Our ability to sequence has far outpaced our understanding of the regulation of gene expression. Even though we have a good knowledge of cellular RNA diversity and abundance this still does not allow us to infer from the transcriptome on the proteome. In fact one of the major challenges in modern biology is to bridge the evident gap between transcriptome and proteome which requires a better understanding of translational control.

Translational control is an important and critical layer of gene expression control in essentially all eukaryotic cells. It allows both rapid and localized changes in the concentrations of proteins in responses to extra- and intracellular stimuli and it is crucial for a large number of important cellular processes such as cell division and differentiation, embryonic development and memory formation through neuronal plasticity.

Many mRNAs, particularly those encoding oncogenes, cytokines, growth factors etc., carry upstream open reading frames (uORFs) in their 5’ untranslated regions (UTRs). These uORFs are widely recognized as constitutive regulatory elements that impinge on the translation of their associated physiological open reading frames, potentially affecting the protein output of half of the human transcripts. Polymorphisms that disrupt or create uORFs in human patients can result in or increase susceptibility to severe disorders such as hereditary thrombocythaemia, cancer, bipolar affective disorders, and Alzheimer’s disease, underscoring the broad significance of the uORF regulatory potential.

Recently I could uncover a novel paradigm for the regulation of translation by demonstrating that a trans-acting factor – an RNA-binding protein – can modulate the activity of a uORF. Probing the generality of the underlying mechanism unraveled a network of co-regulated, natural Drosophila mRNAs revealing a novel and possibly systematic principle for the regulation of protein synthesis. Building on these findings I now plan to make use of a systematic and unbiased approach that aims to identify novel cases of protein-controlled uORFs, characterize their trans-acting regulatory RNA-binding proteins and study the regulatory mechanism in molecular detail, aiming for a thorough understanding of uORF-mediated translational control and its implication in disease.

... coming soon

Medenbach, J., Seiler, M., and Hentze, MW.: Translational control via protein-regulated upstream open reading frames. Cell, 2011, 145(6):902-13.

- Featured in: Yao P. and Fox PL: Sex lethal and upstream ORFs: a bait-and-trap system for ribosomes. Genome Biology, 2011, 12:121.

- Featured in Faculty of 1000

Rösel, TD.1, Hung, LH.1, Medenbach, J.1, Donde, K., Starke, S., Benes, V., Rätsch, G., and Bindereif, A.: RNA-Seq analysis in mutant zebrafish reveals role of U1c protein in alternative splicing regulation. EMBO Journal, 2011, 30(10):1965-76.

(1 these authors contributed equally)

Pérard, J., Rasia, R., Medenbach, J., Ayala, I., Boisbouvier, J., Drouet, E., and Baudin, F.: Human initiation factor eIF3 subunit binteracts with HCV IRES RNA through its N-terminal RNA recognition motif. FEBS Lett., 2009, 583(1): 70-4.

Licht, K.1, Medenbach, J.1, Lührmann, R., Kambach, C., and Bindereif, A.: 3'-cyclic phosphorylation of U6 snRNA leads to recruitment of recycling factor p110 through LSm proteins. RNA, 2008, 4(8): 1532-8.

(1 these authors contributed equally)

Trede1, N.S., Medenbach, J.1, Damianov1, A., Hung, L.-H., Weber, G.J., Paw, B.H., Zhou, Y., Hersey, C., Zapata, A., Keefe, M., Barut, B.A., Stuart, A.B., Katz, T., Amemiya, C.T., Zon, L.I., and Bindereif, A.: Network of coregulated spliceosome components revealed by zebrafish mutant in recycling factor p110. Proc. Natl. Acad. Sci. USA, 2007, 104(16): 6608-13.

(1 these authors contributed equally)

Medenbach, J., Schreiner, S., Liu, S., Lührmann, R., and Bindereif, A.: Human U4/U6 snRNP Recycling Factor p110: Mutational Analysis Reveals the Function of the Tetratricopeptide Repeat Domain in Recycling”, Molecular and Cellular Biology, 2005, 24(17): 7392-7401.

Medenbach, J., Damianov, A., Schreiner, S., and Bindereif, A.: Sedimentation Analysis of Ribonucleoprotein Complexes. Handbook of RNA Biochemistry, 2005, R. K. Hartmann, A. Bindereif, A. Schön and E. Westhof. Weinheim, Wiley-VCH. 1: 428-437.