Regulation and impact of filamin A RNA editing

Genetic information is stored in DNA. To use this information it is transcribed into RNA before being translated into proteins. Proteins are the essential building blocks of cells and tissues. During this process RNA is not only a simple copy of the genetic information stored in DNA but can also be modified and altered. During a process termed RNA-editing adenosines- one of the four building blocks of RNA- are converted into inosines. Inosines in turn are interpreted as guanosines. Thus RNA-editing can alter genetic information. RNA editing occurs at thousands of positions in mammalian RNAs and is an essential process. However, the consequences of RNA editing on individual proteins is still poorly understood. Here we aim at understanding the consequences of a single amino acid exchange introduced into the actin crosslinking protein Filamin A by RNA editing. Filamin A is an important protein and mutations in this protein can be the cause of several diseases. Here we want to test whether the editing-induced amino acid exchange in Filamin A will affect the arterial smooth musculature and blood pressure control. Based on preliminary data we speculate that blood pressure control will be affected by Filamin A. Moreover, we have developed a model that allows to modulate RNA-editing in living cells. Using those cells we plan to decipher the switches and control points that affect RNA- editing, which is also known to be malfunctioning in several diseases. The proposed project will shed light on the regulation and role of RNA-editing during normal and pathogenic development.

In this project, the influence of an RNA modification in the mRNA of filamin A on the protein properties of Filamin A was tested in cells and mice. We were able to show that the RNA modification changes the mechanical properties of cells. We were also able to show that signal transduction pathways are altered by the modified Filamin A protein. This in turn leads to a slowing down of angiogenesis. In a tumor model, we were therefore able to show that mice carrying the RNA modification on filamin A exhibit less tumor growth. We are currently investigating whether a new therapy for reduced angiogenesis and tumor growth can be derived from this knowledge. We were also able to show that Filamin A altered by RNA-modification dramatically influences the turnover of receptors on the cell surface and thus permanently changes cell migration, wound healing and cell adhesion.