The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites

Cell. 2012 Apr 27;149(3):538-53. doi: 10.1016/j.cell.2012.03.022. Epub 2012 Apr 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Mice
  • Molecular Sequence Data
  • Muscular Dystrophy, Oculopharyngeal / genetics
  • Muscular Dystrophy, Oculopharyngeal / metabolism
  • Mutation
  • Poly(A)-Binding Protein II / genetics
  • Poly(A)-Binding Protein II / metabolism*
  • Polyadenylation*
  • RNA Processing, Post-Transcriptional*
  • RNA-Binding Proteins / metabolism

Substances

  • 3' Untranslated Regions
  • Poly(A)-Binding Protein II
  • RNA-Binding Proteins

Associated data

  • GEO/GSE27452