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CPEB1 coordinates alternative 3′-UTR formation with translational regulation

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Abstract

More than half of mammalian genes generate multiple messenger RNA isoforms that differ in their 3′ untranslated regions (3′ UTRs) and therefore in regulatory sequences1, often associated with cell proliferation and cancer2,3; however, the mechanisms coordinating alternative 3′-UTR processing for specific mRNA populations remain poorly defined. Here we report that the cytoplasmic polyadenylation element binding protein 1 (CPEB1), an RNA-binding protein that regulates mRNA translation4, also controls alternative 3′-UTR processing. CPEB1 shuttles to the nucleus5,6, where it co-localizes with splicing factors and mediates shortening of hundreds of mRNA 3′ UTRs, thereby modulating their translation efficiency in the cytoplasm. CPEB1-mediated 3′-UTR shortening correlates with cell proliferation and tumorigenesis. CPEB1 binding to pre-mRNAs not only directs the use of alternative polyadenylation sites, but also changes alternative splicing by preventing U2AF65 recruitment. Our results reveal a novel function of CPEB1 in mediating alternative 3′-UTR processing, which is coordinated with regulation of mRNA translation, through its dual nuclear and cytoplasmic functions.

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Figure 1: Nuclear CPEB1 co-localizes with SFRS2 and regulates the alternative 3′-UTR formation of BUB3 mRNA.
Figure 2: CPEs and CPEB1 directly regulate the alternative 3′-UTR formation of BUB3 mRNA.
Figure 3: CPEB1 regulates recruitment of U2AF65, the use of proximal polyadenylation sites and BUB3 mRNA translational control.
Figure 4: Model for CPEB1-mediated regulation of the alternative 3′-UTR formation.

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European Nucleotide Archive

Gene Expression Omnibus

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Acknowledgements

We thank A. Nebreda, R. Gomis, T. Yates, M. Fernandez, V. Giangarrà, J. P. Tavanez, F. Lai, I. Novoa, J. La Cava and members of the Valcarcel and Mendez laboratories for comments on the manuscript and other contributions. We also thank the Ultrasequencing Units (CRG, IRB) and the Microscopy Units (CRG, IRB) for technical assistance. This work was funded by research grants as follows: from Consolider, MICINN and Generalitat de Catalunya to J.V., R.G. and R.M.; from RNAREG to J.V. and R.M.; from AICR to R.M.; from EURASNET and Fundacion Marcelino Botin to J.V.; and from the National Institutes of Health and Instituto de Salud Carlos III to R.G. F.-A.B. holds a “la Caixa” predoctoral fellowship, and P.G.F was supported by a FCT-Portugal postdoctoral grant and by a Spanish MICINN Consolider grant.

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R.M., J.V. and F.-A.B. performed the experimental design and data analysis. C.E. contributed to the initial project development, initial experiments, experiment design and analysis. C.B.-D. contributed to the initial stages of the project, with the microarray design and cloning of the BUB-3 minigene. B.M. performed the microarray experiments. F.-A.B. performed the rest of the experiments. P.G.F. performed the bioinformatic analysis. R.G. contributed to the design and interpretation of the bioinformatic analysis. R.M. prepared the manuscript with the help of F.-A.B., P.G.F. and J.V.

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Correspondence to Raúl Méndez.

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The authors declare no competing financial interests.

Additional information

Sequencing data are available at the European Nucleotide Archive (ERP001603). The MIAME-complying microarray data have been deposited in the GEO database (GSE32440).

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This file contains Supplementary Figures 1-24, Supplementary Tables 1-15, Supplementary Text and Supplementary References. (PDF 7610 kb)

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Bava, FA., Eliscovich, C., Ferreira, P. et al. CPEB1 coordinates alternative 3′-UTR formation with translational regulation. Nature 495, 121–125 (2013). https://doi.org/10.1038/nature11901

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