NRDE2 and CCDC174: Linking mRNA Splicing and RNA Degradation

In human cells, accurately interpreting genetic information is crucial for maintaining health and promoting development. A key step in this process is messenger RNA (mRNA) splicing, where initial RNA copies of genes are carefully edited to remove unnecessary sequences. This editing process is highly complex and can result in the production of faulty or even harmful proteins if errors occur during the process. Cells have developed sophisticated quality control mechanisms to monitor mRNA splicing and ensure that incorrectly processed RNA is either corrected or destroyed. However, the mechanism by which cells detect these splicing errors and link them to RNA degradation remains poorly understood. Our research investigates two important proteins, NRDE2 and CCDC174, which appear to function as critical connectors between RNA splicing quality control and RNA degradation by the Exosome, the cells central RNA disposal machinery. Recent studies suggest that these proteins help identify faulty RNA molecules that arise from weak splicing signals, preventing their export from the nucleus and ensuring their degradation before they can cause harm. Notably, mutations in CCDC174 have been linked to severe developmental disorders in children, underscoring the biological and medical significance of understanding these molecular processes. In this project, we aim to uncover how NRDE2 and CCDC174 work together to control RNA splicing fidelity and ensure the safe removal of defective RNA by the Exosome. Using advanced biochemical and structural biology methods, we will determine how these proteins form complexes and how they interact with the Exosome and other key RNA processing factors. Our goal is to elucidate how these systems function at the molecular level and how they safeguard cells against the risks associated with improperly spliced RNA. By shedding light on these fundamental processes, our work will provide critical new insights into how gene expression is surveilled through the coordinated actions of splicing quality control and RNA degradation in human cells, advancing our understanding of how cells maintain the integrity of their gene expression programs.