Grant: Project Grant

In all living organisms, the genetic information stored in DNA is copied into mRNA molecules before translated into proteins, the functional molecules the perform most cellular functions. The flow of information from DNA to RNA and proteins is termed the gene expression pathway and regulating the expression of its genes is an essential task for all cells. Mis-regulation, for instance by mutations in factors acting along the gene expression pathway, results in various pathologies, including cancer predisposition, development and progression and a multitude of neurological disorders. RNA has a central molecule of this process, and consists of a copy of an DNA sequence, forming a long polymer of several hundreds to several thousand nucleotides in length. However, RNA does not exist as a linear molecule but is packaged into a 3D assembly with the help of proteins that bind to RNA. The structural organization of the RNA-protein complexes influences many aspects of what happens with an RNA in cells, including whether an RNA is translated into proteins. For example, the two extremities for an RNA have to be in close proximity to allow translation. Inhibiting this interaction inhibits translation of many RNAs and reduces cell growth, and drugs interfering with this process are used as anti-cancer drugs. Understanding how the cell assures the communication between different regions of these long RNA molecules, however is not understood. Furthermore, in general, we completely lack understanding on the structural organization of the RNA polymer. In this project, we will determine how mRNA molecules are organized and how the binding of proteins to the RNA changes the 3D organization of mRNA molecules. This will reveal important insight into the role of mRNP conformation in regulating translation, sensitivity to anti-cancer drugs and RNA metabolism in general, which, in turn, will allow the development of better tools for diagnosis and treatment.