. 288(37) 26856-63. PMID:23867455.
Photos By: Rajan Chawla, UVM Medical Photography
Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, Cassidy RP, Fiorentini CJ, Heiken KF, Lawrence JJ, Mahoney MH, Miller CJ, Nair DT, Politi KA, Worcester KN, Setton RA, Dipiazza R, Sherman EA, Eastman JT, Francklyn C , Robey-Bond S, Rider NL, Gabriel S, Morton DH, Strauss KA. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. Epub 2012 Jan 17
Farris M, Lague A, Manuelyan Z, Statnekov J, Francklyn C Altered nuclear cofactor switching in retinoic-resistant variants of the PML-RARα oncoprotein of acute promyelocytic leukemia. Proteins. 2012 Apr;80(4):1095-109. doi: 10.1002/prot.24010. Epub 2012 Jan 7.
Huang W, Bushnell EA, Francklyn CS , Gauld JW. The α-amino group of the threonine substrate as the general base during tRNA aminoacylation: a new version of substrate-assisted catalysis predicted by hybrid DFT. J Phys Chem A. 2011 Nov 17;115(45):13050-60. Epub 2011 Sep 26
Pasman Z, Robey-Bond S, Mirando AC, Smith GJ, Lague A, Francklyn CS. Substrate specificity and catalysis by the editing active site of Alanyl-tRNA synthetase from Escherichia coli. Biochemistry. 2011 Mar 8;50(9):1474-82. Epub 2011 Jan 31.
Minajigi A, Deng B, Francklyn CS .Fidelity escape by the unnatural amino acid β-hydroxynorvaline: an efficient substrate for Escherichia coli threonyl-tRNA synthetase with toxic effects on growth. Biochemistry. 2011 Feb 15;50(6):1101-9. Epub 2011 Jan 24.
Minajigi A, Francklyn CS . Aminoacyl transfer rate dictates choice of editing pathway in threonyl-tRNA synthetase. J Biol Chem. 2010 Jul 30;285(31):23810-7. Epub 2010 May 26.
Guth E, Farris M, Bovee M, Francklyn CS. Asymmetric amino acid activation by class II histidyl-tRNA synthetase from Escherichia coli. J Biol Chem. 2009 Jul 31;284(31):20753-62.
* indicates equal contribution
Novoa EM, Camacho N, Tor A, Wilkinson B, Moss S, Marín-García P, Azcárate IG, Bautista JM, Mirando AC, Francklyn CS, Varon S, Royo M, Cortés A, Ribas de Pouplana L (2014) Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo. Proc Natl Acad Sci U S A in press.
Wellman TL, Eckenstein M, Wong C, Rincon M, Ashikaga T, Mount SL, Francklyn CS, Lounsbury KM (2014) Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer. BMC Cancer 14: 620.
Abbott JA, Francklyn CS, Robey-Bond SM (2014) Transfer RNA and human disease. Front Genet 5: 158.
Farina NH, Wood ME, Perrapato SD, Francklyn CS, Stein GS, Stein JL, Lian JB (2014) Standardizing analysis of circulating microRNA: clinical and biological relevance. J Cell Biochem 115(5): 805-11.
Williams TF, Mirando AC, Wilkinson B, Francklyn CS, Lounsbury KM (2013) Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. Sci Rep 3: 1317.
Huang W, Bushnell EA, Francklyn CS, Gauld JW (2011) The α-amino group of the threonine substrate as the general base during tRNA aminoacylation: a new version of substrate-assisted catalysis predicted by hybrid DFT. J Phys Chem A 115(45): 13050-60.
Pasman Z, Robey-Bond S, Mirando AC, Smith GJ, Lague A, Francklyn CS (2011) Substrate specificity and catalysis by the editing active site of Alanyl-tRNA synthetase from Escherichia coli. Biochemistry 50(9): 1474-82.
J. Walter Juckett Scholar Award (1995)
College of Medicine Faculty Development Award (College of Medicine Faculty Development Award)
Co-Organizer and Chair, Aminoacyl-tRNA Synthetases Symposium (2002)
Standing Member, NIH Biochemistry Study Section (2002-2004)
Chair, Molecular Genetics A Study Section, NIH (2005-2006)
Editorial Board, Journal of Biological Chemistry (2006-2010)
Department of Biochemistry
Office: B401 Given
Lab: Given B403
Jamie Abbott, Biochem Grad Student
Astrid Hedbor-Lague, Research Technician
Adam Mirando, Biochem Grad Student
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