Prof. Dr. Bindereif
Justus Liebig University of Giessen, Institute of Biochemistry, Department of Biology and Chemistry
Heinrich-Buff-Ring 17 D-35392 Giessen Germany
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PROJECT INFORMATION :
The human IGF2BP proteins (Insulin like Growth Factor 2 mRNA Binding-Protein; or shortly IMP) are a small, highly conserved family of RNA-binding proteins, characterized by a unique modular structure with two N-terminal RRM motifs and four C-terminal KH domains. Three human paralogs are known, IMP1/2/3, of which in particular IMP1 and IMP3 show an oncofetal expression pattern and are involved in development, cancer progression, and metastasis. Here we focus on IMP3, which is least characterized and particularly interesting as a pancreatic cancer marker.
In unpublished work we addressed the specific functions of IMP3, using RNA-Seq and iCLIP (individual nucleotide resolution UV-crosslinking and immunoprecipitation) in human hepatocellular carcinoma cells (HepG2), as well as in two pancreas tumor cell lines. Our preliminary analysis of IMP3 crosslink sites revealed a striking preference for and clustering in 3´UTRs of mRNAs, which were strongly enriched for mRNAs coding for membrane and secretory proteins. Together with other data this suggests a potential new, post-transcriptional role of IMP3 in ER (endoplasmic reticulum)-proximal localization, facilitating localized translation at the ER. In addition, our preliminary work indicates a role of IMP3 in mRNA stability and in the assembly of circular RNA-protein complexes.
On this basis, we plan to investigate in detail the molecular mechanisms and functions of IMP3 as an mRNP component, focussing on these three specific aims:
- first, to define the complex RNA-binding specificity of the IMP3 protein, based on in vitro SELEX in combination with our unpublished iCLIP in vivo binding data;
- second, to study two functions of IMP3 as an mRNP constituent: determining mRNA stability and mediating ER-localized translation;
- third, to functionally characterize IMP3-associated circular RNAs, thereby searching for potential new roles of IMP3 at the interphase between coding mRNAs and noncoding circRNAs.
Overall, our project will investigate the functional spectrum of IMP3, in particular its role as an mRNP constituent; at the same time, our studies aim to bridge coding mRNAs and noncoding circular RNAs, expecting to reveal new RNP networks.
Focus of the group (i.e. structural biology of RNPs, proteomics of mRNPs etc.)
mRNA processing and noncoding RNAs in the mammalian system
Extracellular vesicles and RNA
Structure and functions of circular RNAs
KEY TECHNOLOGIES :
RNA and RNP biochemistry,
CLIP technology, RNA-Seq libraries, and RNA bioinformatics
Analysis of extracellular vesicles
Characterization of circular RNAs and RNA-protein complexes
Schneider, T., Hung, L.H., Schreiner, Starke, S., Eckhof, H., Rossbach, O., Reich, S., Medenbach, J., and Bindereif, A. (2016). CircRNA-protein complexes: IMP3 protein component defines subfamily of circRNPs. Sci. Rep. 6, 31313.
Starke, S., Jost, I., Rossbach, O., Schneider, T., Schreiner, S., Hung, L.-H., and Bindereif, A. (2015).
Exon circularization requires canonical splice signals.
Cell reports 10, 103-111.
Rösel-Hillgärtner, T.D., Hung, L-H., Khrameeva, E., Le Querrec, P., Gelfand, M.S., and Bindereif, A. (2013). A novel intra-U1 snRNP cross-regulation mechanism: Alternative splicing switch links U1C and U1-70K expression. PLoS Genet. 9(10):e1003856.
Hui, J., Hung, L.-H., Heiner, M., Schreiner, S., Neumüller, N., Reither, G., Haas, S.A., and Bindereif, A. (2005). Intronic CA-repeat and CA-rich elements: a new class of regulators of mammalian alternative splicing. EMBO J. 24, 1988-1998.
Hui, J., Stangl, K., Lane, W.S., and Bindereif, A. (2003). HnRNP L stimulates splicing of the eNOS gene by binding to variable-length CA repeats. Nature Struct. Biol. 10, 33-37.