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

被引：273
作者：
Jenal, Mathias [1 ]
Elkon, Ran [1 ]
Loayza-Puch, Fabricio [1 ]
van Haaften, Gijs [1 ]
Kuehn, Uwe [2 ]
Menzies, Fiona M. [3 ]
Vrielink, Joachim A. F. Oude [1 ]
Bos, Arnold J. [1 ]
Drost, Jarno [1 ]
Rooijers, Koos [1 ]
Rubinsztein, David C. [3 ]
Agami, Reuven [1 ,4 ]
机构：
[1] Netherlands Canc Inst, Div Gene Regulat, NL-1066 CX Amsterdam, Netherlands
[2] Univ Halle Wittenberg, Inst Biochem & Biotechnol, D-06120 Halle, Germany
[3] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England
[4] Ctr Biomed Genet, NL-3584 CG Utrecht, Netherlands
来源：
CELL | 2012年 / 149卷 / 03期
基金：
欧洲研究理事会; 瑞士国家科学基金会; 英国惠康基金;
关键词：
OCULOPHARYNGEAL MUSCULAR-DYSTROPHY; MESSENGER-RNA POLYADENYLATION; 3' UNTRANSLATED REGIONS; B-CELL DIFFERENTIATION; POLY(A) TAIL LENGTH; BINDING PROTEINS; CANCER; MICRORNAS; GENES; TRANSCRIPTION;
D O I：
10.1016/j.cell.2012.03.022
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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 30 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.
引用
收藏
页码：538 / 553
页数：16
相关论文
共 44 条
  • [1] To localize or not to localize: mRNA fate is in 3′UTR ends
    Andreassi, Catia
    Riccio, Antonella
    [J]. TRENDS IN CELL BIOLOGY, 2009, 19 (09) : 465 - 474
  • [2] Nuclear poly(A)-binding protein PABPN1 is associated with RNA polymerase II during transcription and accompanies the released transcript to the nuclear pore
    Bear, DG
    Fomproix, N
    Soop, T
    Björkroth, B
    Masich, S
    Daneholt, B
    [J]. EXPERIMENTAL CELL RESEARCH, 2003, 286 (02) : 332 - 344
  • [3] Patterns of variant polyadenylation signal usage in human genes
    Beaudoing, E
    Freier, S
    Wyatt, JR
    Claverie, JM
    Gautheret, D
    [J]. GENOME RESEARCH, 2000, 10 (07) : 1001 - 1010
  • [4] 3′-End Sequencing for Expression Quantification (3SEQ) from Archival Tumor Samples
    Beck, Andrew H.
    Weng, Ziming
    Witten, Daniela M.
    Zhu, Shirley
    Foley, Joseph W.
    Lacroute, Phil
    Smith, Cheryl L.
    Tibshirani, Robert
    van de Rijn, Matt
    Sidow, Arend
    West, Robert B.
    [J]. PLOS ONE, 2010, 5 (01):
  • [5] Rules of engagement: co-transcriptional recruitment of pre-mRNA processing factors
    Bentley, DL
    [J]. CURRENT OPINION IN CELL BIOLOGY, 2005, 17 (03) : 251 - 256
  • [6] Epidemiology and inheritance of oculopharyngeal muscular dystrophy in Israel
    Blumen, SC
    Nisipeanu, P
    Sadeh, M
    Asherov, A
    Blumen, N
    Wirguin, Y
    Khilkevich, O
    Carasso, RL
    Korczyn, AD
    [J]. NEUROMUSCULAR DISORDERS, 1997, 7 : S38 - S40
  • [7] Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy
    Brais, B
    Bouchard, JP
    Xie, YG
    Rochefort, DL
    Chrétien, N
    Tomé, FMS
    Lafrenière, RG
    Rommens, JM
    Uyama, E
    Nohira, O
    Blumen, S
    Korcyn, AD
    Heutink, P
    Mathieu, J
    Duranceau, A
    Codère, F
    Fardeau, M
    Rouleau, GA
    [J]. NATURE GENETICS, 1998, 18 (02) : 164 - 167
  • [8] Deciphering the cellular pathway for transport of poly(A)-binding protein II
    Calado, A
    Kutay, U
    Kühn, U
    Wahle, E
    Carmo-Fonseca, M
    [J]. RNA, 2000, 6 (02) : 245 - 256
  • [9] Over-expression of BCL2 rescues muscle weakness in a mouse model of oculopharyngeal muscular dystrophy
    Davies, Janet E.
    Rubinsztein, David C.
    [J]. HUMAN MOLECULAR GENETICS, 2011, 20 (06) : 1154 - 1163
  • [10] Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice
    Davies, JE
    Wang, L
    Garcia-Oroz, L
    Cook, LJ
    Vacher, C
    O'Donovan, DG
    Rubinsztein, DC
    [J]. NATURE MEDICINE, 2005, 11 (06) : 672 - 677
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