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  • Review Article
  • Published:

Cytoplasmic RNA: a case of the tail wagging the dog

Nature Reviews Molecular Cell Biology volume 14, pages 643–653 (2013)Cite this article

Subjects

Key Points

  • RNA nucleotidyl transferases related to the canonical nuclear poly(A) polymerase modify various cytoplasmic RNAs in most eukaryotes, with the notable exception of Saccharomyces cerevisiae.

  • Regulated deadenylation is used in many biological contexts to generate cytoplasmic stores of stable, translationally inactive mRNAs. Non-canonical poly(A) polymerases restore such mRNAs to translational competence in a manner that is important for synaptic plasticity in the central nervous system.

  • Non-canonical poly(A) polymerases may also stabilize certain microRNAs, by adding single AMP residues to their 3′ ends.

  • Similarly, cytoplasmic RNA terminal uridylyl transferases add single UMP residues, or oligo(U) tails, to a range of microRNAs and their precursors. This results in the proper processing or turnover of the RNA substrate, according to its identity and the extent of its uridylation.

  • Cytoplasmic uridylyl transferases also modify mRNA 3′ ends in many eukaryotes, targeting the mRNAs for decapping and/or exonucleolytic decay.

  • The addition of non-templated nucleotides to RNA 3′ ends is consequently a widespread and multifaceted aspect of regulation of eukaryotic gene expression.

Abstract

The addition of poly(A) tails to eukaryotic nuclear mRNAs promotes their stability, export to the cytoplasm and translation. Subsequently, the balance between exonucleolytic deadenylation and selective re-establishment of translation-competent poly(A) tails by cytoplasmic poly(A) polymerases is essential for the appropriate regulation of gene expression from oocytes to neurons. In recent years, surprising roles for cytoplasmic poly(A) polymerase-related enzymes that add uridylyl, rather than adenylyl, residues to RNA 3′ ends have also emerged. These terminal uridylyl transferases promote the turnover of certain mRNAs but also modify microRNAs, their precursors and other small RNAs to modulate their stability or biological functions.

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Figure 1: Cytoplasmic mRNA deadenylation, decay and quality control.
Figure 2: Cytoplasmic polyadenylation and the control of synaptic plasticity.
Figure 3: Addition of non-templated nucleotides to pre-miRNAs and miRNAs.
Figure 4: Uridylation of cytoplasmic mRNAs.

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Acknowledgements

The author apologises to those whose work could not be cited directly owing to space constraints and is grateful to D. Scott for comments on the manuscript. Work in the author's laboratory is supported by the Breast Cancer Campaign and Cancer Research UK.

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  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK

    Chris J. Norbury

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  1. Chris J. Norbury
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PowerPoint slides

Glossary

DNA polymerase-β

(Pol β). A non-processive eukaryotic DNA polymerase that acts in the base excision DNA repair pathway to fill in single-strand DNA gaps.

Poly(A) polymerases

(PAPs). Nucleotidyl transferases that covalently add multiple AMP moieties from ATP to the 3′-OH group of an RNA substrate.

Exosome

In this context, a multisubunit ribonuclease complex with associated endonuclease and 3′–5′ exonuclease activities (note that the same term is used in other contexts to denote a membrane-bound secretory vesicle generated by exocytosis). The catalytic subunit of the cytoplasmic exosome is Rrp44 (also known as Dis3) in yeast and DIS3L in human cells.

Terminal uridylyl transferases

(TUTs). Nucleotidyl transferases that covalently add one or more UMP moieties from UTP to the 3′-OH group of an RNA substrate.

Nonsense-mediated decay

(NMD). A quality control pathway by which mRNAs containing premature termination codons are targeted for destruction. A substantial proportion of fully functional mRNAs are also targeted for degradation by NMD factors.

MicroRNAs

(miRNAs). Short (∼22 nucleotides) single-stranded cytoplasmic RNAs, processed from highly structured primary transcripts via sequential cleavage by the RNase III enzymes Drosha and Dicer. When loaded onto proteins of the Argonaute family, miRNAs negatively regulate target mRNAs to which they are at least partially complementary.

Sm-like proteins

A widely conserved family of RNA-binding proteins that are structurally related to the Sm proteins. LSM1–LSM7 form a seven-membered ring, initially identified through its association with the U6 small nuclear RNA.

Meiotic maturation

The hormonally triggered resumption of meiosis in a metazoan oocyte, resulting in the formation of an egg.

Synaptic plasticity

The phenomenon, thought to be fundamental to memory and learning, by which synaptic connections between neurons can become potentiated or attenuated as a result of particular patterns of stimulation.

Long-term potentiation

A form of synaptic plasticity in which long-term synaptic strength is increased in response to repeated neuronal stimulation.

PIWI-interacting RNAs

Short, non-coding RNAs that are expressed in animal germ cells and bound by PIWI proteins of the Argonaute family. They act principally to inhibit the expression of retrotransposons.

siRNAs

Short, non-coding RNAs that negatively regulate target gene expression when bound to Argonaute proteins, these approximately 21 base pair duplex RNAs with two-nucleotide 3′ overhangs are generated by Dicer cleavage of double-stranded RNA.

Circularized rapid amplification of cDNA ends

(cRACE). A technique involving circularization of RNA molecules using RNA ligase, subsequent reverse transcription and PCR amplification of the junction corresponding to the two ends of the RNA molecule. It allows the description of the two ends of an RNA molecule without requiring prior knowledge of their precise positions or sequences.

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Norbury, C. Cytoplasmic RNA: a case of the tail wagging the dog. Nat Rev Mol Cell Biol 14, 643–653 (2013). https://doi.org/10.1038/nrm3645

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