October 15, 2012

mRNA stability depends on its structure and sequence

  • The modifications at both ends of mRNA protect it against degradation by exonucleases.
  • Specific sequences within an mRNA may have stabilizing or destabilizing effects.
  • Destabilization may be triggered by loss of poly(A)  
The major features of mRNA that affect its stability are summarized in Figure 5.21. Both structure and sequence are important. The 5 and 3 terminal structures protect against degradation, and specific sequences within the mRNA may either serve as targets to trigger degradation or may protect against degradation:
  • The modifications at the 5 and 3 ends of mRNA play an important role in preventing exonuclease attack. The cap prevents 53 exonucleases from attacking the 5 end, and the poly(A) prevents 35 exonucleases from attacking the 3 end.
  • Specific sequence elements within the mRNA may stabilize or destabilize it. The most common location for destabilizing elements is within the 3 untranslated region. The presence of such an element shortens the lifetime of the mRNA.
  • Within the coding region, mutations that create termination codons trigger a surveillance system that degrades the mRNA (see 5.14 Nonsense mutations trigger a surveillance system).
Destabilizing elements have been found in several yeast mRNAs, although as yet we do not see any common sequences or know how they destabilize the mRNA. They do not necessarily act directly (by providing targets for endonucleases), but may function indirectly, perhaps by encouraging deadenylation. The criterion for defining a destabilizing sequence element is that its introduction into a new mRNA may cause it to be degraded. The removal of an element from an mRNA does not necessarily stabilize it, suggesting that an individual mRNA can have more than one destabilizing element.

A common feature in some unstable mRNAs is the presence of an AU-rich sequence of ~50 bases (called the ARE) that is found in the 3 trailer region. The consensus sequence in the ARE is the pentanucleotide AUUUA, repeated several times. Figure 5.22 shows that the ARE triggers destabilization by a two stage process: first the mRNA is deadenylated; then it decays. The deadenylation is probably needed because it causes loss of the poly(A)-binding protein, whose presence stabilizes the 3 region (see 5.13 mRNA degradation involves multiple activities).

In some cases, an mRNA can be stabilized by specifically inhibiting the function of a destabilizing element. Transferrin mRNA contains a sequence called the IRE, which controls the response of the mRNA to changes in iron concentration. The IRE is located in the 3 nontranslated region, and contains stem-loop structures that bind a protein whose affinity for the mRNA is controlled by iron. Figure 5.23 shows that binding of the protein to the IRE stabilizes the mRNA by inhibiting the function of (unidentified) destabilizing sequences in the vicinity. This is a general model for the stabilization of mRNA, that is, stability is conferred by inhibiting the function of destabilizing sequences (for review see Sachs, 1993; Ross, 1995).