KEY TERMS:
- Nonsense-mediated mRNA decay is a pathway that degrades an mRNA that has a nonsense mutation prior to the last exon.
- Surveillance systems check nucleic acids for errors. The term is used in several different contexts. One example is the system that degrades mRNAs that have nonsense mutations. Another is the set of systems that react to damage in the double helix. The common feature is that the system recognizes an invalid sequence or structure and triggers a response.
- Nonsense mutations cause mRNA to be degraded.
- Genes coding for the degradation system have been found in yeast and worm.
Another pathway for degradation is identified by nonsense-mediated mRNA decay. Figure
5.26 shows that the introduction of a nonsense mutation often leads to
increased degradation of the mRNA. As may be expected from dependence on a
termination codon, the degradation occurs in the cytoplasm. It may represent a
quality control or surveillance system for removing
nonfunctional mRNAs (for review see Hilleren and Parker, 1999).
The surveillance system has been studied best in yeast and
C. elegans, but may also be important in animal cells. For example,
during the formation of immunoglobulins and T cell receptors in cells of the
immune system, genes are modified by somatic recombination and mutation (see 25 Immune diversity). This generates a
significant number of nonfunctional genes, whose RNA products are disposed of by
a surveillance system.
In yeast, the degradation requires sequence elements (called
DSE) that are downstream of the nonsense mutation (Peltz, Brown, and Jacobson, 1993; Ruiz-Echevarria et al., 1998). The simplest
possibility would be that these are destabilizing elements, and that translation
suppresses their use. However, when translation is blocked, the mRNA is
stabilized. This suggests that the process of degradation is linked to
translation of the mRNA, or to the termination event in some direct way.
Genes that are required for the process have been identified
in S. cerevisiae (upf loci) and C. elegans
(smg loci) by identifying suppressors of nonsense-mediated degradation
(Pulak and Anderson, 1993; Cui et al., 1995). Mutations in these genes stabilize
aberrant mRNAs, but do not affect the stability of most wild-type transcripts.
One of these genes is conserved in eukaryotes (upf1/smg2). It codes for
an ATP-dependent helicase (an enzyme that unwinds double-stranded nucleic acids
into single strands). This implies that recognition of the mRNA as an
appropriate target for degradation requires a change in its structure (Weng, Czaplinski, and Peltz, 1996; Weng, Czaplinski, and Peltz, 1996).
Upf1 interacts with the release factors (eRF1 and eRF3) that
catalyze termination, which is probably how it recognizes the termination event
(Czaplinski et al., 1998). It may then "scan" the mRNA
by moving toward the 3![]()
end to
look for the downstream sequence elements.
In mammalian cells, the surveillance system appears to work
only on mutations located prior to the last exon—in other words, there must be an intron after the site
of mutation. This suggests that the system requires some event to occur in the
nucleus, before the introns are removed by splicing. One possibility is that
proteins attach to the mRNA in the nucleus at the exon-exon boundary when a
splicing event occurs (Le Hir, Moore, and Maquat, 2000). Figure 5.27 shows a general model for the operation of such
a system. This is similar to the way in which an mRNA may be marked for export
from the nucleus (see 24.10 Splicing
is connected to export of mRNA). Attachment of a protein to the exon-exon
junction creates a mark of the event that persists into the cytoplasm. Human
homologues of the yeast Upf2,3 proteins may be involved in such a system (Lykke-Andersen, Shu, and Steitz, 2000). They bind
specifically to mRNA that has been spliced.