Nonsense-mediated mRNA decay (NMD) is one of the best characterized and most evolutionarily conserved cellular quality control mechanisms. Although NMD was first found to target one-third of mutated, disease-causing mRNAs, it is now known to also target ~10% of unmutated mammalian mRNAs to facilitate appropriate cellular responses — adaptation, differentiation or death — to environmental changes. Mutations in NMD genes in humans are associated with intellectual disability and cancer. In this Review, we discuss how NMD serves multiple purposes in human cells by degrading both mutated mRNAs to protect the integrity of the transcriptome and normal mRNAs to control the quantities of unmutated transcripts.
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The authors thank X. Rambout and H. Cho for critically reading the manuscript and R. Green for helpful conversations. The authors apologize to colleagues whose work was not referenced owing to space limitations. Work on nonsense-mediated mRNA decay in the Maquat laboratory is supported by the National Institutes of Health R01 grant GM059614. T.K. was partially supported by a Schmitt Program in Integrative Neuroscience from the University of Rochester Medical Center.
- Dominant-negative proteins
Mutated proteins that can antagonize the function of the wild-type protein, often because the proteins are part of a macromolecular complex, which is rendered defective by the presence of the mutated protein.
Thalassaemia is a blood disorder causing anaemia. In the severe form of β0-thalassaemia, no β-globin protein is detectable in peripheral blood.
- NMD-activating feature
An mRNA feature that increases the probability of the mRNA undergoing nonsense-mediated mRNA decay. Examples include an exon–exon junction complex deposited as a consequence of splicing more than ~30–35 nucleotides downstream of a termination codon, an unusually long (>1 kb) 3′ untranslated region or a selenocysteine codon that is interpreted as a stop codon.
- Upstream open reading frame
(uORF). A short ORF in the 5′ end of mRNA (upstream of the main ORF) that can regulate the translation of the main ORF.
- A site
The amino-acyl site on the ribosome is where charged tRNA molecules (with the exception of the translation-initiating charged tRNA) bind during protein synthesis.
- Peptidyl-tRNA hydrolysis
A process that occurs during translation when a water molecule attacks the bond between the nascent peptide and the tRNA molecule in the ribosome, thereby releasing the completed polypeptide.
- Staufen-mediated mRNA decay
An mRNA decay pathway in which the staufen protein recruits UPF1 to an mRNA 3′ untranslated region, causing translation-dependent destabilization of the mRNA.
A large protein complex that degrades mRNAs through its 3′-to-5′ exoribonuclease activities.
An amino acid that is inserted into mRNA bearing a selenocysteine insertion sequence that directs its incorporation at UGA codons, which otherwise would be recognized as termination codons.
- Intron retention
Occurs when an intron fails to be excised out of a pre-mRNA during alternative splicing, giving rise to a transcript with a premature termination codon.
- Programmed ribosomal frameshifts
(PRFs). During translation, incidents of ribosome ‘slippage’ and adoption of a new reading frame.
A tertiary RNA structure formed by base pairing between the loop of a stem–loop structure and nearby ribonucleotides. It is extremely difficult for helicases to unwind this structure.
- Waardenburg syndrome
A disease manifesting defects in tissues derived from cells in the neural crest lineage (neurocristopathy). Individuals with Waardenburg syndrome have defects in hair, skin and eye pigmentation and may suffer from hearing loss.
- Hirschprung disease
A congenital malady in which nerve cells are missing from the end of the bowel, thereby causing problems with passing stool.
- Lujan–Fryns syndrome
An X-linked disorder causing mild to moderate intellectual disability, facial dysmorphism and arms and legs that are abnormally long and slender.
- FG syndrome
An X-linked disorder characterized by intellectual disability, poor muscle tone and macrocephaly.
- Tumour neo-antigens
Peptides absent from normal cells that are produced by tumour-mutated genes that are presented to and activate the immune system.