The Merrick laboratory seeks 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.
- Merrick W.C., Pavitt G.D.
“Protein Synthesis Initiation in Eukaryotic Cells.”
Cold Spring Harb Perspect Biol. pii: a033092 (2018)
- Guan B.J., van Hoef V., Jobava R., Elroy-Stein O., Valasek L.S., Cargnello M., Gao X.H., Krokowski D., Merrick W.C., Kimball S.R., Komar A.A., Koromilas A.E., Wynshaw-Boris A., Topisirovic I., Larsson O., Hatzoglou M.
“A Unique ISR Program Determines Cellular Responses to Chronic Stress.”
Mol Cell. 68(5):885-900.e6.(2017)
- Golovko A., Kojukhov A., Guan B.J., Morpurgo B., Merrick W.C., Mazumder B., Hatzoglou M., Komar A.A.
“The eIF2A knockout mouse.”
Cell Cycle. 15(22):3115-3120 (2016)
- Merrick W.C.
“The Celebration of 40 years of structural biology at Aarhus University as seen through the eyes of a translationalist.”
N Biotechnol. 38(Pt A):26-28 (2017)
- Carelli J.D., Sethofer S.G., Smith G.A., Miller H.R., Simard J.L., Merrick W.C., Jain R.K., Ross N.T., Taunton J.
“Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.”
Elife pii: e10222 (2015)
- Merrick W.C.
“eIF4F: a retrospective.”
J Biol Chem. 290(40):24091-9 (2015)
- Chen H., Song R., Wang G., Ding Z., Yang C., Zhang J., Zeng Z., Rubio V., Wang L., Zu N., Weiskoff A.M., Minze L.J., Jeyabal P.V., Mansour O.C., Bai L., Merrick W.C., Zheng S., Shi Z.Z.
“OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation..”
Sci Rep. 5:13241 (2015)
- Khan M.A., Ma J., Walden W.E., Merrick W.C., Theil E.C., Goss D.J.
“Rapid kinetics of iron responsive element (IRE) RNA/iron regulatory protein 1 and IRE-RNA/eIF4F complexes respond differently to metal ions.”
Nucleic Acids Res. 42(10):6567-77 (2014)
- Guan B. J., Krokowski D., Majumder M., Schmotzer C. L., Kimball S. R., Merrick W. C., Koromilas A. E., and Hatzoglou M.
“Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor eIF2alpha”
J Biol Chem 289 (18): 12593-611 (2014).
- Khan M. A., Ma J., Walden W. E., Merrick W. C., Theil E. C., and Goss D. J.
“Rapid kinetics of iron responsive element (IRE) RNA/iron regulatory protein 1 and IRE-RNA/eIF4F complexes respond differently to metal ions”
Nucleic Acids Res 42 (10): 6567-77 (2014). Read article in PubMedCentral
- Merrick W. C. and Harris M. E.
“Control not at initiation? Bah, humbug!”
EMBO J 33 (1): 3-4 (2014).
- Barth-Baus D., Bhasker C. R., Zoll W. L., and Merrick W. C.
“Influence of translation initiation factor activities on start site selection in six different mRNAs”
Translation 1: e24419 (2013).
- Bentley A. A., Merkulov S. M., Peng Y., Rozmarynowycz R., Qi X., Pusztai-Carey M., Merrick W. C., Yee V. C., McCrae K. R., and Komar A. A.
“Chimeric glutathione S-transferases containing inserts of kininogen peptides: potential novel protein therapeutics”
J Biol Chem 287 (26): 22142-50 (2012).
- Komar A. A., Mazumder B., and Merrick W. C.
“A new framework for understanding IRES-mediated translation”
Gene 502 (2): 75-86 (2012).
- Ma J., Haldar S., Khan M. A., Sharma S. D., Merrick W. C., Theil E. C., and Goss D. J.
“Fe2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation”
Proc Natl Acad Sci U S A 109 (22): 8417-22 (2012).
- Krokowski D., Gaccioli F., Majumder M., Mullins M. R., Yuan C. L., Papadopoulou B., Merrick W. C., Komar A. A., Taylor D., and Hatzoglou M.
“Characterization of hibernating ribosomes in mammalian cells”
Cell Cycle 10 (16): 2691-702 (2011).
- Parsyan A., Svitkin Y., Shahbazian D., Gkogkas C., Lasko P., Merrick W. C., and Sonenberg N.
“mRNA helicases: the tacticians of translational control”
Nat Rev Mol Cell Biol 12 (4): 235-45 (2011).
- Reineke L. C., Cao Y., Baus D., Hossain N. M., and Merrick W. C.
“Insights into the role of yeast eIF2A in IRES-mediated translation”
PLoS One 6 (9): e24492 (2011).
- 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).
- 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).