Project summary: The long-term goal of my research program is to understand, in detail, the mechanisms of mammalian mRNA 3’ processing and its regulation. mRNA 3’-end formation, typically involving an endonucleolytic cleavage followed by polyadenylation, is an essential step of eukaryotic gene expression and it significantly impacts many aspects of RNA metabolism, including mRNA stability, subcellular localization and translation. In addition, the majority of eukaryotic genes produce multiple mRNA isoforms with distinct 3’ ends through alternative polyadenylation (APA). Recent studies have revealed that APA is highly regulated in development and plays an important role in post-transcriptional gene regulation. Aberrant APA patterns have been associated with a wide range of diseases, from cancer to neurological disorders. Key outstanding questions in the mRNA 3’ processing field include: 1) what is the structure-function relationship of the mRNA 3’ processing complex; 2) how is mRNA 3’ processing regulated by cell signaling; 3) how is APA regulated by RNA-binding proteins? We will address these questions by using biochemical, structural, and genomic analyses. The results of these studies will not only provide novel insights into this key step in eukaryotic gene expression, but also pave the way for developing novel therapy for many diseases.