9.7
Nonsense-mediated mRNA Decay
When an mRNA molecule is transported from the nucleus to the cytosol, as its 5ʹ end emerges from a nuclear pore, a ribosome begins to translate it.
This test translation checks the mRNA for errors and flags irregularly processed mRNAs for degradation.
In this mRNA surveillance mechanism, called the nonsense-mediated mRNA decay pathway, or NMD, the ribosome can detect if an mRNA molecule has a nonsense or stop codon in the wrong place.
Generally, a pre-mRNA can contain stop codons within introns, in addition to the intended stop codon. When this pre-mRNA is spliced and processed in the nucleus, exon junction complexes, or EJCs, bind the mRNA at each splice site.
In the test round of translation, the EJCs are displaced by the moving ribosome.
In a normally spliced mRNA, the stop codon, marked by the sequence UAA, UAG or UGA, lies within the last exon. So, when the ribosome reaches it and the translation is terminated, there are no bound EJCs.
Such an mRNA passes the quality check and is now available for further rounds of translation.
Incompletely spliced mRNAs still have nonsense codons present in the reading frame of the mRNA. This phenomenon is observed more frequently in organisms with longer introns.
As a ribosome translates this mRNA, it reaches a stop codon, before interacting with the final EJC. The stalled ribosome terminates the translation prematurely while the pathway activates the NMD response.
The bound EJC serves as a binding platform for NMD factors including Up-frameshift proteins, Upf1, Upf2, and Upf3, and a phosphorylating enzyme SMG. These proteins recruit exonucleases that degrade the faulty mRNA.
NMD surveillance is critical in selecting for genetic combinations that can produce a functional protein.
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA, Upf3 and EJC are displaced during translation. However, if there is a premature stop codon, Upf3 remains bound to EJC and marks the mutant mRNA for degradation.
Nonsense codon sequences may naturally occur in the intronic regions of an mRNA. However, a mutation can also produce a nonsense codon within a gene sequence. Such mutations are called nonsense mutations. As in the NMD pathway, these mutations also lead to premature termination of translation. The incomplete polypeptide synthesized is usually inactive. Normal function can be restored to the gene if a second mutation corrects the termination codon to an amino acid coding sequence, or suppresses the effects of the termination codon. These rectifying mutations are called nonsense suppressors. The most common nonsense suppressors are mutations in tRNA genes that produce specialized tRNAs called suppressor tRNAs. These can bind to the premature termination codon and insert an amino acid at that position.
When an mRNA molecule is transported from the nucleus to the cytosol, as its 5ʹ end emerges from a nuclear pore, a ribosome begins to translate it.
This test translation checks the mRNA for errors and flags irregularly processed mRNAs for degradation.
In this mRNA surveillance mechanism, called the nonsense-mediated mRNA decay pathway, or NMD, the ribosome can detect if an mRNA molecule has a nonsense or stop codon in the wrong place.
Generally, a pre-mRNA can contain stop codons within introns, in addition to the intended stop codon. When this pre-mRNA is spliced and processed in the nucleus, exon junction complexes, or EJCs, bind the mRNA at each splice site.
In the test round of translation, the EJCs are displaced by the moving ribosome.
In a normally spliced mRNA, the stop codon, marked by the sequence UAA, UAG or UGA, lies within the last exon. So, when the ribosome reaches it and the translation is terminated, there are no bound EJCs.
Such an mRNA passes the quality check and is now available for further rounds of translation.
Incompletely spliced mRNAs still have nonsense codons present in the reading frame of the mRNA. This phenomenon is observed more frequently in organisms with longer introns.
As a ribosome translates this mRNA, it reaches a stop codon, before interacting with the final EJC. The stalled ribosome terminates the translation prematurely while the pathway activates the NMD response.
The bound EJC serves as a binding platform for NMD factors including Up-frameshift proteins, Upf1, Upf2, and Upf3, and a phosphorylating enzyme SMG. These proteins recruit exonucleases that degrade the faulty mRNA.
NMD surveillance is critical in selecting for genetic combinations that can produce a functional protein.
From Chapter 9:
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9.7 : Nonsense-mediated mRNA Decay
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9.1 : Translation
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9.2 : tRNA Activation
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9.3 : Ribosomes
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9.5 : Initiation of Translation
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