Bert L. Semler

Ph.D., University of California, San Diego, 1979

University of California, Irvine
Medical Sciences I, B237
Irvine, CA 92697-4025
(949) 824-7573
blsemler@uci.edu

UCI Faculty Profile: Bert L. Semler

Research Interests:

RNA virus gene expression; RNA-protein and protein-protein interactions; mechanisms of replication of picornavirus genomic RNAs.

Our research focuses on how RNA viruses regulate the expression of their genetic information in infected mammalian cells. The viruses under investigation are picornaviruses, which include poliovirus, human rhinovirus, hepatitis A virus, and others. 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 have generated site-directed mutations of genomic RNAs by in vitro manipulation of infectious cDNAs and have carried out RNA structure probing of stem-loop structures within the poliovirus IRES. We found that the translation initiation signals encoded in the 5' noncoding region of picornavirus RNAs are comprised of specific RNA-RNA and RNA-protein interactions. In particular, the RNA-protein interactions form signals important in the mechanism of cap-independent translation initiation of picornavirus mRNAs, signals that may 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 (known as PCBP2) in translation initiation functions required by poliovirus and other picornaviruses (e.g., human rhinovirus and coxsackievirus) in an attempt to identify the precise step(s) in translation initiation in which PCBP2 functions. Another focus of our research is elucidation of the mechanisms involved in replicating poliovirus and rhinovirus genomic RNAs during an infection of human cells. Such mechanisms are of interest because picornaviruses employ covalent linkages between viral proteins and newly-synthesized viral RNAs to effect the efficient replication of their genetic information. The initiation of viral RNA replication appears to also utilize RNA-protein interactions between sequences present in the termini of viral RNAs and both viral and cellular polypeptides. These interactions must confer template specificity to the viral replication apparatus that allows synthesis of progeny RNAs from defined templates present among a myriad of cellular mRNAs in the cytoplasm of infected cells. We are also studying the role of poliovirus polypeptide 3CD in both proteolytic cleavage and RNA replication. This protein is a key player in the picornavirus life cycle since it recognizes specific protein and RNA sequences as a prerequisite to carrying out its molecular functions. Protein 3CD also interacts independently with two cellular proteins to augment its functions in protein processing and viral RNA replication. Results from our studies should identify molecular targets for antiviral chemotherapy and will ultimately reveal the nature of specific macromolecular interactions that regulate viral and cellular gene expression.

Selected Publications:

Bedard, K. M., and Semler, B. L. Regulation of picornavirus gene expression. Microbes Infect. 6:702-713 (2004).

Semler, B. L. Poliovirus proves IRES-istible in vivo. J. Clin. Invest. 113:1678-1681 (2004).

Bedard, K. M., Walter, B.L., and Semler, B. L. Multimerization of poly(rC) binding protein 2 is required for translation initiation mediated by a viral IRES. RNA 10:1266-1276 (2004).

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).

Cornell, C. T., Brunner, J. E., and Semler, B. L. Differential rescue of poliovirus RNA replication functions by genetically-modified RNA polymerase precursors. J. Virol. 78:13007-13018 (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).

List of Publications via PubMed (NIH National Library of Medicine)