Sebastian Falk’s project ‘NRDE2 and CCDC174: Linking mRNA Splicing and RNA Degradation’ explores how human cells detect and eliminate damaged RNA molecules resulting from errors in mRNA splicing. While splicing is a well-characterized step in gene expression, the mechanisms which ensure that only correctly processed RNA is retained remain unclear. Recent findings suggest that two proteins – NRDE2 and CCDC174 – may form a molecular link between the splicing machinery and RNA degradation by the exosome. Sebastian’s research aims to uncover how CCDC174 interacts with components of the spliceosome and how NRDE2 influences exosome activity to ensure defective mRNAs are degraded. Sebastian explains: “Using advanced biochemical and structural biology methods, we will study how these proteins cooperate to achieve RNA quality control. Our work promises to deepen the understanding of how cells ensure the fidelity of gene expression through the coordinated action of splicing and RNA decay.” Notably, mutations in CCDC174 have been associated with severe developmental disorders in children, highlighting the project’s clinical relevance. The project is funded for a duration of three years.
Robert Konrat’s project ‘Paramagnetic NMR Spin Relaxation in IDPs’ focuses on intrinsically disordered proteins (IDPs), a class of proteins that do not form stable three-dimensional structures. Their dynamic nature makes them inaccessible to X-ray crystallography or electron microscopy, necessitating alternative tools that can probe molecular motion. While nuclear magnetic resonance (NMR) spectroscopy has proven powerful in studying IDPs, Robert’s team aims to push its boundaries further by developing new spectroscopic probes to investigate the structural preferences and dynamic behavior of these proteins. The project will involve the design of novel paramagnetic relaxation interference (PRI) experiments and solvent paramagnetic spin relaxation methods to explore complex formation in IDPs and their electrostatic properties. Robert says: “The tools developed are expected to provide new perspectives on IDP behavior and may be of use to the broader structural biology community.” The project is funded for a duration of three years.
In Peter Schlögelhofer’s project ‘Non-cohesive roles of cohesin in meiotic prophase‘, the main goal is to explore how cohesin, a key protein complex best known for holding sister chromatids together, plays fundamental non-cohesive roles in organizing the genome during meiosis. These non-cohesive roles, conserved from bacteria to plants and humans, are crucial for the maintenance of chromosome architecture and the regulation of gene expression, but are not fully understood. Using yeast as a model system, the Schlögelhofer lab will examine how the cohesin regulator Scc2 (also known as NIPBL in humans) influences the structure of chromosomes during homolog pairing, a critical step in gamete formation. They have found that, even when sister chromatids remain attached, chromosome organization collapses in the absence of Scc2 – suggesting that cohesion and chromosome architecture are separable. Remarkably, the collapse of chromosome architecture is reversible, enabling the live study of chromosome disassembly and reassembly with high-resolution imaging and genome-wide techniques. It is hoped that the work will shed light on the molecular origins of cohesinopathies like Cornelia de Lange Syndrome, which stem from mutations in cohesin regulators. The project will span 3.5 years and aims to deepen the understanding of genome organization in meiosis, with the potential to provide crucial insights into conserved regulatory mechanisms across species.