Department of Molecular, Cellular and Developmental Biology, University of Colorado-Boulder, Boulder, CO 80309-0347 USA
* Author for correspondence (e-mail: Jens.Lykke-Andersen{at}colorado.edu )
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Summary |
---|
Key words: mRNA surveillance, Nonsense-mediated decay, Exon-junction complex
![]() |
Introduction |
---|
In addition to having a damage-control function, NMD is a critical process
in normal cellular development. For example, the immunoglobulin and T-cell
receptor genes in mammalian lymphocytes undergo dramatic rearrangement during
maturation of the immune system. This somatic recombination results in a high
frequency (66%) of frame-shifted genes containing PTCs. To cope with
this, the PTC-containing mRNAs in lymphocytes are downregulated by 90-99% by
NMD, which prevents the synthesis of defective proteins
(Carter et al., 1995
).
mRNA surveillance is an enigmatic process because it requires a cellular
machinery that can discriminate normal from aberrant mRNAs. Recent studies
have shown that in mammals, detection of PTC-containing mRNAs relies on
communication of the nuclear history of an mRNP to the translation apparatus
by a protein complex deposited upstream of exon-exon junctions after pre-mRNA
splicing. Another aspect of mRNA surveillance has recently been discovered
that functions to remove cellular mRNAs that lack in-frame termination codons.
This nonstop decay process occurs in the cytoplasm and is mediated by the
exosome, a multisubunit complex of 3'5' exonucleases. mRNA
surveillance mechanisms thus function both to maintain proper levels of normal
transcripts and to deplete aberrant transcripts from the cell.
![]() |
Biology of mRNA turnover |
---|
The prevalent route of mRNA degradation in Saccharomyces
cerevisiae proceeds via removal of the poly-A tail by deadenylation,
followed by decapping and 5'3' exonucleolytic decay
(Fig. 1)
(Decker and Parker, 1993
).
Alternatively, transcripts can be degraded from the 3' end by the
exosome (Jacobs et al., 1998
),
which may be responsible for the majority of mRNA degradation in mammals
(Mukherjee et al., 2002
;
Wang and Kiledjian, 2001
). In
addition, mRNAs can be targeted for cleavage by endoribonucleases, followed by
exonucleolytic decay from the 5' and 3' ends
(Binder et al., 1994
). By
contrast, the NMD pathway in S. cerevisiae acts via
deadenylation-independent decapping, followed by 5'
3'
exonucleolytic decay (Muhlrad and Parker,
1994
), whereas nonstop decay appears to proceed via
deadenylation-independent 3'
5' exonucleolytic decay
(Frischmeyer et al., 2002
;
van Hoof et al., 2002
). In
bypassing the rate-limiting step of deadenylation, the mRNA surveillance
pathways allow the rapid removal of irregular mRNAs from cells.
|
The NMD pathway is not solely limited to mRNAs containing a PTC within the
proper coding region. Other types of aberrant transcripts subject to NMD
include pre-mRNAs with retained introns (containing in-frame stop codons)
(Mitrovich and Anderson,
2000), a subset of mRNAs with upstream open reading frames in
their 5' UTRs (Ruiz-Echevarria and
Peltz, 2000
; Welch and
Jacobson, 1999
) and mRNAs that inherit extended 3' UTRs
owing to improper polyadenylation site usage
(Muhlrad and Parker,
1999
).
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The role of translation in mRNA surveillance |
---|
![]() |
Upf proteins: factors involved in NMD |
---|
Upf1p is the best-studied factor in NMD. It is a cytoplasmic protein that
has a cysteine-histidine-rich region at its N-terminus, reminiscent of a zinc
finger (Applequist et al.,
1997; Atkin et al.,
1997
; Bhattacharya et al.,
2000
). Upf1p is a group I helicase that has RNA-dependent ATPase
and ATP-dependent 5'
3' helicase activities
(Bhattacharya et al., 2000
;
Weng et al., 1996a
). It
interacts with translation release factors eRF1 and eRF3, which is consistent
with its roles in both translation termination and NMD
(Czaplinski et al., 1998
;
Wang et al., 2001
). Mutations
in the S. cerevisiae UPF1 gene have shown that the roles of Upf1p in
translation termination and NMD are genetically separable. For example, a
mutation in the cysteine-histidine-rich domain results in a
nonsense-suppression phenotype, but the NMD pathway remains intact. By
contrast, mutations in the Upf1p helicase domain abolish NMD function, but
translation termination proceeds normally
(Weng et al., 1996b
).
Upfs 1, 2 and 3 interact with each other in yeast and humans, and they have
been collectively termed the Upf complex. However, indirect immunofluorescence
indicates that the Upf complex is highly dynamic, because human Upf proteins
accumulate at different cellular locations. hUpf1 is cytoplasmic, hUpf2 is
mainly perinuclear, whereas hUpf3 is a predominantly nuclear,
nucleocytoplasmic shuttling protein
(Lykke-Andersen et al., 2000;
Serin et al., 2001
).
Recent results demonstrate that phosphorylation of Upf1 by SMG-1 plays an
important role in NMD in C. elegans and humans
(Denning et al., 2001;
Page et al., 1999
;
Yamashita et al., 2001
).
Phosphorylated hUpf1 preferentially interacts with hUpf3, rather than the
unphosphorylated form, which suggests that the activity of hUpf1 is modulated
by phosphorylation (Yamashita et al.,
2001
). Phospho-hUpf1 also copurifies with polysomal cell
fractions, which suggests that it functions concomitantly with translation
(Pal et al., 2001
).
Overexpression of human SMG-1 increases decay of an NMD reporter mRNA. By
contrast, overexpression of a kinaseinactive hSMG-1 mutant protein resulted in
its stabilization (Yamashita et al.,
2001
). Thus far, phosphorylation of yeast Upf1 has not been
reported, which is consistent with the absence of a SMG-1 homolog in
yeast.
![]() |
Detection of mRNAs with premature termination codons |
---|
In mammals, a PTC is recognized by its position relative to the last
exon-exon junction. As a general rule, mammalian transcripts that contain a
nonsense codon more than 50 nucleotides upstream of the last exon-exon
junction will be subjected to NMD (Zhang
et al., 1998a
; Zhang et al.,
1998b
). Accordingly, the vast majority of mammalian genes contain
the termination codon in the last exon or <50 nucleotides upstream of the
last intron (Nagy and Maquat,
1998
). This suggests that NMD requires an intron in the target
mRNA. Supporting this view is the observation that intronless transcripts,
such as hsp70 and histone mRNAs, are immune to NMD
(Maquat and Li, 2001
). How
does the mRNA surveillance machinery evaluate the nuclear processing history
of a given mRNA? The observation that pre-mRNA splicing results in alteration
of the mRNP structure and composition supports the idea that the loci of
splicing events in the nucleus are communicated to the translational machinery
by the presence of some identifying `mark' on the mRNA
(Le Hir et al., 2000b
).
Such a `mark' has indeed been found to be deposited 20-24 nucleotides
upstream of the exon-exon junction as a result of pre-mRNA splicing and is
called the exon-junction complex (EJC) (Le
Hir et al., 2000a). The EJC is a highly dynamic structure that
consists of at least eight proteins (Table
1), some of which leave the nucleus with the mRNA
(Kataoka et al., 2001
;
Kim et al., 2001a
;
Kim et al., 2001b
;
Le Hir et al., 2001b
;
Le Hir et al., 2000a
). The EJC
stimulates nuclear export of spliced mRNA
(Le Hir et al., 2001b
),
probably as a result of the interaction between the EJC subunit Aly/REF and
the nuclear export receptor TAP/p15 (Le
Hir et al., 2001a
; Luo et al.,
2001
; Stutz et al.,
2000
; Zhou et al.,
2000
). It may also function in mRNA localization, because the EJC
subunits magoh and Y14 are homologs of the Drosophila proteins Mago
nashi and Tsunagi, which may be important for localization of embryonic mRNAs
(Kataoka et al., 2001
;
Mohr et al., 2001
).
|
The importance of the EJC in NMD was demonstrated by its interaction with
hUpf3 and the observation that specific subunits, RNPS1 and to a lesser extent
Y14, are capable of triggering NMD when tethered downstream of a translation
termination codon (Kataoka et al.,
2001; Kim et al.,
2001b
; Lykke-Andersen et al.,
2001
). These data suggest that every cellular intron-containing
mRNA is tested for the position of the termination codon relative to the EJC.
In PTC-containing mRNAs, in which translation termination occurs upstream of
one or more EJCs, the hUpf proteins will bridge the translation release
factors and the EJC and trigger decay (Fig.
2). Normal mRNAs, however, remain stable because all EJCs have
been displaced by the time of translation termination
(Fig. 2). How the Upf proteins,
once assembled on the PTC-containing mRNA, trigger decay is poorly
understood.
|
![]() |
Trans-acting factors in nonstop decay |
---|
![]() |
Nucleus or cytoplasm - where's the action? |
---|
![]() |
Evolution of mRNA surveillance |
---|
![]() |
Acknowledgments |
---|
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