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 - Vrielink, Joachim A.F.Oude
AU - Bos, Arnold J.
AU - Drost, Jarno
AU - Rooijers, Koos
AU - Rubinsztein, David C.
AU - Agami, Reuven
N1 - Funding Information:
We thank all members of the Agami group including Bob Rosier for technical help and discussions. We thank Roderick Beijersbergen, Pasi Halonen, and Ben Morris from the NKI Robotics and screening center. Further we are grateful to Arno Velds and Ron Kerkhoven at the NKI Central genomics facility for deep sequencing our samples. This work was supported by funds from the ERC (European Research Council), KWF (Dutch cancer foundation), Horizon and VICI-NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek), and CBG (Centre for Biomedical Genetics) to R.A., the SNF (The Swiss National Science Foundation) to M.J., the VENI-NWO to G.v.H., and the Wellcome Trust Principal Research Fellowship to D.C.R.
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.
UR - http://www.scopus.com/inward/record.url?scp=84860317107&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.03.022
DO - 10.1016/j.cell.2012.03.022
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AN - SCOPUS:84860317107
SN - 0092-8674
VL - 149
SP - 538
EP - 553
JO - Cell
JF - Cell
IS - 3
ER -