Structure and function of RNA processing complexes
Alternative splicing of pre-mRNA is a centrally important and extraordinary cellular process that allows the generation of proteomic diversity (estimated at up to 150,000 human proteins) from only 20,000 human genes. More than 90% of human genes use multiple patterns of splicing, sometimes with antagonistic functions, to be expressed from a single gene. The process of alternative splicing is very complex and still poorly understood. The selection of particular splice sites among numerous potential sites is influenced by many proteins, called splicing factors, that bind to the pre-mRNA. These proteins may either enhance or prevent the recognition of a particular splice site in a time, cell-type and cell-cycle dependent manner. It has also been demonstrated that cell signalling plays a major role in the regulation of alternative splicing through post-translational modifications of splicing factors demonstrating a tight link between cell signalling and alternative splicing regulation.
Accordingly, pre-mRNA mutations as well as splicing factor mutations or copy number variations are associated with several genetic diseases including cancer.
Our main research interest is therefore to understand at the molecular level the specific action of splicing factors on alternative splicing decision, the interplay between signalling pathways and post-transcriptional gene regulation. Additionally, we are interested in the role of pre-mRNA secondary and tertiary structures on alternative splicing regulation.
To this aim, we are studying RNA, protein-protein and protein-RNA complexes using structural biology techniques (NMR and X-ray), biophysical methods (ITC, Flourescence polarization) and biochemical methods (RNA footprinting, EMSA,).
Our structural work is complemented by functional assays thank to collaboration with the group of Professor Ian Eperon within the LISCB.
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Ayesha Hasan, Adam Lightfoot, Mohammed Boghodia, Hatice Ezenkaya (joint with Ian Eperon), Rafael Del Villar Guerra, Mohammed Hasan (with Ildiko Gyory), Nora Kogelnik, Idir Malki, Mishal Tariq (with Kayoko Tanaka)