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CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation

Nature volume 473, pages 105–108 (2011)Cite this article

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Abstract

Cytoplasmic polyadenylation-induced translation controls germ cell development1,2, neuronal synaptic plasticity3,4,5 and cellular senescence6,7, a tumour-suppressor mechanism that limits the replicative lifespan of cells8,9. The cytoplasmic polyadenylation element binding protein (CPEB) promotes polyadenylation by nucleating a group of factors including defective in germline development 2 (Gld2), a non-canonical poly(A) polymerase10,11,12, on specific messenger RNA (mRNA) 3′ untranslated regions (UTRs). Because CPEB regulation of p53 mRNA polyadenylation/translation is necessary for cellular senescence in primary human diploid fibroblasts6, we surmised that Gld2 would be the enzyme responsible for poly(A) addition. Here we show that depletion of Gld2 surprisingly promotes rather than inhibits p53 mRNA polyadenylation/translation, induces premature senescence and enhances the stability of CPEB mRNA. The CPEB 3′ UTR contains two miR-122 binding sites, which when deleted, elevate mRNA translation, as does an antagomir of miR-122. Although miR-122 is thought to be liver specific, it is present in primary fibroblasts and destabilized by Gld2 depletion. Gld4, a second non-canonical poly(A) polymerase, was found to regulate p53 mRNA polyadenylation/translation in a CPEB-dependent manner. Thus, translational regulation of p53 mRNA and cellular senescence is coordinated by Gld2/miR-122/CPEB/Gld4.

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Figure 1: Depletion of Gld2 enhances p53 expression.
Figure 2: Gld2 knockdown increases CPEB reporter mRNA and translation by a post-transcriptional mechanism.
Figure 3: miR-122 activates p53 mRNA translation by repressing CPEB.
Figure 4: Gld4 controls p53 mRNA expression.

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Acknowledgements

We thank V. Ambros, J. Steitz, T. Kowalik and R. Davis for comments. S.N. was supported by a fellowship of the Max Planck Society and by European Molecular Biology Organization fellowship ALTF 995-2004. This work was supported by National Institutes of Health grant AG30323. Additional core support from the Diabetes Endocrinology Research Center (DK32520) is acknowledged.

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  1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA

    David M. Burns, Andrea D’Ambrogio, Stephanie Nottrott & Joel D. Richter

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  2. Andrea D’Ambrogio
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Contributions

Experiments were performed by D.B. and A.D. S.N. designed and constructed luciferase reporter constructs. D.B. and J.D.R. designed the experiments and wrote the manuscript.

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Correspondence to Joel D. Richter.

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The authors declare no competing financial interests.

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Burns, D., D’Ambrogio, A., Nottrott, S. et al. CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation. Nature 473, 105–108 (2011). https://doi.org/10.1038/nature09908

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