title: Regulated Intron Retention and Nuclear Pre-mRNA Decay Contribute to PABPN1 Autoregulation.
abstract: The poly(A)-binding protein nuclear 1 is encoded by the PABPN1 gene, whose mutations result in oculopharyngeal muscular dystrophy, a late-onset disorder for which the molecular basis remains unknown. Despite recent studies investigating the functional roles of PABPN1, little is known about its regulation. Here, we show that PABPN1 negatively controls its own expression to maintain homeostatic levels in human cells. Transcription from the PABPN1 gene results in the accumulation of two major isoforms: an unspliced nuclear transcript that retains the 3'-terminal intron and a fully spliced cytoplasmic mRNA. Increased dosage of PABPN1 protein causes a significant decrease in the spliced/unspliced ratio, reducing the levels of endogenous PABPN1 protein. We also show that PABPN1 autoregulation requires inefficient splicing of its 3'-terminal intron. Our data suggest that autoregulation occurs via the binding of PABPN1 to an adenosine (A)-rich region in its 3' untranslated region, which promotes retention of the 3'-terminal intron and clearance of intron-retained pre-mRNAs by the nuclear exosome. Our findings unveil a mechanism of regulated intron retention coupled to nuclear pre-mRNA decay that functions in the homeostatic control of PABPN1 expression.
authors.affiliation: Department of Biochemistry, RNA Group, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Danny
authors.initials: D
authors.lastname: Bergeron
authors.affiliation: Department of Biochemistry, RNA Group, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Pal
authors.affiliation: Department of Biochemistry, RNA Group, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Yves B
authors.initials: YB
authors.lastname: Beaulieu
authors.affiliation: Department of Microbiology, RNA Group, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
authors.affiliation: Department of Biochemistry, RNA Group, Université de Sherbrooke, Sherbrooke, Canada f.bachand@usherbrooke.ca.
authors.forename: François
authors.initials: F
authors.lastname: Bachand
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D055354:Exosomes / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D039122:Poly(A)-Binding Protein I / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068103:Serine-Arginine Splicing Factors
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C115188:SRSF10 protein, human; D000068103:Serine-Arginine Splicing Factors