title: The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites.
abstract: Alternative cleavage and polyadenylation (APA) is emerging as an important layer of gene regulation. Factors controlling APA are largely unknown. We developed a reporter-based RNAi screen for APA and identified PABPN1 as a regulator of this process. Genome-wide analysis of APA in human cells showed that loss of PABPN1 resulted in extensive 3' untranslated region shortening. Messenger RNA transcription, stability analyses, and in vitro cleavage assays indicated enhanced usage of proximal cleavage sites (CSs) as the underlying mechanism. Using Cyclin D1 as a test case, we demonstrated that enhanced usage of proximal CSs compromises microRNA-mediated repression. Triplet-repeat expansion in PABPN1 (trePABPN1) causes autosomal-dominant oculopharyngeal muscular dystrophy (OPMD). The expression of trePABPN1 in both a mouse model of OPMD and human cells elicited broad induction of proximal CS usage, linked to binding to endogenous PABPN1 and its sequestration in nuclear aggregates. Our results elucidate a novel function for PABPN1 as a suppressor of APA.
authors.affiliation: Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Mathias
authors.initials: M
authors.lastname: Jenal
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Fabricio
authors.initials: F
authors.lastname: Loayza-Puch
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.forename: Uwe
authors.initials: U
authors.lastname: Kühn
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.forename: Joachim A F
authors.initials: JA
authors.lastname: Oude Vrielink
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Bos
authors.forename: Jarno
authors.initials: J
authors.lastname: Drost
authors.forename: Koos
authors.initials: K
authors.lastname: Rooijers
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D039103:Poly(A)-Binding Protein II / Q000235:genetics / Q000378:metabolism*; D026723:Polyadenylation; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D039103:Poly(A)-Binding Protein II; D016601:RNA-Binding Proteins