In this project, we look at how RNA-binding proteins regulate the processing of messenger RNA (mRNA), the carrier of the instructions for the production proteins. In particular, we investigate splicing, which is the process in which the parts that do not carry information for the protein (introns) are removed from the parts that do contain relevant information (exons). Variation in the selection of which parts of the mRNA are used for the final product is known as alternative splicing and allows the production of multiple protein products from a single gene. Alternative splicing is one of the mechanisms that allows different cell types to emerge from the same genome, as well as the functioning of similar cells under different conditions. RNA-binding proteins that regulate this process are known as splicing factors and these exist in two forms: those that promote splicing close to where they bind to the mRNA and those that have the opposite effect. Such splicing factors are often found to be in abnormal states in cancer and various other diseases and therefore hold a lot of untapped potential as therapeutic targets.
A traditional way of interfering with splicing factors is to look for inhibitors that block their ability to bind to mRNA. However, inhibition can lead to undesired effects, since a single splicing factor regulates numerous alternative splicing events. Instead, in this project we aim to promote the interaction of a given splicing factor with a specific RNA sequence, so that we can direct splicing on a single (or small number of) event(s) in the desired direction. By doing so, we hope to force the formation of mRNA that produces protein with a beneficial function in a given disease. Such molecules we refer to as protein-RNA interaction molecular glues (PRIGLUEs).
