Key Points
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Changes in mRNA-decay rates account for a large proportion of regulated gene expression.
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The predominant pathway initiates with deadenylation. Subsequently, the mRNA can either undergo decapping and 5′→3′ decay, or 3′→5′ decay. Many of the enzymes and regulatory factors for these processes have now been described.
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Recently, cytoplasmic structures, known as P bodies, which are sites of mRNA decay, have been identified.
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There are minor pathways of decay for certain mRNAs. These include pathways initiated by deadenylation-independent decapping and endoribonucleolytic cleavage.
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There are several surveillance mechanisms to degrade aberrant and unwanted mRNAs. These include nonsense-mediated decay, non-stop decay and no-go decay.
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Turnover of mRNAs is a highly regulated process that responds to cellular signals. Sequences within the mRNA, such as AU-rich elements, can determine the rate of decay under various conditions.
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RNA-binding proteins recognize sequence elements and modulate the rate of decay, some by recruiting the decay machinery, others by remodelling the conformation of messenger ribonucleoprotein.
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The process of mRNA decay is just one aspect of mRNA metabolism, but it is intimately linked with other processes, including translation, transcription and mRNA localization.
Abstract
When considering the control of gene expression, the focus has traditionally been on transcriptional regulation. Recently, however, the large contribution made by mRNA decay has become difficult to ignore. Large-scale analyses indicate that as many as half of all changes in the amounts of mRNA in some responses can be attributed to altered rates of decay. In this article, we discuss some of the mechanisms that are used by the cell to mediate and regulate this intriguing process.
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Acknowledgements
Research in the Wilusz laboratory is supported by grants from the National Institutes of Health. We thank N. Kedersha for supplying Figure 2 and for her insights on P bodies. We are also grateful to members of the Wilusz laboratory and S. Vasudevan for reading and commenting on the manuscript. We apologize to those authors whose work we were unable to cite due to lack of space.
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DATABASES
Saccharomyces Genome database
FURTHER INFORMATION
Glossary
- mRNA-surveillance pathway
-
Mechanism used by the cell to identify and destroy aberrant mRNAs.
- Poly(A) tail
-
A homopolymeric stretch of ∼25–200 adenine nucleotides that is present at the 3′ end of most eukaryotic mRNAs.
- Exonuclease
-
Also known as an exoribonuclease. An enzyme that catalyses the removal of mononucleotides from either the 5′ or 3′ end of an RNA molecule.
- Polysome
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Two or more ribosomes that are bound to different sites on the same mRNA.
- 5′ cap
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The 7-methylguanosine structure found at the 5′ end of a eukaryotic mRNA.
- Decapping
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The removal of the mRNA 5′-cap structure.
- Exosome
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A large complex of 3′→5′ exonucleases that functions in the nucleus and the cytoplasm in several different RNA-processing and RNA-degradation pathways.
- Transcriptome
-
The pool of mRNAs that is present in the cell under a given condition.
- Deadenylase
-
An enzyme that removes the 3′-poly(A) tail from RNA in a 3′→5′ direction.
- RNase D
-
Escherichia coli RNase D is a 3′→5′ exoribonuclease that is required for processing of tRNA precursors. Many eukaryotic proteins with similar exoribonuclease domains have been identified.
- RNA helicase
-
An enzyme that catalyses the unwinding of the RNA secondary structure.
- RNase PH
-
E. coli RNase PH is a phosphorolytic 3′→5′ exoribonuclease that is involved in the maturation of tRNA precursors.
- Sm-like domain
-
A protein domain that is similar to that found in the Sm proteins associated with the small nuclear RNAs of the splicing machinery.
- Endonuclease
-
Also known as an endoribonuclease. An enzyme that catalyses the hydrolysis of ester linkages within an RNA molecule by creating internal breaks.
- Stress granule
-
A cytoplasmic structure that develops in mammalian cells during certain types of cellular stress. It is believed to be a site where translationally repressed mRNAs are stored or sorted for decay. P bodies often assemble close to stress granules.
- Cartilage hair hypoplasia
-
A recessively inherited developmental disorder characterized by short stature, fine and sparse hair, immune deficiency and a predisposition to malignancy. The defect is caused by mutations in RNase MRP.
- Messenger ribonucleoprotein
-
(mRNP). A complex that comprises an mRNA and associated RNA-binding proteins.
- 14-3-3 proteins
-
A large family of small, acidic proteins that interact predominantly with proteins that are phosphorylated on serine or threonine residues. 14-3-3 proteins have been implicated in many intracellular-signalling events through their ability to regulate catalytic activity, subcellular localization and protein–protein interactions.
- A site
-
The site at which the ribosome binds an aminoacylated tRNA for addition to the elongating peptide chain.
- Heterogeneous nuclear ribonucleoprotein
-
(hnRNP). A historic term used to describe protein complexes that associate with mRNAs and pre-mRNAs in the nucleus.
- KH domain
-
An RNA-binding domain that was first identified in the hnRNP K protein.
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Garneau, N., Wilusz, J. & Wilusz, C. The highways and byways of mRNA decay. Nat Rev Mol Cell Biol 8, 113–126 (2007). https://doi.org/10.1038/nrm2104
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DOI: https://doi.org/10.1038/nrm2104
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