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Biochemistry Department - Primary Faculty

Dr. William C. Merrick, Ph.D.

Professor

Education

  • Ph.D.: University of Georgia, Athens, GA (Dr. Leon Dure III)
  • Postdoc: NHI, NIH Bethesda, MD (Dr. French Anderson)

Research Interests

The research goal of this laboratory is to identify all of the eukaryotic translation initiation factors and determine their sequential utilization in the initiation pathway. A secondary goal is to characterize how the initiation pathway is regulated and the different consequences depending on the exact point of regulation.

Current research is focusing on two major aspects of translation initiation, cap-dependent and cap-independent (or internal) initiation. Although much of the gross work has been determined using hemoglobin mRNA as a model mRNA, it has become clear that other elements influence both the regulation and mechanism of translation initiation in mammalian systems. Within the realm of cap-dependent translation, we are examining the influence of individual initiation factors on both overall affect on translation initiation and the affect of increased or decreased levels of initiation factors on start site selection in mRNAs containing in frame start sites which yield two proteins, one with a slightly longer N-terminal region than the other.

At the same time, we are also examining more closely the interaction of the mRNA specific initiation factors (eIF4A, eIF4B, eIF4F, eIF4H) with RNA. Both the characteristics of ideal RNAs for binding to the factors and ideal duplexes for unwinding are being examined.

As companion studies, yeast are being used to assess in vivo function of elements that influence internal initiation. Previous work has defined the Ure2p IRES (internal ribosome entry site) and has shown that IRES-mediated expression is specifically inhibited by the presence of eIF2A. We are currently trying to identify the minimal IRES element based upon the Ure2p IRES and determine how eIF2A regulates internal initiation. Preliminary data suggest that the regulation by eIF2A is controlled by both the amount of protein and by post-translational modification.

Selected References

  • Dmitriev S. E., Terenin I. M., Andreev D. E., Ivanov P. A., Dunaevsky J. E., Merrick W. C., and Shatsky I. N.
    “GTP-independent tRNA delivery to the ribosomal P-site by a novel eukaryotic translation factor”
    J Biol Chem 285 (35): 26779-87 (2010). Read article in PubMedCentral
  • Merrick W. C.
    “Eukaryotic protein synthesis: still a mystery”
    J Biol Chem 285 (28): 21197-201 (2010). Read article in PubMedCentral
  • Andreev D. E., Dmitriev S. E., Terenin I. M., Prassolov V. S., Merrick W. C., and Shatsky I. N.
    “Differential contribution of the m7G-cap to the 5' end-dependent translation initiation of mammalian mRNAs”
    Nucleic Acids Res 37 (18): 6135-47 (2009). Read article in PubMedCentral
  • Kaye N. M., Emmett K. J., Merrick W. C., and Jankowsky E.
    “Intrinsic RNA binding by the eukaryotic initiation factor 4F depends on a minimal RNA length but not on the m7G cap”
    J Biol Chem 284 (26): 17742-50 (2009). Read article in PubMedCentral
  • Reineke L. C. and Merrick W. C.
    “Characterization of the functional role of nucleotides within the URE2 IRES element and the requirements for eIF2A-mediated repression”
    RNA 15 (12): 2264-77 (2009). Read article in PubMedCentral
  • Svitkin Y. V., Evdokimova V. M., Brasey A., Pestova T. V., Fantus D., Yanagiya A., Imataka H., Skabkin M. A., Ovchinnikov L. P., Merrick W. C., and Sonenberg N.
    “General RNA-binding proteins have a function in poly(A)-binding protein-dependent translation”
    EMBO J 28 (1): 58-68 (2009). Read article in PubMedCentral
  • Reineke L. C., Komar A. A., Caprara M. G., and Merrick W. C.
    “A small stem loop element directs internal initiation of the URE2 internal ribosome entry site in Saccharomyces cerevisiae”
    J Biol Chem 283 (27): 19011-25 (2008). Read article in PubMedCentral
  • Zeenko V. V., Wang C., Majumder M., Komar A. A., Snider M. D., Merrick W. C., Kaufman R. J., and Hatzoglou M.
    “An efficient in vitro translation system from mammalian cells lacking the translational inhibition caused by eIF2 phosphorylation”
    RNA 14 (3): 593-602 (2008). Read article in PubMedCentral
  • Dmitriev S. E., Andreev D. E., Terenin I. M., Olovnikov I. A., Prassolov V. S., Merrick W. C., and Shatsky I. N.
    “Efficient translation initiation directed by the 900-nucleotide-long and GC-rich 5' untranslated region of the human retrotransposon LINE-1 mRNA is strictly cap dependent rather than internal ribosome entry site mediated”
    Mol Cell Biol 27 (13): 4685-97 (2007). Read article in PubMedCentral
  • Mathonnet G., Fabian M. R., Svitkin Y. V., Parsyan A., Huck L., Murata T., Biffo S., Merrick W. C., Darzynkiewicz E., Pillai R. S., Filipowicz W., Duchaine T. F., and Sonenberg N.
    “MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F”
    Science 317 (5845): 1764-7 (2007).
  • Elroy-Stein, O. and Merrick, W. C.
    “Translation initiation by cellular internal ribosome entry sites.”
    in Translational control in biology and medicine
    (ed. N. Sonenberg, J. W. H. Hershey and M. Matthews), Cold Spring Harbor Press, Cold Spring Harbor, New York, pages 155-172, (2007)
  • Robert F., Kapp L. D., Khan S. N., Acker M. G., Kolitz S., Kazemi S., Kaufman R. J., Merrick W. C., Koromilas A. E., Lorsch J. R., and Pelletier J.
    “Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2.GTP.Met-tRNA(i)(Met) ternary complex availability”
    Mol Biol Cell 17 (11): 4632-44 (2006). Read article in PubMedCentral
  • Terenzi F., Hui D. J., Merrick W. C., and Sen G. C.
    “Distinct induction patterns and functions of two closely related interferon-inducible human genes, ISG54 and ISG56”
    J Biol Chem 281 (45): 34064-71 (2006).
  • Fernandez J., Yaman I., Huang C., Liu H., Lopez A. B., Komar A. A., Caprara M. G., Merrick W. C., Snider M. D., Kaufman R. J., Lamers W. H., and Hatzoglou M.
    “Ribosome stalling regulates IRES-mediated translation in eukaryotes, a parallel to prokaryotic attenuation”
    Mol Cell 17 (3): 405-16 (2005).

 

William C. Merrick Faculty's publications at pubmed