Splicing Regulation in Context: Next-Generation mechanistic studies

Ziel

Precise and faithful removal of non-coding introns from the precursors of messenger RNAs is critical for productive gene expression. This process is catalysed by the spliceosome - one of the cell’s most complex molecular machines. Aberrant splicing is responsible for numerous diseases, including neuropathies, developmental disorders and cancers. In the past decade, structural studies of the spliceosome have transformed the field by providing unprecedented insights into its fundamental mechanism of action. Despite this rapid progress, many aspects of splicing biology remain poorly understood. In particular, how is splicing regulated and how does the outcome of splicing depend on its interaction with other cellular components? To address this knowledge gap, the SPRING project was developed with the aim to provide insights into three fundamental aspects of the context-dependent splicing regulation in humans: 1) splicing quality control mechanisms; 2) coupling of the transcription and splicing machinery; 3) regulation through the interaction with the local environment in the native cellular context. These fundamental questions in gene expression biology will be addressed by employing state-of-the-art methods in structural and molecular cell biology, including native complexes purification, cryoEM/ET and correlative imaging. This project aims to bring groundbreaking insights into the molecular mechanisms of splicing regulation and has the potential to be transformative for the field.