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

Mathias Jenal, Ran Elkon, Fabricio Loayza-Puch, Gijs Van Haaften, Uwe Kühn, Fiona M. Menzies, Joachim A.F.Oude Vrielink, Arnold J. Bos, Jarno Drost, Koos Rooijers, David C. Rubinsztein, Reuven Agami*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

283 Scopus citations

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.

Original languageEnglish
Pages (from-to)538-553
Number of pages16
JournalCell
Volume149
Issue number3
DOIs
StatePublished - 27 Apr 2012
Externally publishedYes

Funding

FundersFunder number
Dutch cancer foundation), Horizon and VICI-NWO
VENI-NWO
Wellcome Trust
Seventh Framework Programme201900
European Research Council
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
KWF Kankerbestrijding

    Fingerprint

    Dive into the research topics of 'The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites'. Together they form a unique fingerprint.

    Cite this