Cell, Voi.

81, 179-188, April 21, 1995, Copyright 1995 by Cell Press

Review

Degradation of mRNA in Eukaryotes

Clare A. Beelman* and Roy Parker*t

*Department of Molecular and Cellular Biology
tHoward Hughes Medical Institute
University of Arizona
Tucson, Arizona 85721

decay independently of deadenylation. This diversity of

decay pathways, in addition to different rates of decay for
individual mRNAs within one pathway, allows for a wide
spectrum of mRNA half-lives and for their differential regulation.

mRNA turnover is important in determining the levels and

regulation of gene expression. Recent results have defined several different, yet somewhat related, mechanisms
by which eukaryotic mRNAs are degraded (Figure 1). One
mRNA decay pathway is initiated by shortening of the
poly(A) tail followed by decapping and 5' to 3' exonucleolytic degradation of the transcript. A variation of this pathway has been observed in which transcripts undergo 3' to
5' decay after poly(A) shortening. Decay of mRNAs can also
initiate prior to shortening of the poly(A) tail. For example,
some specific transcripts can be degraded via deadenylation-independent decapping followed by 5' to 3' degradation. In addition, mRNA decay can also begin by endonucleolytic cleavage in the transcript body. These pathways
suggest a model of mRNA turnover in which all polyadenylated mRNAs are degraded by a"default" pathway initiated
by poly(A) shortening. In addition, pathways limited to subsets of mRNAs exist in which specific sequences trigger

Deadenylation Can Be the First Step

in mRNA Decay
Several observations suggest that shortening of poly(A)
tails is required for the decay of many eukaryotic mRNAs
(for reviews see Decker and Parker, 1994; Bernstein and
Ross, 1989; Peltz et al., 1991). Some of the key observations are as follows. First, in transcriptional pulse-chase
experiments (wherein a regulatable promoter is used to
produce a burst of synchronous transcription), the mammalian c-los mRNA and several yeast mRNAs do not decay until their poly(A) tails have been shortened (Shyu et
al., 1991; Decker and Parker, 1993), This temporal correlation is significant because mutations within unstable
mRNAs that decrease the rate of deadenylation or transfer
of sequences capable of stimulating rapid deadenylation
to a stable reporter mRNA correspondingly alter the time
at which the transcript begins to decay (Shyu et al., 1991;
Wilson and Triesman, 1988; Muhlrad and Parker, 1992;
Decker and Parker, 1993; Chen et al., 1994). In addition,

DEADENYLATION-DEPENDENT DECAY

DEADENYLATION-INDEPENDENT DECAY

UM

m7GI AUG

POLY (A) SHORTENING

m7GI AUG

UAA

T/

DEADENLYATION- /

ENDONUCLEOL'gTIC

CLEAVAGE

JAAA LOt~,

I AAA ou~

I/gkA u~a

m7G[ AUG

5' TO 3' DECAY

DECAPPING
~AOG l i ~ ;
/

u.

\
3' TO 5' DECAY

IAAA~
5' TO 3' DECAY

5'TO 3' DECAY

~;,oG

o"

I~ ou~o

Figure 1. mRNA Decay Pathwaysin Eukaryotes

The left pathway depicts deadenylation-dependentdecay, which can lead to decapping and 5' to 3' exonucleolyticdecay or to 3' to 5' decay
mediated by endonucleases,exonucleases,or both. All eukaryotic mRNAs may undergo decay via this deadenylation-dependentpathwayunless
they are targeted for rapid deadenlyation-independentdecapping, by a nonsensecodon,or for endonucleolyticcleavage,by presenceof a cleavage
site (right). After deadenylation-independentdecapping, mRNA is degraded in a 5' to 3' manner. Endonucleolyticcleavage of mRNA may serve
as a one-step deadenylationthat leads to decapping and 5' to 3' decay.

Cell
180

intermediates in decay can be detected in yeast that accumulate after deadenylation and have oligo(A) tails, even
at times when the population consists of a mixture of
poly(A) and oligo(A) tails (Decker and Parker, 1993; Muhltad et al., 1994).
The length to which a poly(A) tail must be shortened
for subsequent decay may differ between mammals and
yeast. A poly(A) tail of - 25-60 adenosine residues is sufficient to allow decay of some mammalian transcripts (Shyu
et al., 1991; Chen et al., 1994), whereas yeast transcripts
decay when the poly(A) is - 1 0 - 1 2 adenosine residues
(Decker and Parker, 1993). Deadenylation to - 10-12 residues as seen in yeast might lead to the loss of the last
poly(A)-binding protein associated with the transcript, and
the loss of poly(A)-binding protein may trigger further decay events. It is possible that the disassociation of poly(A)binding protein may occur at a longer poly(A) tail length
in mammalian cells.

Deadenylation Can Trigger Decapping

and 5' to 3' Decay of mRNA
One important question is how deadenylation leads to
mRNA degradation. In yeast, observations indicate that
deadenylation to an oligo(A) tail allows the mRNA to become a substrate for a decapping reaction within the first
few nucleotides of the transcript, thereby exposing the
transcript body to 5' to 3' exonucleolytic decay. The critical
observations are that when 5' to 3' decay is blocked in
yeast, either by deletion of the XRN1 gene, which encodes
a major 5' to 3' exonuclease (Larimer and Stevens, 1990),
or by the insertion of strong RNA secondary structures,
mRNA fragments lacking the cap structure accumulate
after deadenylation (Muhlrad et al., 1994, 1995). This is
true for both unstable and stable mRNAs. In addition, several other mRNAs also accumulate in xrnl/t strains as
transcripts that have, at most, short (A) tails and that lack
the cap structure (Hsu and Stevens, 1993). These results
suggest this pathway of degradation is a general mechanism of decay that acts on many yeast transcripts.
Since poly(A) tails and cap structures are common features of eukaryotic transcripts, an appealing model is that
mRNA decay by deadenylation-dependent decapping and
5' to 3' digestion is a conserved mechanism of m R NA tu rnover. Although there is to date no direct data for such a
pathway in more complex eukaryotes, mRNAs lacking the
cap structure are rapidly degraded in many eukaryotic
cells (e.g., Drummond et al., 1985). In addition, enzymes
that could catalyze the removal of the cap structure and
subsequent 5' to 3' degradation of the transcript have been
described in mammalian cells (e.g., Coutts and Brawerman, 1993). Finally, the oat phytochrome A mRNA undergoes a cleavage near the 5' terminus of the mRNA and is
degraded, in part, in a 5' to 3' direction (Higgs and Colbert,
1994). Taken together, these data raise the possibility that
deadenylation-dependent decapping followed by 5' to 3'
exonucleolytic decay may be a conserved eukaryotic
mRNA decay mechanism.
Interactions between the 5' and 3' Termini
of mRNAs
The observation that deadenylation can lead to removal

of the 5'cap structure (Muhlrad et al., 1994, 1995) suggests

an interaction between the 5' and 3' ends of an mRNA.
Interactions between the transcript termini have been proposed to explain the effects that the poly(A) tail and 3'
untranslated region (3'UTR) sequences can have on translation initiation (Munroe and Jacobson, 1990; for review
see Jackson and Standart, 1990). A unifying hypothesis
is that the same 5' to 3' interaction may mediate the rates
of translation initiation and decapping. Although there is
no direct biochemical evidence for such a 5' to 3' interaction, the abundance of circular polysomes seen in some
electron micrographs suggests that the transcript termini
can be in close proximity (e.g., Christensen et al., 1987).
The nature of the 5' to 3' interaction may allow the poly(A)
tail to inhibit decapping indirectly or directly. For example,
because mRNAs may interact with the cytoskeleton
through their poly(A) tails (e.g., Taneja et al., 1992), the
putative 5' to 3' interaction may cause deadenyiation to
alter the subcellular localization of an mRNA, thereby
exposing it to a localized decapping activity. Alternatively,
the poly(A) tail might inhibit decapping directly by forming
or stabilizing an mRNP structure involving the 5' and 3'
termini of the mRNA.

Deadenylation Can Also Lead to 3' to 5' Decay

of mRNA
Eukaryotic mRNAs can also be degraded in a 3' to 5' direction following deadenylation. For example, fragments of
the yeast PGK1 mRNA shortened at the 3' end accumulate
when the 5' to 3' decay pathway is blocked (Muhlrad and
Parker, 1994; Muhlrad et al., 1995). Decay intermediates
that are consistent with 3' to 5' decay following deadenylation have also been observed for the oat phytochrome A
mRNA in vivo (Higgs and Colbert, 1994). It is not known
whether exonucleases, endonucleases, or both are involved in 3'to 5'decay or how prevalent this decay pathway
may be. However, it should not be expected that deadenylation necessarily exposes transcripts to 3' to 5' degradation since several mRNAs can be quite stable with essentially no poly(A) tail (e.g., Decker and Parker, 1993; Chert
et al., 1994).
An important point is that an individual transcript can
simultaneously be a substrate for more than one mechanism of decay. For example, both the oat phytochrome A
and yeast PGK1 transcripts undergo deadenylation-dependent 3' to 5' decay in addition to a 5' to 3' decay mechanism
(Higgs and Colbert, 1994; Muhlrad et al., 1995). The presence of multiple overlapping pathways has several consequences. First, the observed half-life for an mRNA will be
a summation of the rates of decay through each individual
pathway. In addition, the mechanism by which an mRNA
is degraded may change under different conditions, even
without a significant alteration of decay rate (e.g., Muhlrad
et al., 1995). The existence of multiple decay pathways
also suggests that mutations that inactivate one pathway
may not always have significant effects on mRNA stability,
yet combinations of mutations inactivating different pathways may exhibit synergistic effects on stability and possibly viability. A system of redundant overlapping mechanisms of mRNA turnover is highly analogous to that

Review:rnRNADegradation
181

observed in Escherichia coil (for review see Belasco and

Brawerman, 1993).

In deadenylation-dependent mRNA decay, differences in

mRNA stability result from differences in the rates of
poly(A) shortening and steps required for the subsequent
decay of the deadenylated transcript. Thus, features of
mRNAs that influence the rates of poly(A) shortening, decapping, and possibly 3' to 5' decay will affect mRNA stability. The rate of 5' to 3' digestion of the transcript body
appears to be relativelyfast and therefore unlikely to contribute to differences in decay rates. This is based on the
observation that intermediates of 5' to 3' decay are not
observed unless the XRN1 nuclease has been deleted or
a secondary structure blocks the nuclease (Decker and
Parker, 1993; Hsu and Stevens, 1993; Muhlrad et al.,
1994). Several sequence elements within mRNAs that promote rapid poly(A) shortening have been identified. These
include sequences within the c-fos coding region and
3'UTR, which contains a prototypical AU-rich element
(ARE) (Wilson and Triesman, 1988; Shyu et al., 1989; Wellington et al., 1993; Chen et al., 1994; Schiavi et al., 1994),
and in the yeast MFA2 3'UTR (Muhlrad and Parker, 1992;
Decker and Parker, 1993; Muhlrad et al., 1994). Interestingly, mutations in the c-los ARE and the MFA2 3'UTR
can also slow degradation following deadenylation (Shyu
et al., 1991; Muhlrad and Parker, 1992). Thus, at least for
the MFA2 mRNA, 3'UTR sequences can also specify the
rate of decapping.
There is little information about the nucleases involved
in deadenylation-dependent decay and how mRNA sequences modulate their rate of activity. The product of the
XRN1 gene appears to be the primary nuclease responsible for 5'to 3' degradation of yeast mRNAs after decapping
(Hsu and Stevens, 1993; Muhlrad et al., 1994). Decapping
activities (Nuss et al., 1975; Kumagai et al., 1992; Coutts
and Brawerman, 1993) and poly(A) nucleases (,~str0m et
al., 1991, 1992; Sachs and Deardorff, 1992; Lowell et al.,
1992) have been biochemically defined in cell extracts of
yeast and mammals, although the in vivo roles of these
particular activities remain to be established. Several proteins have been identified that interact with the ARE
(Malter, 1989; Bohjanen et al., 1991; Vakalopoulou, 1991;
Chen et al., 1992; Zhang et al., 1993; Katz et al., 1994)
and therefore might modulate deadenylation rate. However, only one of these proteins, called the ARE/poly(U)binding factor, has been shown to stimulate decay in an
in vitro system (Brewer, 1991). Progress in this area may
be aided by the identification of proteins that bind to a
small sequence, UUAUUUA(U/A)(U/A), determined to be
important for a functional ARE to stimulate mRNA decay
(Lagnado et al., 1994; Zubiaga et al., 1995).
~

(Muhlrad and Parker, 1994; Hagan et al., 1995). The degradation of mRNAs with nonsense codons is part of a process, termed mRNA surveillance, that ensures the rapid
degradation of aberrant transcripts. These aberrant
mRNAs contain early nonsense codons (Losson and Lacroute, 1979; Leeds et al., 1991; Peltz et al., 1993; Pulak
and Anderson, 1993), unspliced introns (He et al., 1993),
or extended 3'UTRs (Pulak and Anderson, 1993). mRNA
surveillance occurs in many organisms and thus appears
to be a conserved process. Mutations in related genes
that inactivate this surveillance pathway have been identified in yeast and nematodes, named upland smg mutants,
respectively (Hodgkin et al., 1989; Leeds et al., 1991,
1992).
mRNA surveillance may exist, in part, to increase the
fidelity of gene expression by degrading aberrant mRNAs
that, if translated, would produce truncated proteins. This
process would be relevant since truncated proteins can
have dominant negative phenotypes. A striking example
of this phenomenon is seen in Caenorhabditis elegans,
where mutations in smg genes convert recessive nonsense mutations in the myosin gene uric-54 into dominant
negatives (Pulak and Anderson, 1993). Since mRNA surveillance degrades unspliced and aberrantly processed
transcripts, this decay mechanism might be most important in organisms with a large number of introns where
processing errors might lead to truncated proteins.
How a nonsense-containing transcript is recognized as
aberrant and how mRNA decay is triggered are unclear.
The simplest model is that premature translation termination sends a signal to expose the 5' end immediately to
decapping by the same nucleases that degrade normal
mRNAs. This hypothesis is supported by the observations
that the sites of decapping are the same in deadenylationindependent and deadenylation-dependent decapping (cf.
Muhlrad and Parker, 1994 with Muhlrad et al., 1995), and
the XRN1 exonuclease performs 5' to 3' decay in both
cases. The generation of the destabilizing signal requires
both the failure to translate a significant part of the coding
region and the presence of specific sequences downstream of the nonsense codon (Cheng et al., 1990; Peltz
et al., 1993; Zhang et al., 1995). In a similar mechanism,
transcripts with extended 3'UTRs may also be recognized
and degraded because destabilizing sequences that are
not normally in the mRNA are now included within the
extended 3'UTR.
A related and surprising observation is that early nonsense mRNAs can reduce the levels of fully spliced but
nuclear-associated transcripts (Belgrader et al., 1994;
Baserga et at., 1992). One possibility is that the first round
of translation occurs while the transcripts are still nuclear
associated and that premature termination during this
round of translation can generate the signal to expose the
5' end to decapping.

Deadenylation-lndependent Decapping:
mRNA Surveillance

Decay of EukaryoUc mRNA via

Endonucleolytic Cleavage

mRNA decay can also be initiated by decapping and 5'

to 3'decay of the transcript independent of poly(A) shortening. An example of this process is the degradation of the
yeast PGK1 mRNA containing an early nonsense codon

Eukaryotic mRNAs can be degraded via endonucleolytic

cleavage prior to deadenylation. Evidence for this mechanism comes from the analysis of transcripts such as mammalian 9E3, IGF2, transferrin receptor (TfR), and Xenopus

Determination of mRNA Decay Rates via

Deadenylation-Dependent Decay

Cell
182

X/hbox2B mRNA where mRNA fragments are detected in

vivo that correspond to the 5' and 3' portion of the transcript
and are consistent with internal cleavage within the 3'UTR
(Stoekle and Hanafusa, 1989; Nielson and Christiansen,
1992; Binder et al., 1994; Brown et al., 1993). It appears
that deadenylation to an oligo(A) tail length is not required
for endonucleolytic cleavage since the 3' fragment of 9E3
and TfR mRNAs is polyadenylated(Stoekle and Hanafusa,
1989; Binder et al., 1994) and since cleavage of the
Xlhbox2B mRNA is not affected by the adenylation state
of the mRNA (Brown et al., 1993). However, it is possible
that endonucleolytic cleavage of some mRNAs could be
dependent on the length of the poly(A) tail. Endonucleolytic cleavages have also been defined in vitro for the albumin mRNA (Dompenciel et al., 1995) and in the coding
region of the c-myc mRNA (Bernstein et al., 1992). Since
there does not appear to be any similarity between the
cleavage sites in these mRNAs, there may be a wide
variety of endonucleases with different cleavage specificities.
Since sequence-specific endonuclease target sites are
likely to be limited to individual mRNAs or classes of
mRNAs, their presence allows for specific control of the
decay rate of these transcripts. In some cases, the rate
of endonucleolytic cleavage is modulated by the activity
of protective factors that bind at or near the cleavage site
and compete with the endonuclease (Brown et al., 1993;
Binder et al., 1994). For example, the binding of the iron
response element-binding protein in the TfR 3'UTR in response to low intracellular iron concentrations inhibits the
endonucleolytic cleavage of this mRNA (Binder et al.,
1994). Therefore, some endonucleases may be constitutively active, and the accessibility of the cleavage site is
regulated.
In other cases, the endonuclease activity may be directly
regulated. For example, the mammalian endonuclease
RNase L is normally inactive and is only activated by oligomers of 2',5' phosphodiester-bonded adenylate residues,
which are produced in response to the presence of doublestranded RNA (for discussion see Silverman, 1994). Although RNase L is important in mediating interferon responses (e.g., Hassel et al., 1993), it has yet to be
established whether this enzyme normally degrades any
cellular mRNAs.

Summary

Based on the above mechanisms of mRNA degradation,

an integrated model of mRNA turnover can be proposed
(Figure 1). In this model, all polyadenylated mRNAs would
be degraded by the deadenylation-dependentpathway at
some rate. In addition to this default pathway, another
layer of complexity would come from degradation mechanisms specific to individual mRNAs or to classes of
mRNAs. Such mRNA-specific mechanisms would include
sequence-specific endonuclease cleavage and deadenylation-independent decapping. Thus, the overall decay
rate of an individual transcript will be a function of its susceptibility to these turnover pathways. In addition, cisacting sequences that specify mRNA decay rate, as well

as regulatory inputs that control mRNA turnover, are likely

to affect all the steps of these decay pathways.
One important goal in future work will be to identify the
gene products that are responsible for the nucleolytic
events in these pathways and to delineate how specific
mRNA features act to affect the function of these degradative activities. The identification of distinct mRNA decay
pathways should allow genetic and biochemical approaches that can be designed to identify these gene products. A second important goal is to understand the nature
of the interaction between the 5' and 3' termini, which may
also be critical for efficient translation.
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