The Poly(A)-Binding Protein Nuclear 1 Suppresses Alternative Cleavage and Polyadenylation Sites | Zendy

Mathias Jenal | Zendy; Ran Elkon | Zendy; Fabricio LoayzaPuch | Zendy; Gijs van Haaften | Zendy; Uwe Kühn | Zendy; Fiona M. Menzies | Zendy; Joachim A.F. Oude Vrielink | Zendy; Arnold J. Bos | Zendy; Jarno Drost | Zendy; Koos Rooijers | Zendy; David C. Rubinsztein | Zendy; Reuven Agami | Zendy

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The Poly(A)-Binding Protein Nuclear 1 Suppresses Alternative Cleavage and Polyadenylation Sites

Author(s) -

Mathias Jenal,

Ran Elkon,

Fabricio LoayzaPuch,

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

Publication year - 2012

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2012.03.022

Subject(s) - biology , polyadenylation , oculopharyngeal muscular dystrophy , rna interference , cleavage (geology) , three prime untranslated region , psychological repression , cyclin d1 , cleavage and polyadenylation specificity factor , microbiology and biotechnology , microrna , untranslated region , rna , genetics , gene , gene expression , muscular dystrophy , cell cycle , paleontology , fracture (geology)

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.

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