Regulation of RGG-mediated Nuclear Import

• Applicant: Professorin Dr. Dorothee Dormann
• Subject Area: Cell Biology ; Biophysics
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 397983986

Motifs rich in arginine and glycine residues were recognized several decades ago to play functional roles in RNA-binding and were termed RG/RGG motifs. More than 1000 proteins harbor the intrinsically disordered RG/RGG motif, and these proteins play essential roles in a plethora of physiological processes such as transcription, pre-mRNA splicing, DNA damage signaling and mRNA translation. Recently, we have shown that the RG/RGG-motif of the protein Fused-in-Sarcoma (FUS) is involved in transportin-1 – mediated nuclear import, and that transportin-1 can bind both, the known proline-tyrosine nuclear localization signal (PY-NLS) and the RG/RGG-motif of FUS simultaneously. Arginine methylation of the RG/RGG motif in combination with mutations found in Amyotrophic Lateral Sclerosis (ALS) patients decrease the affinity of FUS for transportin-1 and reduces the efficiency of nuclear import. The resulting cytosolic inclusions are probably the hallmark of FUS-associated ALS disease. Despite these findings, the molecular details of regulated nuclear transport of RG/RGG-containing proteins remain unknown.In this project, we aim to reveal molecular details of (mis)regulated nuclear import of the large class of proteins rich in RG/RGG repeats by studying interaction and function of the complexes of FUS and CIRP (cold-inducible RNA-binding protein) with the nuclear import receptor transportin-1 in vitro and in cell-based assays. Given that misregulation of nuclear import linked to RG/RGG motifs is a common feature of severe human diseases such as cancers and neurodegeneration, detailed understanding of the underlying molecular mechanisms is the key for the development of alternative strategies for disease treatment. This project aims towards generalizing our recent findings to the entire class of RG/RGG-containing proteins. This will set the base for the discovery of new potential druggable targets for the treatment of a plethora of diseases with different phenotypes, though caused by the same molecular disease mechanisms (i.e. misregulation of RG/RGG-mediated nuclear import). This is a D-A-CH joint project of Assoc. Univ. Prof. Dr. Tobias Madl (FWF lead agency) and Dr. Dorothee Dormann (DFG partner) and will be carried out at the Institute of Molecular Biology and Biochemistry, Medical University of Graz, and the BioMedizinisches Centrum (BMC), Ludwig-Maximilians-Universität München, respectively.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Professor Dr. Tobias Madl