TY - JOUR
T1 - The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites
AU - Jenal, Mathias
AU - Elkon, Ran
AU - Loayza-Puch, Fabricio
AU - van Haaften, Gijs
AU - Kühn, Uwe
AU - Menzies, Fiona M
AU - Oude Vrielink, Joachim A F
AU - Bos, Arnold J
AU - Drost, Jarno
AU - Rooijers, Koos
AU - Rubinsztein, David C
AU - Agami, Reuven
N1 - Copyright © 2012 Elsevier Inc. All rights reserved.
PY - 2012/4/27
Y1 - 2012/4/27
N2 - 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.
AB - 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.
KW - 3' Untranslated Regions
KW - Animals
KW - Base Sequence
KW - Cell Line
KW - Gene Expression Regulation
KW - Humans
KW - Mice
KW - Molecular Sequence Data
KW - Muscular Dystrophy, Oculopharyngeal/genetics
KW - Mutation
KW - Poly(A)-Binding Protein II/genetics
KW - Polyadenylation
KW - RNA Processing, Post-Transcriptional
KW - RNA-Binding Proteins/metabolism
U2 - 10.1016/j.cell.2012.03.022
DO - 10.1016/j.cell.2012.03.022
M3 - Article
C2 - 22502866
VL - 149
SP - 538
EP - 553
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -