Prof. Daniel Schümperli

During my career as independent scientist, my collaborators and myself have been investigating basic mechanisms active in the expression of genetic information. The genes coding for proteins are first copied into primary RNA transcripts which then need to be processed in various ways. A major focus of our research has been the formation of mRNA 3' ends which requires an endonucleolytic cleavage of the mRNA precursor. For the bulk of mRNAs, the cleavage product is then extended with a polyA tail which protects the mRNA from degradation and allows its translation. A special case are the mRNAs coding for histone proteins. In animals and humans, these are encoded by genes without introns, and the 3' ends are generated by a distinct mechanism in which they do not acquire a polyA tail. My group has worked on both of these 3' end processing reactions, but most intensely on histone RNA processing.

These 3' end processing reactions are highly regulated. Alternative polyA site selection can affect the structure and function of the protein encoded by the gene in question, or it can add or remove regulatory sequences from the mRNA that control its stability, translation or subcellular localization. Moreover, histone RNA 3' end processing is highly regulated during the cell cycle to ensure that histone proteins are synthesized primarily during S phase when the cellular DNA is replicated. These regulations can fail which is an important cause of inherited disorders and also contributes to some acquired diseases such as cancers.

The second process that has interested us more from a medical point of view is the removal of non-coding sequences (introns) from a primary transcript by the process called splicing. Higher organisms, and in particular humans, make extensive use of alternative splicing to produce different proteins from a single gene. Alternative splicing is often regulated and contributes strongly to developmental processes. Moreover, many of the mutations responsible for inherited disorders affect the splicing of the affected gene and thereby lead to the production of a faulty protein or insufficient amounts of the correct one. Over the years, our basic studies on a small nuclear ribonucleoprotein particle involved in histone RNA processing (the U7 snRNP) have allowed us to derive modified versions of this particle that can be used to modulate alternative splicing. We have shown that these tools can be used for the treatment of certain inherited diseases such as the fatal neuromuscular disease Spinal Muscular Atrophy (SMA) and a metabolic disorder that causes a very painful light sensitivity, Erythropoietic Protoporphyria (EPP).