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Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression

Abstract

In eukaryotes, poly(A) tails are present on almost every mRNA. Early experiments led to the hypothesis that poly(A) tails and the cytoplasmic polyadenylate-binding protein (PABPC) promote translation and prevent mRNA degradation, but the details remained unclear. More recent data suggest that the role of poly(A) tails is much more complex: poly(A)-binding protein can stimulate poly(A) tail removal (deadenylation) and the poly(A) tails of stable, highly translated mRNAs at steady state are much shorter than expected. Furthermore, the rate of translation elongation affects deadenylation. Consequently, the interplay between poly(A) tails, PABPC, translation and mRNA decay has a major role in gene regulation. In this Review, we discuss recent work that is revolutionizing our understanding of the roles of poly(A) tails in the cytoplasm. Specifically, we discuss the roles of poly(A) tails in translation and control of mRNA stability and how poly(A) tails are removed by exonucleases (deadenylases), including CCR4–NOT and PAN2–PAN3. We also discuss how deadenylation rate is determined, the integration of deadenylation with other cellular processes and the function of PABPC. We conclude with an outlook for the future of research in this field.

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Fig. 1: Overview of the function of mRNA poly(A) tails as master regulators of gene expression in the cytoplasm.
Fig. 2: mRNA poly(A) tails stimulate translation.
Fig. 3: Eukaryotic mRNA deadenylation and decay.
Fig. 4: Deadenylation by PAN2–PAN3 and CCR4–NOT.
Fig. 5: Factors that influence deadenylation rate.
Fig. 6: Summary of recent insights into gene regulation by poly(A) tails.

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Acknowledgements

We thank A. Jacobson, M. Wickens, F. He, T. Tang, E. Absmeier, J. Leipheimer, S. Martin, R. Kawalerski and members of the Passmore and Coller laboratories for helpful insight and discussion. This Review would not have been possible without contributions from many individuals; this field has been rich in discovery, collaboration and friendship. We thank all of you and apologize for any oversights we may have made. In particular, we dedicate this Review to the memory of Dr Elisa Izaurralde and Dr Richard Jackson; their seminal discoveries and keen intellect have inspired us all. Funding is provided to L.A.P. by the European Union’s Horizon 2020 research and innovation programme (ERC grant No. 725685) and the Medical Research Council as part of United Kingdom Research and Innovation (MRC grant No. MC_U105192715) and to J.C. by the National Institutes of Health (USA; GM118018 and GM125086) and Bloomberg Philanthropies.

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Glossary

mRNA decay

The process of removing mRNA from the cytosolic pool of transcripts. Decay of mRNA occurs in a defined pathway with each mRNA having an intrinsic half-life.

Translation efficiency

The amount of protein output relative to the amount of transcribed mRNA.

Bypass suppressors

A mutation at a distinct locus, which restores viability following mutation of an essential gene. Bypass suppressors often provide insight into the function of essential genes.

Intrinsically disordered regions

(IDRs). Polypeptide segments enriched in polar or charged amino acids and lacking hydrophobic amino acids that would mediate cooperative folding. IDRs generally lack a secondary structure.

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Passmore, L.A., Coller, J. Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00417-y

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