Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes

Subjects

Key Points

  • Nonsense-mediated mRNA decay (NMD) degrades mRNAs with translation termination codons in abnormal contexts.

  • NMD targets mRNAs encoding truncated proteins with no or undesired functions, thereby preventing the accumulation of such transcripts and of the potentially aberrant proteins that they encode.

  • NMD targets some mRNAs with intact open reading frames, thereby directly affecting gene expression programmes.

  • NMD reduces the levels of mRNAs related to various normal cellular processes, through its interplay with programmed DNA rearrangements, changes in pre-mRNA processing or reprogramming of mRNA translation.

  • NMD is essential for embryogenesis and other developmental processes.

  • Upregulation and downregulation of NMD are essential for an efficient cellular response to stress and for its subsequent alleviation, respectively.

Abstract

Nonsense-mediated mRNA decay (NMD) is probably the best characterized eukaryotic RNA degradation pathway. Through intricate steps, a set of NMD factors recognize and degrade mRNAs with translation termination codons that are positioned in abnormal contexts. However, NMD is not only part of a general cellular quality control system that prevents the production of aberrant proteins. Mammalian cells also depend on NMD to dynamically adjust their transcriptomes and their proteomes to varying physiological conditions. In this Review, we discuss how NMD targets mRNAs, the types of mRNAs that are targeted, and the roles of NMD in cellular stress, differentiation and maturation processes.

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Figure 1: Normal and nonsense-mediated mRNA decay (NMD)-activating translation termination.
Figure 2: Nonsense-mediated mRNA decay (NMD) in heterozygous carriers of premature termination codons (PTCs).
Figure 3: Importance of nonsense-mediated mRNA decay (NMD) for T cell maturation.
Figure 4: Regulating the expression homeostasis of splicing activators and splicing repressors.
Figure 5: Translation of alternative open reading frames (ORFs) can activate nonsense-mediated mRNA decay (NMD).
Figure 6: Global and local modulation of nonsense-mediated mRNA decay (NMD) activity.

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Acknowledgements

The authors apologize to those researchers whose work was not cited due to space limitations, and thank Christian Kroun Damgaard, Jens Lykke-Andersen and four insightful reviewers for their critical assessments of the manuscript. Research in the authors' laboratory is funded by the European Research Council, the Danish National Research Foundation (grant DNRF58), the Lundbeck Foundation and the Novo Nordisk Foundation.

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Glossary

Exon–junction complex

(EJC). A complex deposited upstream of most exon–exon junctions following splicing. The EJC stimulates export and translation.

Deadenylase

A 3′–5′ exoribonuclease with specificity for poly(A) moieties.

General decapping complex

A protein complex responsible for the hydrolysis of the 7-methylguanosine (m7G) cap situated at mRNA 5′ ends.

β-thalassaemia

A blood disorder caused by mutations in the β-globin (HBB) gene on chromosome 11, which leads to reduced or absent production of haemoglobin β-chains.

Haploinsufficiency

A phenotype caused by the insufficient expression of a functional factor as a result of a mutation in one of the two encoding alleles.

Waardenburg syndrome type 4C

An auditory–pigmentary syndrome that is characterized by pigmentary abnormalities of the eye, deafness and gastrointestinal disease.

Integrated stress response

Various cellular stresses that act (partly) through the inactivation of the eukaryotic translation initiation factor subunit eIF2.

Programmed ribosomal frameshifting

A shift of the reading frame by one or two nucleotides (in the 5′ or 3′ direction), directed by a mRNA structural element.

Selenoproteins

Proteins containing one or more of the non-conventional amino acid selenocysteine.

Selenocysteine insertion sequence

(SECIS). A 60 nt RNA sequence element situated downstream of a UGA termination codon in selenoprotein-coding mRNAs.

Histone mRNA degradation

An up frameshift 1 (UPF1)-dependent degradation mechanism mediated by its binding of stem–loops at the 3′ end of replication-dependent histone mRNAs.

Staufen 1-mediated mRNA decay

(SMD). The degradation of substrates with extended double-stranded 3′ UTR structures that bind one, or both, of the up frameshift 1 (UPF1)-recruiting Staufen paralogues STAU1 and STAU2.

Axonal growth cones

Dynamic extensions at the tips of axons. Growth cones are able to rapidly change direction and branch in response to stimuli.

Commissural neurons

A tract of nerve fibres passing from one side to the other of the spinal cord or the brain.

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Lykke-Andersen, S., Jensen, T. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol 16, 665–677 (2015). https://doi.org/10.1038/nrm4063

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