Project 453257

Control of gene expression is largely governed by a portion of the genome's messengers, mRNAs, called 3'-untranslated regions (3'UTRs). The sequences and structures of 3'UTRs and the factors that recognize them, such as microRNAs and RNA-binding proteins, are key determinants in deciding when and where to turn genes off or on. In recent years, it became clear that the majority of genes in the human genome can dynamically reorganize 3'UTR sequences through regulatory elements called alternative polyadenylation sites (or APA), and enhancing or inhibitory sequences. Under different physiological conditions, and under hyper-proliferative states often observed in cancer, the 3'UTR sequences are profoundly reorganized, and this is thought to reorganize gene networks. This proposal will leverage the latest in molecular genetics and genome engineering to assess the mechanisms underlying- and the importance of this phenomenon in a most important signalling cascade for many cancers, namely in the PTEN/PI3K/AKT signalling axis. The proposed work is the first to directly assess the functional importance of APA regulation in functional models, and decipher the molecular events that underlie broad stroke changes in APA.