CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation
Open accessAbstract
Cytoplasmic polyadenylation-induced translation controls germ cell development, neuronal synaptic plasticity and cellular senescence, a tumour-suppressor mechanism that limits the replicative lifespan of cells. 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) polymerase, 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 fibroblasts, 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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Gld2-mediated stabilization of miR-122 enables its binding to the CBEP 3' UTR, resulting in decreased p53 mRNA polyadenylation and translation.
“Also, Gld2-mediated stabilization of miR-122 enables its binding to the CBEP 3 0 UTR, resulting in decreased p53 mRNA polyadenylation and translation (Burns et al., 2011).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Burns et al., 2011
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References 27 · Cited by 193
- Authors
- Burns, D. M., D’Ambrogio, A., Nottrott, S., & Richter, J. D.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Richter, Joel D.
- ORCID
- Richter, Joel D.
- Venue
- Nature
- Published
- 2011-04-10
- Volume
- 473
- Issue
- 7345
- Pages
- 105-108
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3088779
- OpenAlex
- W2065538503
- Cited by
- 193
- References
- 27
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 10 · 2023: 9 · 2022: 12 · 2021: 9 · 2020: 18 · 2019: 13 · 2018: 15 · 2017: 10 · 2016: 12 · 2015: 7 · 2014: 14 · 2013: 17 · 2012: 33
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG030323, AG30323)
- National Cancer Institute (T32CA009151)
- National Institute of General Medical Sciences (R01GM046779)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 32520, P30DK032520)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD037267)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- CPEB, poly(A) polymerase, miR-122, mRNA translation, 3' untranslated region, cellular senescence, microRNA binding sites, translational regulation, RNA-binding proteins, hepatocellular carcinoma, liver fibrosis
- MeSH terms
- Cells, Cultured, Fibroblasts, Gene Expression Regulation, Humans, Polynucleotide Adenylyltransferase, RNA, Messenger, Transcription Factors, Tumor Suppressor Protein p53, Polyadenylation, MicroRNAs, mRNA Cleavage and Polyadenylation Factors, Gene Knockdown Techniques
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