Investigating potential functions of nuclear and cytoplasmic condensation of the SMN complex in RNP homeostasis

• Applicants: Professor Dr. Utz Fischer; Professor Dr. Oliver Gruß
• Subject Area: Biochemistry ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517386593

Macromolecular complexes accomplish a wide spectrum of cellular tasks. Being composed of different proteins or proteins and nucleic acids, their faithful assembly often requires assistance by trans-acting factors. Spliceosomal UsnRNPs represent a well-studied group of abundant macromolecular complexes that undergo assisted assembly in vivo. They form under the guidance of the SMN-complex, which itself constitutes a macromolecular entity that reversibly condenses in nuclear and cytoplasmatic membraneless compartments. While we comprehend core functions of the SMN-complex in U snRNP at biochemical level, its spatial and temporal regulation, its potential roles in cellular UsnRNP homeostasis and the functional significance of its condensation remain only poorly understood. In this application we propose to investigate phase separation of the SMN complex in response to cellular signaling and its impact for UsnRNP homeostasis and as a regulator for biosynthetic pathways. In the first part, experiments are proposed that focus on the role of the nuclear SMN-complex. We will test the hypothesis that nuclear SMN-complexes, condensing in Cajal bodies, serve as turnover centers, where the steady state level of cellular UsnRNP and/or the removal of defective UsnRNPs are regulated. In the second part, we will exploit previously identified signaling cues that govern SMN condensation to evaluate the function of cytoplasmic SMN condensates to regulate U snRNP assembly under stress conditions but also in novel functions of the SMN complex in translational control. Our studies will not only unravel how the biosynthetic functions of the SMN complex are integrated into cell signaling and stress response but provide insight into how phase separation enables and regulates novel functions of the SMN complex.

• DFG Programme: Research Grants