The 3′ untranslated regions (3′ UTRs) of mRNAs function as regulatory platforms that determine mRNA stability, subcellular localization and translation efficiency. These functions are mediated mostly through binding of microRNAs and RNA-binding proteins to regulatory elements in 3′ UTRs. The proportion of human and mouse genes that use alternative cleavage and polyadenylation (APA) to generate mRNA isoforms with different 3′ UTR lengths is thought to be at least 50%, implicating APA as an important novel layer of gene regulation. By designing a reporter system that comprises a proximal alternative polyadenylation signal (PAS; which recruits the 3′-end processing machinery) upstream of a 3′ UTR fragment containing its canonical PAS, Agami and colleagues screened an RNA interference library for RNA-binding proteins required for APA and identified the nuclear poly(A)-binding protein PABPN1. Loss of PABPN1 resulted in proximal PAS usage, and genome-wide analysis of APA in human cells showed that loss of PABPN1 resulted in extensive 3′ UTR shortening, implicating PABPN1 as a repressor of APA. In vitro and in vivo data suggest that PABPN1 interacts directly with PAS regions and competes with the 3′-end processing machinery for binding to the weak, noncanonical, proximal PASs, thereby suppressing PAS-mediated cleavage at proximal sites. Using the 3′ UTR of cyclin D1—which is a target of the miR-17-19 cluster—as a test case, the authors showed that enhanced proximal PAS usage as a result of PABPN1 knockdown compromises miRNA-mediated repression. Finally, short triplet-repeat expansion mutations in the PABPN1 gene, which cause an autosomal-dominant muscular dystrophy disorder in humans, have a similar effect on PAS selection as PABPN1 knockdown, suggesting that the disease phenotype is associated with misregulated APA. (Cell 149, 538–553, 2012)