mRNA surveillance

mRNA surveillance is the group of cellular processes responsible for the 'quality control' of mRNA transcripts by degrading those transcripts that, as a result of some error in transcription or post-transcriptional modification, would either produce non-functional proteins or damage the protein-translating ability of a ribosome. Surveillance is essential in ensuring that proteins are correctly and efficiently synthesised in the cell. There are three known processes of mRNA surveillance:

  • Nonsense-mediated mRNA decay
  • Nonstop-mediated mRNA decay
  • No-go-mediated mRNA decay

In nonsense-mediated mRNA decay, the goal is to destroy mRNA molecules with nonsense mutations that would lead to premature termination of polypeptide synthesis at the ribosome. When the translation of a protein aborts too early, a surveillance complex of proteins is recruited to the 'suspect' mRNA responsible. The protein complex scans the mRNA for errors. It distinguishes a nonsense mutation from a genuine stop codon by its relative position to the DNA sequence downstream of it. Various studies suggest that an mRNA will be marked for decay if the mutation is >50 nucleotides upstream of the last exon-exon junction on the transcript (such junctions are marked by proteins called exon junction complexes, EJCs). If the stop codon were <50 nucleotides of this location then it would be assumed to be a genuine stop codon and no decay pathway would be initiated. However, exceptions have been found: some mRNAs with a nonsense mutation very early in the reading frame (close to the 3' UTR) have evaded decay via this pathway.

In nonstop-mediated mRNA decay, the goal is to destroy mRNA molecules that lack any stop codons at all. This can arise, for example, when the 3' polyadenylated tail added during post-transcriptional modification is attached to the mRNA prematurely, before the stop codon sequence has been transcribed. This is problematic in the cell because without a stop codon, release factors do not become available, and the ribosome is 'stalled', unable to release the mRNA transcript. The NSMD pathway not only liberates the ribosome so it is free to continue translation, but also marks the aberrant mRNA for degradation by the cell's nucleases. The NSMD pathway has two sub-pathways which likely act together to destroy the mRNA:
  • The Ski-7 pathway is dependent on a protein called Ski-7. Ski-7 binds to the A site of the ribosome (see the translation article for details of ribosome sites) and liberates the ribosome for further translation. It is then associated with the non-stop mRNA, targeting it to an exosome. The Ski-7-exosome complex then degrades the poly-A tail on the 5' end of the mRNA, allowing the exosome to proceed and decay the mRNA in a 5'-3' direction.
  • The non-Ski-7 pathway the 5'-methyl7guanosine cap is lost and the mRNA is open to degradation by exonucleases

In no-go-mediated mRNA decay, mRNA that has stalled a ribosome and become trapped mid-translation due to strong secondary structure interactions is cleaved (thereby liberating the stalled ribosome) and then endonucleolytically degraded by proteins such as Dom34-Hbs1. The proteins involved in this pathway also serve to block further translation factors from binding to the ribosome. The degraded fragments of mRNA are then fully degraded in the 3' to 5' direction by the exosome and in the 5' to 3' direction by an exonuclease called Xnr1.