PROJECT SUMMARY Most mammalian genes have multiple cleavage and polyadenylation (C/P) sites, or pAs, resulting in mRNA isoforms with different coding sequences (CDS) and/or 3' untranslated regions (3'UTRs). Alternative cleavage and polyadenylation (APA) is rapidly recognized as an important layer of gene regulation, affecting protein diversity and mRNA metabolism. The APA pattern of genes varies across cell/tissue types and is dynamically regulated under different conditions, such as proliferation, differentiation, and in response to extracellular cues. The mechanisms of APA, however, are poorly understood. Our long-term goal is to understand the `regulatory code' of APA in different cells/tissues under physiological and pathological conditions and its biological consequences. In this proposal, we have three specific aims: First, we will examine the role of C/P factors in APA regulation. Second, we will examine how C/P genes are regulated by APA. Third, we will examine the interplay between nuclear export and APA. We expect that the result of this grant will provide systematic views on the mechanisms of APA and shed light on its significance in different cells and tissues, as well as development and differentiation.