Leading Edge

Review

RNA Quality Control in Eukaryotes

Meenakshi K. Doma1,2 and Roy Parker1,*
1
Department of Molecular and Cellular Biology and Howard Hughes Medical Institute, University of Arizona, Tucson, AZ 85721, USA
2
Present address: HHMI and Division of Biology, Mail Code 156-29, California Institute of Technology, 1200 E. California Blvd.,
Pasadena, CA 91125, USA.
*Correspondence: rrparker@email.arizona.edu
DOI 10.1016/j.cell.2007.10.041

Eukaryotic cells contain numerous RNA quality-control systems that are important for
shaping the transcriptome of eukaryotic cells. These systems not only prevent accumulation
of nonfunctional RNAs but also regulate normal mRNAs, repress viral and parasitic RNAs,
and potentially contribute to the evolution of new RNAs and hence proteins. These quality-
control circuits can be viewed as a series of kinetic competitions between steps in normal
RNA biogenesis or function and RNA degradation pathways. These RNA quality-control
circuits depend on specific adaptor proteins that target aberrant RNAs for degradation as
well as the coupling of individual steps in mRNA biogenesis and function.

Introduction mechanisms have evolved that preferentially degrade

The biogenesis and function of RNAs in eukaryotic cells aberrant or nonfunctional RNAs. Here, we discuss the
involves a series of transitions of RNAs between differ- diversity, principles, and consequences of RNA quality
ent protein complexes and subcellular compartments. control in eukaryotes.
For example, the process of mRNA biogenesis and func- Aberrant RNAs arise by a variety of events. For exam-
tion involves transcription, capping, splicing, polyadeny- ple, aberrant mRNAs can be caused by mutations in the
lation, nuclear-cytoplasmic transport, translation, and gene—such as those that create premature translation
degradation in the cytoplasm. During these processes, termination codons—that trigger rapid mRNA degra-
the mRNA associates in a dynamic manner with vari- dation (Maquat, 2004). Aberrant RNAs also arise from
ous complexes that both catalyze steps in biogenesis the inherent error rate of transcription, nuclear pre-RNA
or function and promote exchange between the proteins processing, or ribonucleoprotein (RNP) assembly of oth-
that associate with the mRNA, thereby affecting subse- erwise normal transcripts. For example, transcription of
quent events (Dreyfuss et al., 2002; Moore, 2005). Similar variant 5S ribosomal genes from a large gene family in
complex mechanisms of biogenesis and function occur frog oocytes produces some transcripts that fail to termi-
for small nuclear (sn)RNAs, small nucleolar (sno)RNAs, nate properly; such transcripts then misfold and are tar-
tRNAs, rRNAs, and micro (mi)RNAs (reviewed in Wolin geted for degradation (Shi et al., 1996). Indeed, aberrant
and Matera, 1999; Nazar, 2004; Kim, 2005). To avoid RNAs may often be produced from multigene families
errors in RNA biogenesis and function, quality-control due to the reduced selective pressure on each individual

Table 1. Quality Control of Cytoplasmic RNAs

RNA Defect Basis of Specificity Consequence of Quality Control
tRNA Defective tRNA unknown Rapid tRNA decay (RTD) by an unknown nuclease (Alex-
­modification androv et al., 2006)
rRNA Functional defect in unknown Nonfunctional rRNA decay (NRD), decay of mutant rRNA
rRNA by an unknown mechanism (LaRiviere et al., 2006)
mRNA Aberrant translation Recruitment of Upf proteins to Nonsense-mediated decay (NMD), rapid deadenylation,
termination termination complex decapping, 3′-5′ decay, and some endonuclease cleav-
ages (Isken and Maquat, 2007)
mRNA No stop codon Recruitment of Ski7p to elonga- Nonstop decay (NSD), Ski7p recruitment of exosome, and
tion stall with no mRNA in A site rapid 3′-5′ degradation (van Hoof et al., 2002; Frischmey-
of the ribosome er et al., 2002)
mRNA Strong stall in transla- Recruitment of Hbs1p and No-Go decay (NGD), endonucleolytic cleavage, and exo-
tion elongation Dom34p to A site of the ribosome nucleolytic decay of fragments (Doma and Parker, 2006)
mRNA Translation beyond Unknown, removal of 3′ UTR Ribosome extension-mediated decay (REMD), accelerat-
normal stop codon into binding proteins? ed deadenylation, and decay (Kong and Liebhaber, 2007;
3′ UTR Inada and Aiba, 2005)

660  Cell 131, November 16, 2007 ©2007 Elsevier Inc.

Figure 1. Diversity of RNA Quality-Control Systems in Eukaryotes
The figure depicts some of the known RNA quality-control systems for aberrant rRNA, mRNA, and tRNA in eukaryotic cells. These and additional
quality-control mechanisms are summarized in Tables 1 and 2.

gene copy (O’Brien and Wolin, 1994). Aberrant RNAs can 2000), whereas in mammals the Rrp6p ortholog, PM/
also be produced by transcription of intergenic regions, Scl100, is observed in both the cytoplasm and nucleus
which yields RNAs that lack functional characteristics (Lejeune et al., 2003).
and are thus rapidly degraded (Thompson and Parker,
2007; Wyers et al., 2005; Davis and Ares, 2006). Finally, Quality Control of Cytoplasmic RNAs
quality-control systems also repress the function of, or Several quality-control mechanisms in the cytoplasm
degrade, parasitic RNAs arising from repetitive elements degrade eukaryotic mRNAs that have abnormalities in
and transposons. translation (Table 1; Figure 1). An emerging principle is
RNA quality-control mechanisms are known to tar- that aberrant mRNAs can be distinguished from normal
get aberrant RNAs for degradation by a few conserved mRNAs by adaptor proteins that interact with the trans-
nucleases (reviewed in Parker and Song, 2004; House- lation machinery and direct the aberrant mRNAs into a
ley et al., 2006; Isken and Maquat, 2007). Quality con- degradation pathway. In a pathway referred to as non-
trol in the cytoplasm is carried out by the exosome sense-mediated decay (NMD), mRNAs with premature
comprising a ten-subunit core complex that catalyzes translation termination codons are distinguished from
3′ to 5′ exonucleolytic degradation and Xrn1p, a 5′ to 3′ normal mRNAs in a process involving the conserved Upf
exonuclease that requires its mRNA target molecules proteins and their interactions with a translation termina-
to be decapped. In the nucleus, the exosome plays the tion complex (for detailed review, see Isken and Maquat,
major role in RNA quality control, although a paralog 2007). Depending on the organism or cell type, NMD can
of Xrn1p, termed Xrn2/Rat1p in yeast, may also affect target aberrant mRNAs for decapping and 5′ to 3′ deg-
nuclear RNA degradation (Fang et al., 2005; Danin-Kre- radation by Xrn1p; endonucleolytic cleavage; or acceler-
iselman et al., 2003; Bousquet-Antonelli et al., 2000). ated deadenylation and 3′ to 5′ degradation by the exo-
In the yeast nucleus, the core exosome complex also some (Isken and Maquat, 2007). In a process referred to
associates with an additional 3′ to 5′ exonuclease as nonstop decay (NSD), ribosomes that have reached
called Rrp6p (Allmang et al., 1999; Burkard and Butler, the end of mRNAs lacking translation termination codons

Cell 131, November 16, 2007 ©2007 Elsevier Inc.  661

Table 2. Nuclear RNA Quality Control

RNA Defect Consequences of Quality Control

tRNA (yeast) Missing modification, TRAMP-dependent adenylation and 3′-5′ decay by the exosome (Kadaba et
­processing defects al., 2004; Vanacova et al., 2005; Schneider et al., 2007)
rRNA (yeast and Stochastic errors or defects TRAMP-dependent adenylation and 3′ to 5′ decay by the exosome (Dez et
plants) in rRNA processing and/or al., 2006; Win et al., 2006; LaCava et al., 2005; J. Ecker and D. Belostotsky,
assembly personal communication); retention of immature ribosomes in the nucleus
(Dez et al., 2007); adenylation by poly(A) polymerase and Rrp6-dependent
decay (Kuai et al., 2004); nuclear 5′ to 3′ decay by Rat1p (Fang et al., 2005)
rRNA (yeast) Generation of aberrant Adenylation and Rrp6p-dependent degradation (Fang et al., 2004)
rRNA by incorporation of
5-fluorouracil
5S rRNA (yeast) Mutations or defective Ro protein-dependent decay by unknown mechanism (Shi et al., 1996; Fuchs
processing et al., 2006; O’Brien and Wolin, 1994; Stein et al., 2005); adenylation and 3′ to
5′ degradation (Kadaba et al., 2006)
SnRNAs and Stochastic errors or mutant TRAMP-dependent adenylation and 3′ to 5′ decay by exosome (Kadaba
snoRNAs (yeast forms et al., 2006; Egecioglu et al., 2006; Win et al., 2006; LaCava et al., 2005; J.
and plants) Ecker and D. Belostotsky, personal communication); adenylation and Rrp6p-
dependent degradation (Davis and Ares, 2006)
mRNA (yeast) Hyperadenylation/hypoad- Rrp6p and/or core exosome-dependent nuclear retention and degradation of
enylation; defects in THO/ RNA (Hilleren et al., 2001; Rougemaille et al., 2007; Libri et al., 2002; Thom-
Sub2 complex; defects in 3′ sen et al., 2003; Das et al., 2003, 2006; Torchet et al., 2002)
end processing
mRNA (mammals) Failure of polyadenylation or Retention of the mRNA near or at the transcription site (Custodio et al., 1999)
splicing defects
mRNA (mammals) Absence of introns in a Accelerated nuclear degradation dependent on 3′ poly(A) tail (Conrad et al.,
gene that normally contains 2006)
introns
mRNA (yeast) Splicing defect: not recog- Export and cytoplasmic decapping and 5′ to 3′ decay (Hilleren and Parker,
nized by spliceosome 2003; Legrain and Rosbash, 1989); retention in nucleus by MLP proteins
(Sommer and Nehrbass, 2005)
mRNA (yeast) Splicing defect; trapped Nuclear degradation by exosome (Bousquet-Antonelli et al., 2000); debranch-
lariat intermediate ing, export, and cytoplasmic 5′ to 3′ decay by Xrn1p (Hilleren and Parker,
2003)
mRNA (yeast) Defect in capping Export and 5′ to 3′ decay by cytoplasmic Xrn1p (Schwer et al., 1998)

dsRNA (mammals) Double-stranded RNA RNA editing and nuclear retention (Zhang and Carmichael, 2001; DeCerbo
and Carmichael, 2005)
Intergenic No known function after TRAMP-dependent adenylation and 3′ to 5′ decay by the exosome (Thomp-
­transcripts (yeast transcription son and Parker, 2007; Wyers et al., 2005; Davis and Ares, 2006; J. Ecker and
and plants) D. Belostotsky, personal communication); export and 5′ to 3′ degradation by
decapping and Xrn1p (Thompson and Parker, 2007)

recruit the exosome through the action of Ski7p—a para- act with the stalled ribosome. Finally, when ribosomes
log of the eEF1A (eukaryotic translation elongation fac- inappropriately translate and then terminate within the
tor 1A)—and eRF3 (eukaryotic release factor 3) proteins, 3′ UTR at least some mRNAs are destabilized in a pro-
which interact with the ribosomal A site during elon- cess referred to as ribosome extension-mediated decay
gation or termination, respectively (Frischmeyer et al., (REMD) (Inada and Aiba, 2005; Kong and Liebhaber,
2002; van Hoof et al., 2002). This suggests that Ski7p 2007).
recognizes the empty A site produced when a ribosome Pathways also exist to degrade cytoplasmic rRNA and
reaches the 3′ end of an mRNA. Similarly, when mRNAs tRNAs that are defective in function. Specifically, yeast
have strong pauses in elongation, the mRNA is targeted rRNAs incorporated into ribosomes that are defective in
for endonucleolytic cleavage in a process referred to as either peptide bond formation or the initiation of transla-
No-Go decay (NGD) (Doma and Parker, 2006). NGD is tion are degraded faster than wild-type rRNAs (LaRiviere
promoted by the Hbs1 and Dom34 proteins, which are et al., 2006). Similarly, yeast tRNAs that are missing mul-
paralogs of the translation termination factors eRF3 and tiple modifications are more rapidly degraded (Alexan-
eRF1 (eukaryotic release factor 1) and presumably inter- drov et al., 2006). The manner by which these defective

662  Cell 131, November 16, 2007 ©2007 Elsevier Inc.

rRNAs and tRNAs are targeted for degradation remains aberrant mRNAs are more rapidly degraded and accumu-
to be determined. One possibility is that ribosomes or late in the nucleus when degradation is inhibited (Conrad
tRNAs that are not engaged in translation are more sus- et al., 2006).
ceptible to general nucleases, perhaps because of the An important aspect of RNA quality control in the
absence of appropriate interacting proteins. nucleus are specialized polyadenylation complexes
referred to as TRAMP complexes, which contain a non-
Quality Control of Nuclear RNAs canonical poly(A) polymerase (Trf4 or Trf5 in yeast), an
Numerous quality-control systems target nuclear RNAs RNA-binding protein (Air1 or Air2), and an RNA helicase
that are defective in RNA-processing events (summa- (Mtr4) (LaCava et al., 2005). Multiple lines of evidence
rized in Table 2, Figure 1). These nuclear quality-control argue that TRAMP complexes adenylate aberrant RNAs
systems lead to three related mechanisms for preventing and thereby stimulate 3′ to 5′ degradation by Rrp6p and/
the function of the aberrant RNA. First, some defective or the exosome by providing a single-stranded extension
RNAs are exported to the cytoplasm for degradation. For for nuclease loading. For example, many of the aberrant
example, mutant yeast pre-mRNAs that are trapped as RNAs or precursors that accumulate in yeast strains or
lariats prior to the second step of pre-mRNA splicing are plants defective in nuclear exosome function contain 3′
debranched and exported to the cytoplasm for 5′ to 3′ poly(A) tails, which are often dependent on the action of
digestion by Xrn1p (Hilleren and Parker, 2003). Similarly, Trf4 and/or Trf5 (Kadaba et al., 2004, 2006; Dez et al.,
some apparently nonfunctional intergenic transcripts 2006; Egecioglu et al., 2006; LaCava et al., 2005; Wyers
appear to be exported and degraded in the cytoplasm et al., 2005; J. Ecker and D. Belostotsky, personal com-
(Thompson and Parker, 2007). munication). Moreover, experiments in vitro have shown
Aberrant or unprocessed nuclear RNAs can also be that polyadenylation of defective tRNAs can promote their
retained within the nucleus (Table 2). Nuclear retention degradation by the exosome (Vanacova et al., 2005). The
may be important both to give time for RNA processing role of polyadenylation in stimulating RNA decay by 3′ to
to be completed and to allow for a kinetically unfavor- 5′ exonucleases—which is similar to the role of polyade-
able nuclear degradation pathway to degrade the RNA nylation in prokaryotes—is a conserved mechanism to
(see below). Examples of nuclear retention of aberrant target RNAs for 3′ to 5′ destruction (Dreyfus and Regnier,
mRNAs include the retention of mRNAs with defects 2002). The features that dictate preferential polyadeny-
in splicing or polyadenylation in both yeast and mam- lation, and thereby degradation, of some RNAs by the
malian cells (Custodio et al., 1999; Hilleren et al., 2001; TRAMP complex are unresolved. Possibilities include
Jensen et al., 2001). Interestingly, these aberrant RNAs the specific recruitment of the TRAMP complex by RNA-
are retained in the vicinity of the gene (Custodio et al., binding proteins preferentially bound to aberrant RNAs.
1999; Thomsen et al., 2003), which has the potential Alternatively, TRAMP complexes may polyadenylate any
to have feedback effects on transcription (see below). exposed RNA 3′ end at some rate such that whether an
Similarly, long double-stranded (ds)RNAs that are RNA is a substrate for polyadenylation and degradation
extensively edited to contain inosines can be retained may simply be a kinetic competition with normal RNA
within the nucleus by binding a nuclear lamin-associ- processing and export (see below).
ated complex consisting of p54nrb, PSF, and matrin Several perplexing observations indicate that our
3 (Zhang and Carmichael, 2001; DeCerbo and Carmi- understanding of the functions of the TRAMP and/or exo-
chael, 2005). some complexes in nuclear RNA metabolism is incom-
Some aberrant RNAs appear to be degraded within the plete. First, strains lacking Trf4 and Rrp6 show increased
nucleus (Table 2). This conclusion is based on the obser- levels, but also increased RNA decay rates, of the inter-
vation that lesions in the nuclear 5′ to 3′ exonuclease genic Srg1 transcript, which is primarily degraded in
Xrn2p, Rrp6p, and/or core exosome components show the cytoplasm (Thompson and Parker, 2007). Second,
increased levels of several RNAs, processing interme- in addition to their role in nuclear degradation, Rrp6p
diates, or intergenic transcripts. For example, yeast or and the nuclear core exosome are required for retention
plants defective in nuclear exosome function accumulate of mRNAs with aberrant 3′ end processing in the vicin-
precursors of tRNAs, snoRNAs, snRNAs, and rRNAs, ity of the gene (Hilleren et al., 2001; Rougemaille et al.,
suggesting that some of these precursors are normally 2007; Thomsen et al., 2003; Libri et al., 2002). Finally,
targeted for degradation by the exosome and are only the observable population of yeast mRNAs with defects
revealed when the degradation process is blocked (All- in poly(A) tail lengths, or defects in the THO/Sub2 com-
mang et al., 2000; Kadaba et al., 2004, 2006; van Hoof et plex, which promotes mRNP biogenesis and export, are
al., 2000; Egecioglu et al., 2006; J. Ecker and D. Belosto- surprisingly stable (Mandart and Parker, 1995; Hilleren
tsky, personal communication). Evidence that at least the and Parker, 2001; Rougemaille et al., 2007). One pos-
defective ribosomal subunits are degraded in the nucleus sible explanation for these observations is that aberrant
is that when degradation is inhibited, the defective ribo- transcripts retained at the gene have a feedback effect
somal subunits are observed to accumulate in nuclear to decrease transcription, perhaps by forming RNA-DNA
foci (Dez et al., 2006). Similarly, when mammalian intron- hybrids and decreasing transcriptional elongation (Huer-
containing mRNAs are lacking their introns, the resulting tas and Aguilera, 2003), although recent nuclear run-on

Cell 131, November 16, 2007 ©2007 Elsevier Inc.  663

experiments argue against this model (Rougemaille et Recent observations also suggest connections
al., 2007). Alternatively, nuclear degradation may occur between silencing by small RNAs and degradation of RNA
in competition with assembly of the RNA-processing by the TRAMP and exosome complexes. For example, in
machinery on nascent transcripts. In this view, either fission yeast, efficient silencing of centromeric regions
transcripts are degraded so rapidly that they cannot be by small RNAs involves TRAMP-dependent targeting of
observed in the steady-state population (Thompson and some transcripts to Rrp6p and/or the exosome (Buhler
Parker, 2007; Rougemaille et al., 2007) or the transcripts et al., 2007). Defects in the exosome also reduce silenc-
associate with the processing machinery and are stable ing at the mating type locus, suggesting that silencing
until processed, which would prevent ongoing degrada- of heterochromatic regions may sometimes involve RNA
tion of transcripts undergoing processing. degradation of nascent transcripts (Buhler et al., 2007).
Moreover, in Chlamydomonas reinhardtii, a noncanoni-
Quality Control of Parasitic RNAs cal poly(A) polymerase is required for efficient decay
RNA quality-control systems, some of which involve of siRNA-targeted transcripts and appears to stimulate
the TRAMP and exosome complexes, also play a role their exosome-dependent decay (Ibrahim et al., 2006).
in limiting the expression of RNAs from repetitive ele- Finally, Arabidopsis plants defective in exosome function
ments, transposons, and viruses. For example, the accumulate transcripts from regions highly coincident
host antiviral protein ZAP specifically recruits the exo- with repetitive elements and DNA methylation includ-
some to some viral RNAs and thereby promotes their ing multiple small RNA-producing loci (J. Ecker and D.
degradation (Guo et al., 2007). Moreover, because Belostotsky, personal communication), suggesting that
dsRNA is often a signature of parasitic or viral tran- RNA degradation may commonly contribute to silencing
scripts, metazoan cells have evolved numerous mech- of heterochromatic regions.
anisms to degrade or repress the function of dsRNA
molecules including activation of the RNaseL endo- Kinetic Competition and Quality Control
nuclease (Malathi et al., 2007), activation of the PKR A key to effective quality-control systems is accurate
protein kinase (Garcia et al., 2006), and a response to mechanisms to distinguish between aberrant and nor-
extracellular dsRNA that activates transcription of anti- mal RNAs. A unifying principle is that quality-control
viral genes (Alexopoulou et al., 2001). Nuclear dsRNA circuits for RNA often can be viewed as kinetic competi-
can also undergo extensive adenosine to inosine edit- tions between the rate of a normal reaction in the life of
ing and then be selectively retained within the nucleus an RNA and a quality-control event targeting the RNA for
(DeCerbo and Carmichael, 2005). Most eukaryotic cells degradation (Figure 2). For example, the process of NGD
also respond to dsRNA by RNA interference (RNAi), appears to be the result of a competition between trans-
wherein small-interfering (si)RNAs are generated from lation elongation and interaction of the Hbs1/Dom34
the dsRNA and then assemble into the RNA-induced complex with the stalled ribosome (Doma and Parker,
silencing complex (RISC). The RISC:siRNA complex 2006). Note that if an aberrant RNA undergoes multiple
then silences the expression of RNAs with sequences cycles of quality control to determine whether it is nor-
complementary to the siRNA by RNA degradation, or in mal or aberrant, then the overall effectiveness of quality
some cases in plants and some fungi, siRNAs-directed control can be quite high even if the absolute difference
methylation helps to silence repetitive regions of the in the rate between degradation and function at each
genome (reviewed in Meister and Tuschl, 2004; Grewal cycle is small.
and Jia, 2007). Examination of quality-control systems reveals
Metazoans also express a class of 24–29 nucleotide recurring mechanistic features, often used in combina-
RNAs called rasiRNA (repeat associated small-interfer- tions, by which the efficiency of quality control and its
ing RNA) or piRNAs (piwi-associated RNA) that function cost can be optimized. First, some aberrant RNAs or
to silence transposons, repetitive sequences, and some RNPs have features that decrease the rate of the nor-
heterochromatic regions (reviewed in Hartig et al., 2007; mal forward reaction, thereby giving more time for qual-
Saito et al., 2006). Generally, numerous ­piRNAs are pro- ity control (Figure 2B(i)). For example, assembly of the
duced from genomic clusters, often have homology to spliceosome, but failure to complete splicing, impedes
repetitive elements, and assemble with members of the nuclear mRNA export, at least in yeast (Legrain and
PIWI protein family, which are related to the Argonaute Rosbash, 1989). Therefore, the completion of pre-
proteins that are the core component of the RISC com- mRNA processing prevents nuclear RNA degradation
plex for siRNAs and miRNAs. The mechanisms by which by removing inhibitors of export from the transcript.
piRNAs and PIWI proteins silence their targets are not Second, some normal RNAs have features that pro-
yet clear but may involve aspects of RNA degradation mote the downstream normal event (Figure 2B(ii)). For
as well as chromatin modifications and repression of example, nuclear pre-mRNA splicing also exerts a pos-
transcription. Thus, this system of piRNAs represents a itive effect on transport to the cytoplasm by delivering
mechanism to repress the function of transposons and export factors to the mRNA (Zhou et al., 2000; Cheng et
repetitive RNAs and, like other quality-control systems, al., 2006; Reed and Cheng, 2005). Finally, some aber-
is also likely to regulate some normal mRNAs. rant RNAs have features that promote their recognition

664  Cell 131, November 16, 2007 ©2007 Elsevier Inc.

by specific adaptor proteins that funnel those RNAs
into the quality-control fate (Figure 2B(iii)). For example,
the Ro protein binds to variant and misfolded 5S RNAs
that contain an aberrant 3′ extension and may target
them for degradation (O’Brien and Wolin, 1994; Shi et
al., 1996; Stein et al., 2005; Fuchs et al., 2006).
An important feature of kinetic competitions leading
to quality control is that any defect leading to a delay in
the normal forward reaction will trigger quality control. In
this manner, quality-control systems do not need to rec-
ognize specific defective features of an RNA or RNP but
instead can function on a broad range of defects affect-
ing the rate of a given step in biogenesis or function. One
example of this phenomenon is in yeast where a vari-
ety of defects in proteins affecting 3′ end processing,
hypoadenylation, or hyperadenylation of mRNAs all lead
to retention of the aberrant mRNAs at the gene in a man-
ner that can be suppressed by loss of Rrp6p (Hilleren et
al., 2001; Rougemaille et al., 2007; Thomsen et al., 2003;
Libri et al., 2002).

Consequences of Quality Control

One consequence of RNA quality control is that some
“normal” RNAs will be subjected to degradation by
quality control. For example, approximately 1% of the
yeast mRNAs with a wild-type intron are estimated to
be degraded at the second step of pre-mRNA splicing
(Hilleren and Parker, 2003). Although these discarded
mRNAs could represent errors in splicing such as the
use of aberrant 5′ splice sites or branch points, they
could simply reveal the cost of this specific quality-con-
trol circuit. Moreover, cells use quality-control circuits
to control the levels of normal transcripts. For example,
microarray analysis has revealed that levels of several
“normal” mRNAs are reduced by the NMD pathway
(reviewed in Isken and Maquat, 2007). Similarly, the levels
of the yeast histone mRNAs are reduced in abundance
by the TRAMP and nuclear exosome systems (Reis and
Campbell, 2007). Cells also use the regulation of pre-
mRNA splicing to produce mRNAs that are targeted to
NMD, thereby downregulating the levels of transcripts
from specific genes (Matlin et al., 2005). Thus, quality-
control systems play a role in determining the levels of
accumulation of normal RNAs.
The existence of RNA quality-control systems argues
that numerous steps in RNA biogenesis have relatively
low fidelity and a substantial population of transcripts
is rapidly degraded. One example of this phenomenon
is the process of 3′ end formation and polyadenylation
of mRNAs in yeast. In yeast cDNA databases, approxi-
mately 1% of the ESTs correspond to mRNAs aberrantly
polyadenylated within the coding region (Graber et al., Figure 2. Kinetic Competition and RNA Quality Control
1999). Because these “nonstop” mRNAs are degraded (A) A general model for quality-control circuits as a kinetic competition
between the rate of normal function in the life of an RNA and a quality-
at least ten-fold faster than the normal mRNA pool, this control event that targets the RNA for degradation.
implies that up to 10% of the polyadenylation reactions (B) Three ways in which aberrant RNAs can be preferentially chan-
occur inappropriately within coding regions of genes neled into different quality-control fates. (i) Aberrant RNAs are defec-
tive in normal function. (ii) Normal mRNAs promote normal function
(van Hoof et al., 2002). In addition, strains defective in and thereby reduce quality control. (iii) Aberrant ribonucleoproteins
NMD accumulate mRNAs from a number of genes where (RNPs) recruit quality-control machinery.

Cell 131, November 16, 2007 ©2007 Elsevier Inc.  665

the transcript has been aberrantly polyadenylated at (reviewed in Bickel and Morris, 2006), many of which
sites distal to the normal poly(A) site (Jungwirth et al., may be substrates for RNA quality-control mechanisms.
2001). These observations indicate that polyadenylation Indeed, recent experiments in Arabidopsis using tiling
occurs at a variety of both premature and distal sites, microarrays—which use oligonucleotides to detect tran-
but these mRNAs are then rapidly degraded by either scripts from any region of the genome—to examine the
nonstop or NMD mechanisms. Thus, RNA processing amount and diversity of RNAs present when exosome
creates a diverse pool of transcripts; only those that function is inhibited have revealed significant popula-
survive quality control accumulate to substantial levels. tions of transcripts that appear to be produced but rap-
Note that the ability to degrade the products of errors idly degraded and hence are only observed at very low
in RNA processing allows the cell to maintain a more levels under normal conditions (J. Ecker and D. Belosto-
flexible RNA-processing machinery, which allows for tsky, personal communication).
increased regulation of RNA-processing patterns and One expects that new classes of quality-control mech-
for the evolution of new RNAs. anisms will emerge where defects in RNPs lead not to
This “Darwinian” view of mRNA biogenesis suggests degradation of the transcript but to repair of the defect.
that quality-control mechanisms might also function as For example, RNA polymerase II can repair defects in
an evolutionary capacitor, which is a system that silences transcriptional elongation by degrading the 3′ end of the
the phenotypic consequences of mutations, thereby nascent transcript, resulting in restarting elongation a
allowing a population to build up greater genetic diversity, few nucleotides back on the template (Fish and Kane,
which can then be revealed at a later time (Rutherford 2002). Similarly, in yeast it has been suggested that the
and Lindquist, 1998). In this case, mRNA quality control exosome can process aberrant 3′ extended mRNAs
allows for the accumulation of mutations, or alternate in yeast to restore their function (Torchet et al., 2002).
RNA-processing patterns, by silencing their phenotypic Moreover, systems may exist to repair chemical dam-
consequences. However, under conditions where mRNA age to RNA such as demethylation of methyl lesions
quality control is compromised, or additional mutations (Falnes et al., 2007). Indeed, as our understanding of the
occur that allow specific mRNAs to evade a limiting qual- diversity of RNA quality-control pathways matures, the
ity-control system, the phenotypic consequences would relevant question may become: What stage of RNA bio-
be revealed. Consistent with a possible role of aberrant genesis and function is not subject to quality control?
RNAs in evolving new functions, some intergenic tran-
scripts in yeast are exported to the cytoplasm and even Acknowledgments
associate with polysomes (Thompson and Parker, 2007).
We thank members of the Parker laboratory, C. Decker, C. Dieck-
Thus, mRNA quality-control systems may not only have
mann, and A. Webb for helpful discussions. This work was supported
important roles to play in the day-to-day operation of the by the Howard Hughes Medical Institute and grant GM45443 from the
cell but may also make long-term contributions to evo- National Institutes of Health.
lutionary change.
References

Future Issues in Quality Control

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