Research: tRNA in Translation and Protein Synthesis
Structure and Function of Nucleic Acid Binding Proteins
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.