title: Poly(A) Polymerase and the Nuclear Poly(A) Binding Protein, PABPN1, Coordinate the Splicing and Degradation of a Subset of Human Pre-mRNAs.
abstract: Most human protein-encoding transcripts contain multiple introns that are removed by splicing. Although splicing catalysis is frequently cotranscriptional, some introns are excised after polyadenylation. Accumulating evidence suggests that delayed splicing has regulatory potential, but the mechanisms are still not well understood. Here we identify a terminal poly(A) tail as being important for a subset of intron excision events that follow cleavage and polyadenylation. In these cases, splicing is promoted by the nuclear poly(A) binding protein, PABPN1, and poly(A) polymerase (PAP). PABPN1 promotes intron excision in the context of 3'-end polyadenylation but not when bound to internal A-tracts. Importantly, the ability of PABPN1 to promote splicing requires its RNA binding and, to a lesser extent, PAP-stimulatory functions. Interestingly, an N-terminal alanine expansion in PABPN1 that is thought to cause oculopharyngeal muscular dystrophy cannot completely rescue the effects of PABPN1 depletion, suggesting that this pathway may have relevance to disease. Finally, inefficient polyadenylation is associated with impaired recruitment of splicing factors to affected introns, which are consequently degraded by the exosome. Our studies uncover a new function for polyadenylation in controlling the expression of a subset of human genes via pre-mRNA splicing.
authors.affiliation: Wellcome Trust Centre for Cell Biology, Edinburgh, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Muniz
authors.affiliation: Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Davidson
authors.affiliation: Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom steve.west@sheffield.ac.uk.
authors.forename: Steven
authors.initials: S
authors.lastname: West
mesh_terms: D002460:Cell Line; D006801:Humans; D007438:Introns; D011061:Poly A / Q000378:metabolism*; D039122:Poly(A)-Binding Protein I / Q000378:metabolism*; D011062:Polynucleotide Adenylyltransferase / Q000378:metabolism*; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing
chemical_list: C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D012322:RNA Precursors; D011061:Poly A; D011062:Polynucleotide Adenylyltransferase