Bert L. SemlerProfessor, Microbiology & Molecular Genetics Associate Director, Center for Virus Research |
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Research Interests |
RNA virus gene expression; RNA-protein and protein-protein interactions; mechanisms of replication of picornavirus genomic RNAs; mechanisms of translation initiation for viral and cellular mRNAs | |
| URL | www.ucihs.uci.edu/microbio/ | |
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Academic Distinctions | American Cancer Society Postdoctoral Fellowship; NIH National Research Service Award; American Cancer Society Faculty Research Award; NIH Research Career Development Award; Athalie Clark Outstanding Research Award-UCI College of Medicine; ISI Highly Cited Researcher; Elected, Fellow of the American Academy of Microbiology | |
| Appointments | Postdoctoral Fellow, Department of Microbiology, State University of New York at Stony Brook, 1979-1983 | |
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Research Abstract |
Our research focuses on how picornaviruses (including poliovirus, human rhinovirus, and coxsackievirus) regulate the expression and replication of their genomic RNAs in infected human cells. We are investigating the mechanism of picornavirus translation initiation as directed by an internal ribosome entry site (IRES) in the 5’ noncoding region of viral genomic RNAs. We found that the translation initiation signals encoded in the IRES elements of picornavirus RNAs are comprised of specific RNA-RNA and RNA-protein interactions. In particular, the RNA-protein interactions provide signals important in the mechanism of cap-independent translation initiation of picornavirus mRNAs, signals that have counterparts in eukaryotic cellular translation of specific messenger RNAs that harbor internal ribosome entry sites. We are investigating the role of a cellular RNA binding protein (PCBP2) in translation initiation functions required by poliovirus, human rhinovirus, and coxsackievirus in an attempt to identify the precise step(s) in translation initiation in which PCBP2 functions. We have recently demonstrated that dimerization of PCBP2 and its interaction with a cellular mRNA splicing/shuttling factor (SRp20) are required steps in poliovirus translation initiation. Another research area is elucidation of the mechanisms involved in replicating picornavirus genomic RNAs during an infection of human cells. The initiation of viral RNA replication utilizes RNA-protein interactions between sequences present in viral RNAs and both viral and cellular polypeptides. Such interactions confer template specificity to the viral replication apparatus that allows synthesis of progeny RNAs from viral templates present among a myriad of cellular mRNAs in the cytoplasm of infected cells. Part of this template specificity is derived from the activity of picornavirus polypeptide 3CD, a viral replication protein known to recognize specific protein and RNA sequences as a prerequisite to carrying out its replication functions in initiation of viral RNA synthesis. Protein 3CD also interacts with at least one cellular protein to carry out these functions. Our research efforts are aimed at defining the protein interfaces of 3CD that generate an ordered sequence of events during the formation of active viral RNA replication complexes. Results from our studies should identify molecular targets for antiviral therapies as well as the nature of specific macromolecular interactions that regulate viral gene expression. A second research focus of our laboratory stems from our interest in IRES-mediated translation initiation mechanisms. These mechanisms are utilized by a limited number of cellular mRNAs whose functions may be required when normal cap-dependent translation is shut down (e.g., during mitosis or in cells undergoing physiological stress). One such mRNA encodes a murine voltage-gated potassium channel, Kv1.4. The specific mRNA for Kv1.4 is expressed in brain, heart, and skeletal muscle, and there appears to be translational regulation of its expression. In collaboration with George Gutman, we have shown that the long 5’ noncoding region of the Kv1.4 mRNA contains an IRES element capable of translation initiation by internal ribosome entry. We have mapped the RNA secondary structures of the downstream sequences of the 5’ noncoding region of this mRNA to identify RNA elements required for translation functions. Our research is currently focused on identification of RNA binding proteins that interact with the Kv1.4 IRES and facilitate non-canonical mechanisms of translation initiation. Results from our studies should provide insights into the mechanisms of internal ribosome entry used by specific viral and cellular mRNAs, mechanisms that will ultimately be crucial to our understanding of cellular growth control (and its loss in transformed cells) since key cellular regulatory proteins like c-myc, vascular endothelial growth factor, and fibroblast growth factor 2 are all produced from mRNAs harboring IRES elements in their 5’ noncoding regions. |
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| Publications | Jang, G. M., Leong, L. E.-C., Hoang, L. T., Wang, P. H., Gutman, G. A., and Semler, B. L. Structurally distinct elements mediate internal ribosome entry within the 5' noncoding region of a voltage-gated potassium channel mRNA. J. Biol. Chem. 279:47419-47430 (2004) | |
| Brunner, J. E., Nguyen, J. H. C., Roehl, H. H., Ho, T. V., Swiderek, K. M., and Semler, B. L. Functional interaction of hnRNP C with poliovirus RNA synthesis initiation complexes. J. Virol. 79:3254-3266 (2005) | ||
| Kuznetsov, Y. G., Daijogo, S., Zhou, J., Semler, B. L., and McPherson, A. Atomic force microscopy analysis of icosahedral virus RNA. J. Mol. Biol. 347:41-52 (2005) | ||
| Boerner, J. E., Lyle, J. M., Daijogo, S., Semler, B. L., Schultz, S. C., Kirkegaard, K., and Richards, O. C. Allosteric effects of ligands and mutations on poliovirus RNA-dependent RNA polymerase. J. Virol. 79:7803-7811 (2005) | ||
| Semler, B. L. Resistance is futile. Nat. Genet. 37:665-666 (2005) | ||
| Jimenez, J., Jang, G. M., Semler, B. L., and Waterman, M. L. An Internal ribosome entry site mediates translation of lymphoid enhancer factor-1. RNA 11:1385-1399 (2005) | ||
| Brown, D. M., Cornell, C. T, Tran, G. P., Nguyen, J. H. C., and Semler, B. L. An authentic 3’ noncoding region is necessary for efficient replication of poliovirus transcripts with non-viral terminal nucleotides. J. Virol. 79:11962-11973 (2005) | ||
| Bedard, K. M., Daijogo, S., and Semler, B. L. A nucleo-cytoplasmic SR protein functions in viral IRES-mediated translation initiation. EMBO J. 26:459-467 (2007) | ||
| Perera, R., Daijogo, S., Walter, B. L., Nguyen, J. H. C., and Semler, B. L. Cellular protein modification by poliovirus: the two faces of poly(rC)-binding protein. J. Virol. 81:8919-8932 (2007) | ||
| Jang, G. M., Tanaka, B. S., Gutman, G. A., Goldin, A. L., and Semler, B. L. Alternative polyadenylation signals in the 3' noncoding region of a voltage-gated potassium channel gene are major determinants of mRNA isoform expression. Gene 408:133-145 (2008) | ||
| Semler, B. L., and Waterman, M. L. IRES-mediated pathways to polysomes: nuclear versus cytoplasmic routes. Trends Microbiol. 16:1-5 (2008) | ||
| Semler, B. L., and Ertel, K. J. Picornaviridae: molecular biology, pp. 129-140. In: B. Mahy and M. Van Regenmortel, eds. Encyclopedia of Virology, 3rd edition, vol. 4. Elsevier Ltd., Oxford, U.K. (2008). | ||
| Sean, P., Nguyen, J. H. C., and Semler, B. L. The linker domain of poly(rC) binding protein 2 is a major determinant in poliovirus cap-independent translation. Virology 378:243-253 (2008). | ||
| Sean, P., and Semler, B. L. Coxsackievirus B RNA replication: lessons from poliovirus. Curr. Top. Microbiol. Immunol. 323:89-121 (2008). | ||
| Sean, P., Nguyen, J. H. C., and Semler, B. L. Altered interactions between stem-loop IV within the 5' noncoding region of coxsackievirus RNA and poly(rC) binding protein 2: effects on IRES-mediated translation and viral infectivity. Virology 389:45-58 (2009). | ||
| Fitzgerald, K. D., and Semler, B. L. Bridging IRES elements in mRNAs to the eukaryotic translation apparatus. Biochim. Biophys. Acta, doi:10.1016/j.bbagrm.2009.07.004 (2009). | ||
| Grants | National Institutes of Health, "Poliovirus Gene Function and Regulation," 7/1/04-6/30/10 (current funding period) | |
| National Institutes of Health, "Functions of 5' NCRs of Picornavirus and Cellular mRNAs," 7/1/09-12/31/14 (current funding period) | ||
| National Institutes of Health, “Molecular Biology of Eukaryotic Viruses,” T32 Pre-doctoral graduate student training grant, 9/01/08-8/31/13 (current funding period) | ||
| American Asthma Foundation, “Identification of a Novel Anti-viral Target for a Respiratory Tract Pathogen,” 7/1/08-6/30/2011 (current funding period) | ||
| National Institutes of Health, “Development of in vitro Assays to Study Flavivirus RNA Replication,” 5/1/09-4/30/10 (current funding period) | ||
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Professional Societies |
American Society for Microbiology American Society for Virology RNA Society |
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| Graduate Programs |
Cellular and Molecular Biosciences |
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| Research Center | Center for Virus Research | |
| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=2242 | |
| Last updated | 08/14/2009 | |