Regulation of cytoplasmic mRNA decay

An Erratum to this article was published on 09 May 2012

This article has been updated

Key Points

  • Cytoplasmic mRNA decay constitutes an important post-transcriptional mechanism in mammalian cells that, together with gene transcription, precursor mRNA (pre-mRNA) processing and mRNA transport mechanisms, regulates the ultimate level of protein-encoding gene expression.

  • The regulation of cytoplasmic mRNA half-life is mediated by mRNA-binding proteins and non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs. The level and/or activity of mRNA-binding proteins can vary depending on their post-translational modifications, which can differ between different cell types or changes in cell signalling within a particular cell type; the level and/or activity of ncRNAs can be regulated by the efficiency of their formation.

  • The regulation of cytoplasmic mRNA half-life can also be affected by the translational status of the mRNA. Translation can remove regulatory proteins or ncRNAs from mRNAs should they associate with mRNA coding regions.

  • Some mechanisms of mRNA decay largely maintain the quality of gene expression, as exemplified by nonsense-mediated mRNA decay (NMD). NMD generally degrades newly synthesized mRNAs, depending on where translation terminates, and it is regulated as a means of maintaining cellular homeostasis.

  • Genes encoding protein products that contribute to a distinct phase (or phases) of the cell cycle are often regulated at the level of mRNA half-life as well as the level of transcription. An example of this is provided by metazoan histone genes, whose mRNAs that are degraded at the end of S phase when DNA synthesis is completed and there is no further need for histone protein synthesis.

  • mRNA decay is a target of numerous signal transduction pathways. Site-specific phosphorylation controls the subcellular distribution of stabilizing and destabilizing proteins and their ability to interact with degradative enzymes to activate decay.

  • Nuclear receptors can have a dual function in activating decay, by inducing the expression of one or more destabilizing proteins or by binding directly to mRNAs to activate their degradation.

  • The AU-rich elements (AREs) are the largest group of cis-acting elements controlling mRNA decay. Destabilizing ARE-binding proteins function primarily by recruiting enzymes that catalyse shortening of the poly(A) tail, and ARE-containing mRNAs are stabilized by modifications (for example, by phosphorylation) that block the recruitment of deadenylases or by competitive binding of stabilizing ARE-binding proteins.

  • Some of the enzymes that catalyse mRNA decay are themselves targets for regulation. To date, these are all endonucleases, and they are either induced in response to a particular stimulus or their enzymatic activity is increased in response to stress or to a particular stimulus.

Abstract

Discoveries made over the past 20 years highlight the importance of mRNA decay as a means of modulating gene expression and thereby protein production. Up until recently, studies largely focused on identifying cis-acting sequences that serve as mRNA stability or instability elements, the proteins that bind these elements, how the process of translation influences mRNA decay and the ribonucleases that catalyse decay. Now, current studies have begun to elucidate how the decay process is regulated. This Review examines our current understanding of how mammalian cell mRNA decay is controlled by different signalling pathways and lays out a framework for future research.

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Figure 1: NMD factors as regulators of NMD.
Figure 2: Signalling pathways that regulate translation and nonsense-mediated mRNA decay (NMD).

Change history

  • 09 May 2012

    In panel a of the figure in Box 1 of this article, the labels for the exonuclease activities were reversed. The figure has now been corrected. The editors apologize for this error.

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Acknowledgements

We thank M. Gorospe for her helpful comments and C. Gong for assistance constructing figures. We also apologize to colleagues whose work we could not cite because of page and/or reference limitations. Research in the Schoenberg and Maquat laboratories is supported by grants from the US National Institute of General Medical Sciences.

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Glossary

Nonsense-mediated mRNA decay

(NMD). In mammalian cells, this pathway targets newly synthesized mRNAs undergoing a pioneer round of translation. It generally eliminates spliced mRNAs that prematurely terminate translation but also has some physiologic targets. It competes with STAU1-mediated mRNA decay.

No-go mRNA decay

A pathway that degrades faulty mRNAs associated with stalled ribosomes. Decay is initiated by endonucleolytic cleavage near the stall site to release sequestered ribosomes and associated translation factors for the translation of other mRNAs.

Non-stop mRNA decay

A pathway that degrades mRNAs lacking a stop codon and, thus, direct translation either through the poly(A) tail owing to, for example, premature polyadenylation, or to an mRNA breakpoint. It facilitates the recycling of ribosomes and translation factors.

Exon junction complex

(EJC). A protein complex that is deposited ~20–24 nucleotides upstream of splicing-generated exon–exon junctions. It includes the nonsense-mediated mRNA decay factors UPF3X and UPF3 among many other factors.

Premature termination codon

(PTC). A stop codon that is positioned 5′ to the normal termination codon. It usually activates nonsense-mediated mRNA decay when situated >50 nucleotides upstream of a splicing-generated exon–exon junction.

SURF

A complex of SMG1, UPF1, eRF1 and eRF3 that recognizes a premature termination codon.

Mammalian target rapamycin complex 1

(mTORC1). This complex consists of the phosphatidylinositol 3 kinase (PIK)-related serine/threonine protein kinase mTOR, raptor and LST8. mTORC1 is inhibited by low nutrient levels, growth factor deprivation and other stresses so that cellular protein synthesis is concomitantly inhibited.

STAU1-mediated mRNA decay

(SMD). A pathway that degrades mRNAs that harbour a STAU1-binding site within their 3′ untranslated region. It depends on translation and on the nonsense-mediated mRNA factor UPF1.

Alternative cleavage and polyadenylation

(APA). Provides a means to vary mRNA 3′ end formation and, thus, the regulatory sequences often present within 3′ untranslated region sequences.

Mitogen-activated protein kinase

(MAPK). Proteins of this sort function in signal transduction by amplifying and integrating signals from different receptors followed by delivering each signal to one or more endpoint effector proteins.

14-3-3 adaptor proteins

A group of seven ubiquitously expressed phosphoserine/phosphothreonine-binding proteins. They can assemble into homo- or heterodimers, mediate protein–protein interactions and function in many cellular processes.

Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation

(PAR-CLIP). A method for profiling RNA that is bound to a specific protein. Cells are grown in a medium containing 4-thiouridine or 6-thioguanosine, which, when it is incorporated into RNA, allows for efficient ultraviolet crosslinking to RNA-binding proteins. The immunoprecipitated protein–RNA complexes are then used to generate libraries for deep sequencing.

RNA-binding protein immunoprecipitation

(RIP). A method for recovering RNAs by virtue of their binding by a particular protein. This uses either an antibody specific to a particular RNA-binding protein or antibody to an epitope tag on a recombinant protein expressed in target cells.

Stress granules

Large cytoplasmic foci containing non-translating mRNAs bound by the 40S ribosomal subunit. They accumulate in stressed cells, commonly as a result of translation inhibition that is secondary to the phosphorylation of eIF2α.

P bodies

Processing bodies, or P bodies, are small cytoplasmic RNA granules that are enriched for decapping proteins, activators of decapping, XRN1 and non-translating mRNAs. P bodies function as sites for mRNA storage and possibly decay.

Toll-like receptors

Single-chain, membrane-bound receptors that function in the innate immune response. Binding of bacterial cell wall components, such as lipopolysaccharides or lipomannins, activates binding of adaptor proteins that leads to the activation of NFκB and associated changes in transcription.

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Schoenberg, D., Maquat, L. Regulation of cytoplasmic mRNA decay. Nat Rev Genet 13, 246–259 (2012). https://doi.org/10.1038/nrg3160

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