The goal of our project is to decipher the function of a chemical modification imposed upon the basic building blocks of our genetic code - the mRNA molecules - following their formation. For years it was thought that the sequence of the mRNA - that encodes the productions of proteins - essentially mirrors the DNA sequence (with some exceptions). In recent years it has turned out, however, that following the production of the mRNA it can acquire chemical modifications, that can then alter its stability, localization and ability to encode proteins. These modifications have meanwhile been implicated in a large number of both physiological and pathological conditions, and hence understanding where they are, what their roles are, and how they bring these about are critical questions that will impact our understanding of health and disease. In our proposal, we set to explore the roles of one particularly abundant modification called m6A, involving the methylation of an adenosine, with the goals of identifying the pathways involved in its installation and recognition, and dissecting the function and mechanisms of action of this modification. This modification is deeply connected to the fate of an mRNA, and understanding this modification, the machinery depositing it and the underlying mechanisms therefore has the potential to unlock questions concerning the forces dictating the lifespan and regulation to which mRNAs are subjected in health and in disease. More generally, we sought to address similar questions also in the context of additional post-transcriptional modifications on mRNA. Over 170 such modifications exist, many of which implicated in diverse human diseases, and therefore understanding their distribution and function is of utmost importance, as well as value to society.
