PHILIP J. FARABAUGH
Professor
Ph.D., Biochemistry, Harvard University, 1978
Postdoctoral, Genetics, Cornell University 1979–1981
Office
(410) 455-3018
Laboratory
(410) 455-2659
FAX
(410) 455-3875
Internet
Laboratory website
Research Interests
Gene regulation occurs at all stages of the information transfer process: during replication, transcription and translation, as well as the steps that occur between these fundamental processes. Our laboratory is interested in gene regulation occurring post-transcriptionally. Much of our recent work has concerned a process called programmed translational frameshifting, in which the process of protein synthesis is modified to allow expression of multiple alternative protein products from a single gene. More recently, we have become interested in how the protein synthetic machinery distinguishes correct from incorrect start sites for protein synthesis.
Errors in reading frame occur extremely rarely during translation, yet some genes have evolved sequences that efficiently induce frameshifting. These sequences, termed programmed frameshift sites, manipulate the translational apparatus to promote non-canonical decoding, and therefore provide tools to probe the mechanism by which the translational apparatus maintains frame during elongation. We study the mechanism of frameshifting in a lower eukaryote, the yeast Saccharomyces cerevisiae. Frameshifting occurs when the ribosome, the RNA•protein machine responsible for translating nucleic acid sequences into protein, changes the frame it uses in reading the 3 nucleotide mRNA sequences called codons that specify which amino acid should be inserted. Such a shift causes the ribosome to read the same RNA sequence but to produce a totally different protein product.
Viruses, transposable genetic elements and a few known cellular genes use this mechanism to encode alternative forms of proteins. We have studied a family of ttransposable elements in the yeast Saccharomyces cerevisiae, called Ty elements, that use programmed frameshifting. We find that Ty frameshifting occurs as part of a dual-error mechanism in which the ribosome first recruits the wrong tRNA to read an in-frame codon, and this errant tRNA then induces the ribosome to recognize the next codon in the shifted reading frame. We are actively engaged in determining the mechanism of this dual-error, and in finding the molecular factors which are responsible for its efficiency.
We have also found that phenotypic suppression of frameshift mutations which is caused by mutant tRNAs uses a similar mechanism. It has been thought that these mutant tRNAs cause the ribosome to shift its reading frame by recognizing an enlarged 4 nucleotide anticodon.
Translational frameshifting also has a clinical significance. It is used to express protein products from a class of eukaryotic viruses, including human immunodeficiency virus (HIV-1). The life-cycle of these viruses is critically dependent on this event, suggesting that it might be a useful target for antiviral therapy. Understanding the mechanism underlying these type of events should provide clues to how it might be subverted.
Our most recent work has established a connection between frameshift errors and errors during translational initiation. A sequence found in the Ty3 transposon termed the "context", which stimulates increased frameshifting, also stimulates errant initiation. Normally, yeast initiate protein synthesis nearly exclusively at the codon AUG, but under the influence of the context translation efficiently initiates at AUG or UUG codons. We are pursuing our analysis of this event. The context provides a tool to dissect the structures in the ribosome that regulate initiation codon selection.
Selected Publications:
Bidou, L., Stahl, G., Hatin, I., Namy, O., Rousset, J.-P. and Farabaugh, P. (2000). Nonsense-mediated decay mutants do not affect programmed -1 frameshifting. RNA 6, 952-961. (PDF)
Farabaugh, P., Qian, Q., and Stahl, G. (2000). Translational frameshifting and termination readthrough. In Translational Control. Mathews, M. B., Sonenberg, N., eds. (Cold Spring Harbor Press, Cold Spring Harbor, New York). pp. 741-762.
Farabaugh, P. J. (1999). Translational frameshifting: implications for the mechanism of translational frame maintenance. Progress in Nucleic Acid Research and Molecular Biology 64, 131-170.
Farabaugh, P. (1999). Translational Control and Fidelity. In Encylopedia of Microbiology, J. Lederberg, ed. (San Diego, CA: Academic Press).
Sundararajan, A., Michaud, W. A., Qian, Q., Stahl, G., and Farabaugh, P. J. (1999). Near-cognate peptidyl-tRNAs induce +1 programmed translational frameshifting in yeast. Mol. Cell 4, 1005-1015. (PDF)
Burck, C. L., Chernoff, Y. O., Liu, R., Farabaugh, P. J., and Liebman, S. W. (1999). Translational suppressors and antisuppressors alter the efficiency of the Ty1 programmed translational frameshift. RNA 5, 1451-1457. (PDF)
Farabaugh, P. J., and Bjork, G. R. (1999) How translational accuracy influences reading frame maintenance. EMBO J. 18, 1427-1434. (PDF)
Qian, Q., Li, J.N., Zhao, H., Hagervall, T., Farabaugh, P. and Björk, G. (1998) A new model for phenotypic suppression of frameshift mutations by mutant tRNAs. Molecular Cell, 1, 471-482. (PDF)
Farabaugh, P. and Vimaladithan, A. (1998) Effect of frameshift-inducing mutants of elongation factor 1-a on programmed +1 frameshifting in yeast. RNA, 4, 38-46. (PDF)
Vimaladithan, A., and Farabaugh, P. J. (1998). Identification and analysis of frameshift sites. Methods in Molecular Biology 77, 399-411.
Farabaugh, P. J. 1997. Programmed Alternative Reading of the Genetic Code (R. G. Landes Co., Austin, TX) pp.205 (ISBN # 0-412-13751-8) (Abstract)
Türkel, S., Liao, X. B., and Farabaugh, P. J. 1997. GCR1 dependent transcriptional activation of yeast retrotransposon Ty2-917. Yeast, 13:917-930. (Abstract)
Farabaugh, P. J. 1996. Programmed translational frameshifting. Annual Review of Genetics, 30:507-528 (PDF)
Farabaugh, P. J. 1996. Programmed translational frameshifting. Microbiological Reviews, 60:103-134 (Abstract)
Farabaugh, P. 1995. Post-transcriptional regulation of transposition by Ty retrotransposons of Saccharomyces cerevisiae. Journal of Biological Chemistry 270:10361-10364 (HTML)
Pande, S., Vimaladithan, A., Zhao, H., and Farabaugh, P. J. 1995. Pulling the ribosome out of frame +1 at a programmed frameshift site by cognate binding of aminoacyl-tRNA. Molecular and Cellular Biology 15:298-304 (Abstract)
Vimaladithan, A., and Farabaugh, P. J. 1994. Special peptidyl-tRNA molecules promote translational frameshifting without slippage. Molecular and Cellular Biology 14:8107-8116 (PDF)
Farabaugh, P.J. 1993. Alternative readings of the genetic code. Cell, 74:591-596
Farabaugh, P.J., Zhao, H., and Vimaladithan, A. 1993. A novel programed frameshift expresses the POL3 gene of retrotransposon Ty3 of yeast: frameshifting without tRNA slippage. Cell, 74: 93-103 (PDF)
Belcourt, M. F., Farabaugh, P. J. 1990. Ribosomal frameshifting in the yeast retrotransposon Ty: tRNAs induce slippage on a 7 nucleotide minimal site. Cell 62:339-352 (Abstract)
