Noncoding RNA Surveillance: The Ends Justify the Means - Chemical

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Noncoding RNA Surveillance: The Ends Justify the Means Cedric Belair, Soyeong Sim, and Sandra L. Wolin* RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States ABSTRACT: Numerous surveillance pathways sculpt eukaryotic transcriptomes by degrading unneeded, defective, and potentially harmful noncoding RNAs (ncRNAs). Because aberrant and excess ncRNAs are largely degraded by exoribonucleases, a key characteristic of these RNAs is an accessible, protein-free 5′ or 3′ end. Most exoribonucleases function with cofactors that recognize ncRNAs with accessible 5′ or 3′ ends and/or increase the availability of these ends. Noncoding RNA surveillance pathways were first described in budding yeast, and there are now high-resolution structures of many components of the yeast pathways and significant mechanistic understanding as to how they function. Studies in human cells are revealing the ways in which these pathways both resemble and differ from their yeast counterparts, and are also uncovering numerous pathways that lack equivalents in budding yeast. In this review, we describe both the well-studied pathways uncovered in yeast and the new concepts that are emerging from studies in mammalian cells. We also discuss the ways in which surveillance pathways compete with chaperone proteins that transiently protect nascent ncRNA ends from exoribonucleases, with partner proteins that sequester these ends within RNPs, and with end modification pathways that protect the ends of some ncRNAs from nucleases.

CONTENTS 1. Introduction 2. Principles of Noncoding RNA Surveillance 3. The RNA Exosome 3.1. The RNA Exosome in Budding Yeast 3.2. Role of the Yeast Nuclear Exosome Nucleases in ncRNA Surveillance 3.3. Cofactors of the Yeast Nuclear Exosome 3.3.1. Rrp47 3.3.2. Mpp6 3.3.3. The Mtr4 Helicase and Its Associated Adaptors 3.4. The Nuclear Exosome in Human Cells 3.5. MTR4-Containing Complexes in Human Cells 3.5.1. TRAMP 3.5.2. The NEXT Complex 3.5.3. The PAXT Connection 3.5.4. Other Nuclear Exosome Adaptors in Human Cells 3.6. Role of the Cytoplasmic Exosome in ncRNA Surveillance 4. Uridylation Followed by DIS3L2 Degradation 5. Other Pathways That May Involve 3′ to 5′ Exoribonucleases 5.1. CCACCA Addition Targets Some tRNAs and tRNA-like ncRNAs for Decay 6. Surveillance Pathways Mediated by 5′ to 3′ Exoribonucleases 6.1. ncRNA Surveillance Mediated by Yeast Rat1 6.2. Xrn1 and Rat1 Monitor tRNA Integrity

6.3. Xrn1 Functions with Nonsense-Mediated Decay To Degrade Some lncRNAs 6.4. Roles of Human XRN2 in ncRNA Surveillance 6.5. The DXO/Rai1 Family of De-NADding Enzymes Regulates Levels of Some Mature snoRNAs and scaRNAs in Human Cells 6.6. Other ncRNA Surveillance Pathways That May Involve 5′ to 3′ Exoribonucleases 6.6.1. DUSP11-Dependent ncRNA Degradation 7. Additional Mechanisms of Noncoding RNA Surveillance 7.1. Retrograde tRNA Nuclear Import 7.2. Nonfunctional rRNA Decay 7.3. Noncoding RNA Surveillance by Components of the RNA Interference Machinery 7.4. Trafficking of Unneeded ncRNAs into Extracellular Vesicles 7.5. Noncoding RNA Surveillance Mediated by the Ro60 Autoantigen 8. Competition with Noncoding RNA Biogenesis Pathways 8.1. Competition with Chaperone Proteins That Bind Nascent ncRNAs 8.2. Competition with ncRNP Assembly 8.3. Competition with Enzymes That Mature ncRNA 3′ Ends

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Special Issue: RNA: From Single Molecules to Medicine

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This article not subject to U.S. Copyright. Published 2017 by the American Chemical Society

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Received: August 3, 2017 Published: October 12, 2017 4422

DOI: 10.1021/acs.chemrev.7b00462 Chem. Rev. 2018, 118, 4422−4447

Chemical Reviews 9. Conclusions and Perspectives Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

Review

imately half of all newly synthesized pre-tRNAs in yeast fail to become mature tRNAs and are instead degraded.8 In addition to the roles of surveillance pathways in ensuring quality control of classical ncRNAs, the use of tiling arrays and high-throughput sequencing to interrogate eukaryotic transcriptomes has resulted in the realization that ncRNA surveillance pathways have wide-ranging functions in regulating genomic output, influencing gene expression and ensuring genomic integrity. All examined genomes are extensively transcribed, with numerous transcripts derived from intergenic regions that were previously believed to be silent.9−16 This “pervasive transcription”, which is largely due to the inherent bidirectionality of promoters,11,14,16−18 produces a tremendous diversity of RNAs, most of which do not encode proteins. These newly discovered ncRNAs are often far less stable than classical ncRNAs, since many are only detected when specific ribonucleases are depleted or absent.11,12,14−16 Failure to degrade some of these ncRNAs can alter expression of adjacent genes19−21 and can result in formation of RNA−DNA hybrids (R-loops) that promote DNA breaks.22−25 Thus, surveillance pathways that target these potentially harmful ncRNAs for decay are of critical importance. The focus of this review is primarily on ncRNA surveillance pathways in yeast and mammalian cells. Although ncRNA surveillance occurs in all kingdoms of life, in eukaryotes these pathways have been studied most extensively in the budding yeast Saccharomyces cerevisiae. Recent studies have begun to reveal the extent to which these pathways are conserved in mammalian cells and have identified additional mechanisms that lack budding yeast counterparts. Moreover, the finding that mutations in several components of surveillance pathways are associated with specific human diseases26,27 allows these

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1. INTRODUCTION The pathways that recognize and degrade excess and defective noncoding RNAs (ncRNAs) play critical roles in sculpting the transcriptomes of eukaryotic cells. By mass, the most abundant transcripts at steady state are classical ncRNAs such as ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), spliceosomal small nuclear RNAs (snRNAs), and small nucleolar RNAs (snoRNAs).1−3 These ncRNAs must fold into complex structures and assemble with proteins, and sometimes with other RNAs, to form functional ribonucleoproteins (RNPs). In addition, since many of these ncRNAs are made as 5′ and/or 3′ extended precursors, they must undergo an intricate series of processing events to generate the mature ncRNAs. Defective ncRNAs can arise from genetic mutations, transcriptional errors, misfolding, processing mistakes, and the failure to assemble with partner proteins and RNAs to become functional RNPs. Just as cells have evolved numerous quality control pathways to identify defective mRNAs and proteins and target them for degradation,4−7 cells require surveillance pathways to recognize and rid themselves of aberrant and excess ncRNAs and ncRNPs. The contributions of ncRNA surveillance pathways in shaping transcriptomes is significant, as approx-

Figure 1. Components of noncoding RNA surveillance pathways. Noncoding RNA surveillance pathways occur in competition with formation of functional RNPs. Some targets of these pathways are shown in the left panel. The middle panel describes ways in which cofactors assist in recognizing aberrant ncRNAs and aiding in their degradation. The right panel lists the major ribonucleases that carry out degradation of aberrant ncRNAs. 4423


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Table 1. Examples of Noncoding RNAs and Their Described Surveillance Pathways Budding Yeast noncoding RNAs

defects

pre-rRNAs

aberrant processing; failure to bind proteins

mature 18S rRNAs

pre-tRNAs and mature tRNAs exported to cytoplasm mature tRNAs

nonfunctional in protein synthesis nonfunctional in protein synthesis hypomodified; unspliced; misfolded; unprocessed nonfunctional in protein synthesis weak acceptor stems

pre-snoRNAs

structurally unstable tRNAs failure to assemble with proteins

pre-snRNAs

failure to assemble with proteins

U6 snRNA


5S rRNAs

truncated

lncRNAs SRP RNA

many without known binding proteins truncated

CUTs

no known binding proteins

XUTs


telomeric repeat transcripts


mature 28S rRNAs pre-tRNAs

noncoding RNAs pre-rRNAs

PROMPTs

defects premature termination; aberrant processing aberrant precursors, excised spacers no known binding proteins

nuclease(s)

cofactors

other components

ref

nuclear exosome Rat1 Xrn1

TRAMP, TRAMP5, MPP6, Rrp47 Rai1 Ski7

Dom34, Hbs1

38, 68, 69, 110, 125, 127 −129 31, 209 267, 268

unknown

unknown

Rtt101, Mms1

267, 271, 272

nuclear exosome unknown

Nrd1/Nab3, TRAMP

unknown

CCA-adding enzyme

Rat1, Xrn1 nuclear exosome nuclear exosome XRN1 nuclear exosome nuclear exosome Rat1

unknown Nrd1−Nab3, TRAMP

210, 219−221 8, 33, 45, 47, 65, 143

Nrd1−Nab3, TRAMP

8, 33, 58, 66

Dcp1, Dcp2 TRAMP

58 8, 33, 67

Nrd1−Nab3, TRAMP

33, 65, 67, 143

Dcp1

19

TRAMP

33, 46, 57

Nrd1−Nab3, TRAMP, Rrp47, MPP6 Dcp1, Dcp2

8, 10, 11, 33, 105, 110, 122, 124, 140, 141 15, 225−227, 229−231

nuclear exosome nuclear exosome Xrn1

unknown

8, 30, 33, 46, 65, 67 retrograde nuclear transport CCACCA addition

NMD often important

Rat1 Rai1 Mammals nuclease(s) nuclear exosome XRN2

263 203, 204

22

cofactors

other components

ref

PAPD5/ZCCHC7/MTR4

71, 72

NKRF

126, 249, 250

NEXT complex

nuclear exosome no known binding proteins nuclear exosome unprocessed and nonfunctional in DIS3L2 cytoplasm misfolded DICER1 weak acceptor stems

NEXT complex

70, 72, 73, 85, 150, 151, 160 73, 151, 331

TUT4, TUT7

64, 189

U6 snRNA


TRAMP

64

some lncRNAs, including TUG1 and NEAT1 other lncRNAs

unknown

TUT4, TUT7 PAXT, polysome protector complex unknown

64 73, 153, 163, 165, 154

telomerase RNA precursor

reduced levels of dyskerin protein

mature hTR RNA

unknown

pre-snRNAs


mature snoRNAs

NAD+ caps

pre-snoRNAs


enhancer RNAs pre-tRNAs

unknown

nuclear exosome DIS3L2 nuclear exosome unknown nuclear exosome nucleolar exosome nuclear exosome DIS3L2 XRN1 DXO nuclear exosome DIS3L2 4424

unknown CCA-adding enzyme

CCACCA addition

NMD often important

266, 278 203

231, 235, 238, 239

PAPD5/hTRF4-2, DCP2

59, 155, 156

DGCR8

168

NEXT

151

TUT4, TUT7 DCP2 NEXT

189, 191 58 218, 254 151

TUT4/TUT7

189 DOI: 10.1021/acs.chemrev.7b00462 Chem. Rev. 2018, 118, 4422−4447

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Table 1. continued Mammals noncoding RNAs pre-let-7 miRNA transcripts from Alu elements

defects miRNA harmful to stem cells unknown

nuclease(s) DIS3L2 DICER1

cofactors TUT4/TUT7 unknown

other components

ref 183, 185−188 32, 278

Figure 2. Nuclear RNA exosome. (A) Structure of a complex consisting of the nine-subunit exosome core, Rrp6, Dis3, Rrp47, and single-stranded RNA87 (PDB 5COW). In this structure, RNA directly accesses Dis3. (B) Structure of a complex consisting of the nine-subunit core, Dis3, a fragment of Rrp6 and RNA consisting of a 5′ stem-loop, and a 31 nt single-stranded overhang88 (PDB 4IFD). In this structure, RNA accesses Dis3 via the channel. The RNA within the channel was not fully visualized.88 (C) Structure of a complex consisting of the nine-subunit core, Dis3, Rrp6, the exosome-binding domain of MPP6, and an RNA engineered to have two 3′ ends. One 3′ end enters the Rrp6 active site, while the other uses the direct access path to the Dis3 exoribonuclease89 (PDB 5VZJ). (D−F) Cartoons of RNA paths to the exosome, configured similarly to the view in (A), left panel. (D) Path by which a structured RNA substrate can directly access the Dis3 exoribonuclease. (E) Path by which an RNA substrate passes through the central channel to reach the Dis3 exoribonuclease. The conformation of Dis3 differs between the direct access and channeldependent paths.42,88,90−92 (F) RNA path to Rrp6.

both a 3′ to 5′ exoribonuclease and an endoribonuclease35−37 (Figure 1). A second principle is that although exoribonucleases are key effectors in ncRNA surveillance, they rarely function on their own. To initiate decay, most exoribonucleases require that the RNA substrate contain a protein-free single-stranded end. Thus, exoribonucleases often function with cofactors that recognize ncRNAs with accessible 5′ or 3′ ends and/or increase the availability of these ends (Figure 1). For example, degradation of mutant pre-tRNAs, in both bacteria and budding yeast, involves addition of a short polyA tail to the 3′ end of the aberrant tRNA, followed by degradation by 3′ to 5′ exoribonuclease(s).28,30,38 Additionally, because many exoribonucleases have difficulty progressing through structured substrates, they often function with helicases or other proteins that assist RNA unwinding.10,38−43 Third, since exoribonucleases require a single-stranded protein-free end to initiate degradation, the accessibility of these ends is a major determinant of whether a ncRNA will be targeted for decay. The 5′ ends of newly made RNA polymerase II and III transcripts are usually protected from decay by the presence of caps (RNA polymerase II transcripts)

pathways to be correlated with disease phenotypes, an important step in understanding disease etiology.

2. PRINCIPLES OF NONCODING RNA SURVEILLANCE Although ncRNA surveillance pathways are active in all organisms, they have been studied most extensively in the bacterium Escherichia coli, the budding yeast S. cerevisiae, and mammalian cells. From these studies, as well as findings in other model organisms, several principles have emerged. The first and most obvious principle is that ribonucleases are major players. Most characterized surveillance pathways target defective RNAs to exoribonucleases,28−31 which degrade RNAs from either the 5′ end (5′ to 3′ exoribonucleases) or the 3′ end (3′ to 5′ exoribonucleases). Endoribonucleases, which cleave within the RNA body, also participate,8,32−34 often by cleaving within highly structured ncRNAs to generate additional ends for exoribonucleases. Illustrating the importance of both types of activities, a major decay pathway in eukaryotic cells involves the RNA exosome, a multiprotein complex in which a key nuclease, Dis3 (also called Rrp44), is 4425


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could contribute to the unwinding of structured substrates during degradation42 (Figure 2). In yeast, all exosomes contain Dis3, a multidomain protein that is both an endoribonuclease and a processive hydrolytic 3′ to 5′ exoribonuclease resembling bacterial RNase II and RNase R.35−37,81,84,93 Dis3 consists of an N-terminal PIN domain harboring endonuclease activity, followed by the two coldshock domains, RNB domain and S1 domain91 that are characteristic of RNase II/R family members.35−37,93 Dis3 binds at the bottom of the barrel, largely through interactions between its PIN domain and Rrp41, Rrp43, and 4542,88,90,94 (Figure 2A). Structural studies have revealed that Dis3 can adopt two conformations that allow substrates to access the exonuclease activity by distinct paths.42,88,90−92 In one path, RNAs bypass the channel to directly access the exonuclease active site42,91,92 (Figure 2A,D). In the other path, singlestranded RNA is channeled through the central cavity to the Dis3 exoribonuclease catalytic center88,91,92 (Figure 2B,E). Less is known as to how RNA substrates access the Dis3 endonuclease. In all structures to date, the endonuclease active site faces the solvent.42,87,88,91,92,94 As a circular RNA can be degraded by the intact exosome,42 at least some substrates can directly access this activity. Consistent with direct access to the endonuclease, single-particle electron microscopy of exosomes bound to streptavidin-conjugated RNAs detected a population of exosomes with the RNA near the PIN domain.91 However, experiments in which mutations were used to occlude the channel support a model in which passage through the channel is required to access endonuclease activity.95,96 Most ncRNA surveillance involving the exosome occurs within nuclei. The nuclear form of the exosome contains an additional exoribonuclease, the distributive hydrolytic Rrp6, a member of the RNase D family.76,81,97,98 Rrp6 is a multidomain protein, with an N-terminal domain that binds its cofactor Rrp47 (see section 3.3.1), an EXO domain shared with other members of the DEDD nuclease superfamily,99 a HDRC (helicase and RNase D C-terminal) domain,100 and a Cterminal domain. Both the EXO and HDRC domains are required for exoribonuclease activity. Rrp6 binds at the top of the exosome (Figure 2), with its EXO domain contacting the cap proteins Rrp4 and Rrp40, the HRDC domain contacting Rrp4, and its C-terminal domain contacting a conserved surface formed by Csl4 and the RNase PH-like subunits Mtr3 and Rrp43.87,88,101 Structural and biochemical studies revealed that substrates bind the S1/KH domains of the cap proteins before entering the Rrp6 active site (Figure 2C,F).94,95,101

or 5′ triphosphates (RNA polymerase III transcripts). The 3′ ends of both RNA polymerase II and III transcribed ncRNAs are protected from exoribonucleases by bound partner proteins,44−47 by forming double-stranded stems or triplehelical structures,48−50 or, in the case of mature tRNAs, by CCA addition and aminoacylation.51 Thus, aberrant or excess ncRNAs can be recognized by their failure to bind proteins or fold into the structures that normally protect these ends. Fourth, since the accessibility of ncRNA ends is a critical factor in determining whether an RNA will be degraded, ncRNA surveillance often occurs in competition with chaperone proteins that transiently protect nascent ncRNA ends from exoribonucleases,46,52−57 with the binding of proteins that sequester these ends within stable noncoding RNPs,44,47,54,57−59 and with end modification pathways that protect the ends of some ncRNAs from degradation.60−63 Finally, surveillance pathways are often functionally overlapping, with backup pathways that degrade ncRNAs that escape degradation by other pathways.29,31,64 Consequently, it is often necessary to deplete or inactivate multiple pathways to detect accumulation of aberrant ncRNAs.

3. THE RNA EXOSOME The RNA exosome, a multiprotein nuclease complex, is a prominent contributor to ncRNA surveillance in all examined eukaryotic cells. The role of the exosome in ncRNA surveillance has been most extensively characterized in budding yeast, where its targets include excess and defective pretRNAs,8,30,33,46,65 pre-snoRNAs and pre-snRNAs that are misprocessed and/or have not assembled with core proteins,47,66 truncated forms of 5S rRNA and the signal recognition particle (SRP) RNA,46,57,67 aberrant pre-rRNA processing intermediates,68,69 and cryptic unstable transcripts (CUTs) that originate from bidirectional promoters.10,11,14,16 Although the role of the RNA exosome in ncRNA surveillance in mammalian cells is less well-defined, many of the same ncRNAs have been shown to be exosome targets70−73 (Table 1). 3.1. The RNA Exosome in Budding Yeast

The exosome was first identified in S. cerevisiae as a complex of 3′ to 5′ exoribonucleases associated with Rrp4 (Ribosomal RNA processing 4), a protein required for 3′ processing of 5.8S rRNA.74−76 This complex is essential in yeast and is highly conserved, as it is widespread in eukaryotes and Archaea75,77,78 and shares structural similarities with two bacterial 3′ to 5′ exoribonucleases, RNase PH and polynucleotide phosphorylase (PNPase).75,79,80 In yeast, as in all studied eukaryotes, the “core” exosome consists of a ring formed by six RNase PH domain-containing subunits (Rrp41, Rrp42, Rrp43, Rrp45, Rrp46, and Mtr3) capped by a ring of three proteins harboring RNA-binding S1 and KH domains (Rrp4 and Rrp40) or only a S1 domain (Csl4).81 Together, these subunits form a barrel-like structure with a central channel that can accommodate single-stranded, but not double-stranded, RNA. Although degradation takes place within the central channel of the archaeal exosome,80,82,83 the RNase PH domains of the orthologous eukaryotic subunits contain inactivating mutations, making the central channel catalytically inert.81,84 Thus, in eukaryotes, RNA degradation is carried out by exosome-associated ribonucleases that differ based upon their subcellular location.84−86 For these organisms, passage through the RNA-binding ring and the central channel

3.2. Role of the Yeast Nuclear Exosome Nucleases in ncRNA Surveillance

The ways in which the various catalytic activities of the nuclear exosome contribute to ncRNA surveillance have been parsed out by combining in vivo RNA:protein cross-linking with examination of the RNAs that accumulate in mutant strains. One caveat to these studies is that mutations affecting one nuclease could indirectly affect the other, since in vitro, RNA binding by Rrp6 stimulates Dis3 activity and a mutation that disrupts the exoribonuclease active site of Dis3 inhibits Rrp6 activity.95,102 These experiments revealed significant overlap between Rrp6 and Dis3 targets, as well as between the exonuclease and endonuclease activities of Dis3. For example, CUTs accumulate when either Dis3 or Rrp6 is mutated, and accumulate to higher levels when both Dis3 and Rrp6 contain mutations.8 Although mutating the Dis3 endonuclease domain 4426


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Figure 3. Recruitment of the nuclear exosome to its targets in budding yeast. (A) Following assembly of the pre-rRNA with proteins and snoRNAs to form the 90S pre-ribosome, and endonucleolytic cleavage to release the 5′ external transcribed spacer (5′ ETS), the Utp18 adaptor protein (left) binds the cleaved spacer and also binds the Mtr4 arch domain, targeting the 5′ ETS to the nuclear exosome for degradation.117 After cleavage within ITS1 to separate pre-40S from pre-60S ribosomes, and cleavage within ITS2 to separate pre-25S rRNA from pre-5.8S rRNA, Nop53 interacts with pre-60S ribosomal subunits (right) and also with the Mtr4 arch, an interaction required for the exosome to mature the 5.8S rRNA 3′ end.117 (B) TRAMP, which consists of the Trf4 oligo(A) polymerase, the Air2 RNA-binding protein, and the Mtr4 helicase, adds a short A tail to RNAs destined for degradation and recruits the exosome. Both Trf4 and Air2 contact Mtr4. Air2 interacts with both the Mtr4 helicase domain and the arch domain, with the contacts to the Mtr4 arch resembling those of Nop53 and Utp18.118,119 (C) For RNA polymerase II transcripts, the Nrd1−Nab3 heterodimer of the Nrd1−Nab3−Sen1 complex recognizes short motifs on the nascent ncRNA. Nrd1 also interacts with the C-terminal domain of the large subunit of the polymerase. Following release of the polymerase, Nrd1 interacts with Trf4 to recruit TRAMP and the exosome to the nascent ncRNA.120−123

characterized exosome substrates, a hypomodified pretRNAiMet30 and a truncated 5S rRNA,67 accumulate in yeast containing mutations predicted to prevent Dis3 from forming the direct access conformation.103 Moreover, in vivo crosslinking revealed that association of U6 snRNA, RNase P RNA, and many pre-tRNAs with Dis3 requires the S1 domain, which is predicted to be important for binding RNAs that approach Dis3 via the direct access path, but not for binding RNAs that thread through the channel.104

had little effect, CUTs accumulate more strongly when both the endonuclease and Dis3 exonuclease domains are mutated than when strains carry only a mutation in the exonuclease.8 Consistent with these findings, CUTs cross-link to both domains of Dis3 and to Rrp6.33 Some targets appear to be preferentially degraded by one or the other nuclease. Both snRNA and snoRNA precursors and the mature RNAs appear more dependent on Rrp6, as they accumulate more strongly when Rrp6 is mutated than when both catalytic domains of Dis3 are mutated8 and are more enriched in Rrp6 immunoprecipitates.33 In contrast, pretRNAs, U6 snRNA, and truncated forms of 5S and SRP RNAs are largely Dis3 targets.8,33 In support of a role for endonucleolytic cleavage of highly structured RNAs, both the endonucleolytic and exonucleolytic activities are important for pre-tRNA and U6 degradation.8,33 Remarkably, U6 snRNAs and mature tRNAs increase 2−3-fold when both the endonucleolytic and exonucleolytic domains of Dis3 are mutated,8,33 while both U4 and U5 snRNAs show similar increases when Rrp6 is deleted.66 Thus, more than half the transcripts encoding some nascent ncRNAs are normally degraded. Several studies have addressed the relative roles of the direct access and channel routes to Dis3. Since an RNA substrate must have an ∼31−33 single-stranded tail to reach Dis3 via the channel,42 substrates that lack such tails are good candidates for the direct access path. There is now evidence that some structured ncRNAs are degraded via this pathway. Two well-

3.3. Cofactors of the Yeast Nuclear Exosome

3.3.1. Rrp47. Because Rrp47 initially copurified with the nuclear exosome in substoichiometric amounts, it has been considered an exosome cofactor.105 However, recent functional and structural analyses indicate that Rrp47 is an integral subunit of the nuclear exosome. Rrp47 binds to the N-terminus of Rrp6 and is required for all known Rrp6 activities, including degradation of CUTs and aberrant rRNA processing intermediates.105 One role of Rrp47 is to stabilize Rrp6, since Rrp6 is unstable in cells lacking Rrp47 when yeast cells are grown in minimal media.106 In addition, experiments with reconstituted exosomes have revealed that Rrp6 activity is enhanced in the presence of Rrp47.89 Consistent with roles in stabilizing Rrp6 and increasing its activity, the defects in ncRNA surveillance and RNA processing that are detected in yeast lacking Rrp47 can be ameliorated by overexpressing Rrp6.106 4427


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their bound RNAs. Additional examples of this role are described below. 3.3.3.1. The TRAMP Complex. The TRAMP (Trf4−Air2− Mtr4 polyadenylation) complex is a major contributor to ncRNA surveillance in budding yeast. TRAMP, which adds a short A tail to ncRNAs destined for degradation,10,38,41 was first identified because mutations in its Trf4 catalytic subunit prevent degradation of a hypomodified form of tRNAiMet.30 Other ncRNAs targeted by TRAMP include aberrant 23S rRNA processing intermediates,38 unspliced and/or unprocessed pre-tRNAs, 46,65 truncated 5S rRNAs and SRP RNAs,46,67 snoRNAs that fail to assemble with core proteins,47 U6 snRNA,33,67 antisense ncRNAs,124,125 and CUTs.10 TRAMP consists of a noncanonical oligo(A) polymerase (Trf4), an RNA-binding subunit (the zinc knuckle protein Air2), and the RNA helicase Mtr4 (Figure 3B). The tails added by TRAMP, which average 3−5 A residues,65,126 are too short to be bound by the poly(A) binding protein and thus provide an accessible single-stranded end for Mtr4 binding and subsequent exoribonuclease degradation. Additionally, through interactions between the Mtr4 N-terminus and Rrp6/Rrp47, Mtr4 recruits TRAMP-bound RNAs to the nuclear exosome.107 TRAMP is primarily nucleoplasmic, and a structurally related complex, TRAMP5 (Trf5−Air1−Mtr4), targets nucleolar RNAs for degradation by the nuclear exosome.125,127−129 Structural and biochemical studies have begun to reveal both the architecture of TRAMP and the way in which it recognizes RNA targets. Air2 contains unstructured N- and C-termini that bracket five zinc knuckles, elements which interact with singlestranded RNA in retrovirus nucleocapsid proteins.130 The Air2 N-terminus interacts with the helicase core and arch of Mtr4, the fourth and fifth zinc knuckles interact with Trf4, and the remaining zinc knuckles are implicated in RNA binding.118,131−134 Interestingly, the Air2 contacts with the Mtr4 arch resemble those of Utp18 and Nop53, suggesting that these adaptor proteins may compete with Air2 for Mtr4 binding.118,119 The N-terminus of Trf4 also interacts with the Mtr4 helicase core, with Trf4/Air2 positioned such that RNA could thread from Mtr4 to the Trf4 active site.118 3.3.3.2. Recruitment of TRAMP to ncRNA Targets. In yeast, targeting of TRAMP and the nuclear exosome to RNA polymerase II transcribed ncRNAs, such as CUTs and presnoRNAs, occurs cotranscriptionally. Coupling is mediated by the Nrd1−Nab3−Sen1 complex, which is recruited to the transcribing polymerase. The Nrd1−Nab3 heterodimer recognizes short sequence motifs on nascent ncRNAs65,120,121 and interacts both with TRAMP and with the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II122 (Figure 3C). Because the form of the CTD recognized is phosphorylated on serine 5 of the heptad repeat (Tyr1−Ser2− Pro3−Thr4−Ser5−Pro6−Ser7),122,135 a modification that peaks early in elongation, 136 Nrd1−Nab3−Sen1 binds preferentially to short transcripts. Binding of the Sen1 helicase to the nascent transcript, together with ATP hydrolysis, results in transcription termination and release of the nascent ncRNA.137 Remarkably, the association between the Nrd1−Nab3−Sen1 complex and TRAMP involves interactions between the CTDinteracting domain of Nrd1 and a motif in the Trf4 C-terminus that mimics a Ser5-phosphorylated heptad repeat.123 Thus, following dissociation of the CTD from Nrd1, the Nrd1−Nab3 complex uses similar interactions between Nrd1 and Trf4 to recruit TRAMP to the newly terminated RNAs. Moreover,

Structural analyses have revealed that the N-termini of Rrp6 and Rrp47 interact to form a binding surface that allows the Mtr4 RNA helicase, a component of TRAMP and other cofactor complexes, to associate with the exosome.107 Thus, rather than functioning as a traditional cofactor to recruit RNA substrates and assist in their decay, Rrp47 appears to be a structural component that stabilizes Rrp6 and assists in recruiting cofactors to the exosome. Human cells contain an Rrp47 ortholog, called C1D, that associates with the Rrp6 ortholog EXOSC10/hRRP6 and whose localization to nucleoli also depends on EXOSC10/hRRP6.108 3.3.2. Mpp6. MPP6 was first identified as an exosome cofactor in human cells, where it copurified with the exosome, localized to nucleoli, bound RNA in vitro, and was found to be important for 5.8S rRNA maturation.109 Yeast strains lacking the ortholog Mpp6 resemble rrp47Δ and rrp6Δ strains, in that they accumulate CUTs, intergenic transcripts, and aberrant rRNA processing intermediates.110 Consistent with functional redundancy, strains lacking Mpp6 and either Rrp47 or Rrp6 are inviable.110 Because of both the synthetic lethality with Rrp6 and the fact that the RNAs that accumulate in mpp6Δ strains are also Dis3 targets,8,110 it was proposed that Mpp6 targets these RNAs for degradation by Dis3.111 Notably, recent studies have identified roles for Mpp6 in recruiting the Mtr4 helicase to the exosome and in stimulating Rrp6 activity.89,112 Structures of either the nine-subunit core exosome112 or the Rrp6- and Dis3-containing exosome89 complexed with the minimal Mpp6 domain needed to bind the exosome and stimulate Rrp6 activity revealed that Mpp6 binds the Rrp40 exosome core protein and is positioned near Rrp6, contacting the S1 and KH domains of the Rrp40 cap protein (Figure 2C,F).89,112 Biochemical assays showed that the presence of Mpp6 was sufficient to recruit Mtr4 to exosomes lacking Rrp47, and that maximum Mtr4 binding occurred when both Rrp47 and Mpp6 were present.89 A role for Mpp6 in recruiting Mtr4 is consistent with findings that human MPP6 and the Mtr4 ortholog SKIV2L2/hMTR4 associate in vitro.108 Thus, another explanation for the finding that strains lacking Mpp6 and Rrp47 are inviable110 is that Rrp47 and Mpp6 function redundantly to recruit Mtr4 to the nuclear exosome. 3.3.3. The Mtr4 Helicase and Its Associated Adaptors. The Mtr4 RNA helicase is a central player in both the maturation and surveillance functions of the nuclear exosome. Mtr4 is a superfamily (SF) 2 helicase that is a member of the Ski2-like group of DExH helicases.113 Its closest relative, Ski2, is required for all known functions of the cytoplasmic exosome. Structural analyses revealed that Mtr4 contains a poorly structured N-terminus and a DExH helicase core with a prominent “arch domain” rising from the helicase core.114,115 The N-terminus of Mtr4 binds the N-termini of Rrp6 and Rrp47, tethering Mtr4 to the exosome near the channel entrance,107 where it likely contributes to unwinding structured RNAs.116 The arch domain was shown recently to function as a docking site for two adaptor proteins, Utp18 and Nop53, that target the exosome to specific substrates117 (Figure 3A). Utp18 associates with 90S pre-ribosomes and is important for degradation of the 5′ external transcribed spacer, while Nop53 binds pre-60S ribosomal subunits and is required for 5.8S rRNA processing.117 Remarkably, both Utp19 and Nop53 use a similar short sequence motif (AIM, for arch interaction motif) to interact with Mtr4.117 These data reveal that Mtr4 acts as a scaffold to link the exosome to adaptor proteins and 4428


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Figure 4. tRNA biogenesis competes with tRNA surveillance pathways. The major steps in tRNA biogenesis are depicted with solid arrows. Some tRNAs also contain intervening sequences that are removed by splicing, an event that takes place in the nucleus in mammals and the cytoplasm in yeast. Steps in which misfolded, unprocessed, unstable tRNAs accumulate and/or are targeted for degradation are indicated with dashed arrows. While most depicted steps occur in both yeast and mammals, TUTases and DIS3L2 are not present in budding yeast.

There is now evidence that Nrd1 and Nab3 can target some RNA polymerase I and III transcripts for polyadenylation by TRAMP and degradation by the nuclear exosome.65,143,144 In UV cross-linking studies, Nrd1 and Nab3 were found to crosslink to many RNA polymerase III transcripts, including 5S rRNA, pre-RNase P RNA, and pre-tRNAs.65,143 Many of these RNAs contained nontemplated A tails added by TRAMP. Consistent with a model in which Nab1−Nab3 binds posttranscriptionally to some RNA polymerase III transcripts and targets them to TRAMP, depletion of either Nab1 or Nab3 resulted in reduced levels of polyadenylated pre-RNase P RNAs and accumulation of unspliced pre-tRNAs.65 In support of a role for Nrd1−Nab3 in also targeting defective rRNAs for decay, aberrant polyadenylated pre-rRNAs accumulate in yeast containing mutations in Rrp6, Nrd1, or Nab3.144 For RNA polymerase I transcripts, Nrd1−Nab3 binding may be cotranscriptional and mediated by interactions between Nrd1 and sequences in the C-terminus of Spt5, a transcription elongation factor.144 How does TRAMP identify other substrates, such as already terminated RNA polymerase III transcripts and/or truncated ncRNAs, for targeting to the nuclear exosome? One major determinant is an accessible 3′ single-stranded end. In vitro, TRAMP only adenylates substrates containing a 3′ overhang of at least one nucleotide.126,131 Consistent with a requirement for a single-stranded 3′ end, TRAMP competes with La, a protein

since both Nrd1 and Nab3 also interact directly with Rrp6,123,138,139 they may also contribute to recruiting the exosome. Although binding of the TRAMP/exosome complex to newly transcribed CUTs results in degradation of these ncRNAs,140,141 binding to newly transcribed snoRNAs can result in either degradation of the entire transcript or exonucleolytic removal of the 3′ extension to form mature snoRNAs.47,138,142 For snoRNAs, those precursors that successfully assemble with their protein partners may be protected against further degradation following removal of the 3′ extension, while those pre-snoRNAs that fail to assemble into snoRNPs will be degraded.47 In the case of CUTs, the lack of specific binding partners may result in their complete degradation. Interestingly, purified recombinant Mpp6 and a peptide spanning the Trf4 C-terminus were found to compete with each other for binding to Nrd1.111 Consistent with a model in which Mpp6 and Trf4 bind to similar sites on Nrd1, binding of Mpp6 to Nrd1 requires a sequence near the Mpp6 C-terminus that strongly resembles the Trf4 sequence that interacts with Nrd1.111 These findings support a model in which Nrd1 can hand nascent RNA polymerase II transcripts to either Trf4 or Mpp6.111 Whether the choice of exosome cofactors is stochastic, or whether features of the nascent ncRNAs and/or other cofactors contribute, remains to be determined. 4429


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Figure 5. Mtr4 helicase-containing complexes in human cells. (A) A complex resembling yeast TRAMP targets prematurely terminated ribosomal precursors for degradation by the nucleolar exosome.71,72 (B) The NEXT complex recognizes short capped RNA polymerase II transcripts, such as PROMPTs, enhancer RNAs, and precursors to snoRNAs and snRNAs, during transcription and targets them for degradation by the nuclear exosome.72,151 (C) Following polyadenylation of longer RNA polymerase II transcripts by the canonical poly(A) polymerases PAPα and PAPγ, interaction of PAXT with the nascent ncRNAs targets them for degradation by the nuclear exosome.152,153 A related complex, consisting of ZFC3H1and SKIV2L2/hMTR4 but lacking PABPN1, has also been described.154

3.4. The Nuclear Exosome in Human Cells

that binds the 3′ end of all newly made RNA polymerase III transcripts, for binding to a hypomodified pre-tRNAiMet53,55 (Figure 4). However, TRAMP must also recognize other determinants, since in vitro both TRAMP and a Trf4−Air2 subcomplex preferentially polyadenylate the misfolded forms of several tRNAs compared with their correctly folded counterparts.41,131 As the mutant tRNAs contain alterations that disrupt conserved stems and/or tertiary contacts needed to form the canonical three-dimensional structure, the mutant tRNAs may be less compact and more likely than wild-type tRNAs to have singlestranded RNA available for binding by the Air2 zinc knuckles.30,41,131 In this case, nascent pre-RNAs and other ncRNAs that contain mutations that cause them to misfold and/or fail to assemble with their correct proteins would be preferentially targeted by TRAMP. Although most studies of TRAMP have been carried out in budding yeast, studies in fission yeast revealed that one role of TRAMP is to protect abundant ncRNAs, such as rRNAs and tRNAs, from entering the RNA interference pathway and competing with bona fide substrates of the Dicer1 endoribonuclease for cleavage.145 Although in S. cerevisiae, a yeast lacking an RNA interference (RNAi) pathway, cells lacking both Trf4 and Trf5 are inviable,146 Schizosaccharomyces pombe (S. pombe) cells lacking the single Trf4/Trf5 ortholog Cid14 are viable,147 but have reduced siRNAs derived from heterochromatic regions and defects in heterochromatic silencing.148 Sequencing of Argonaute-associated small ncRNAs in the cid14Δ cells revealed a highly skewed population, with large increases in short RNAs derived from rRNAs and tRNAs.145 Thus, TRAMP may function in cells with a functional RNAi pathway to protect the integrity of this pathway.

Although the human exosome resembles its yeast counterpart in overall structural organization, it can contain up to three distinct catalytic subunits that vary based on their subcellular location. EXOSC10/hRRP6, the homologue of yeast Rrp6, is predominantly nuclear, with strong enrichment in nucleoli.76,85 DIS3 is also largely nuclear, but is excluded from nucleoli.85,86 Human cells also contain a third exosome-associated 3′ to 5′ exonuclease, cytoplasmic DIS3L (DIS3-like), which is structurally similar to DIS3 but contains mutations in the PIN domain that inactivate the endoribonuclease.86,149 These findings have led to a model in which the human exosome exists in multiple forms: a nucleolar form that contains only EXOSC10/hRRP6, a nuclear form that contains both EXOSC10/hRRP6 and DIS3, and cytoplasmic forms that contain either DIS3 or DIS3L and may also contain EXOSC10/hRRP6.85,86 As in yeast, there is considerable overlap in the substrates of the various catalytic subunits (Table 1). For example, a major target of the human exosome is PROMPTs (promoter upstream transcripts), which resemble yeast CUTs in being capped and polyadenylated ncRNAs derived from bidirectional transcription upstream of canonical promoters.70,150 Although the levels of specific PROMPTs increase 30−50-fold when the exosome is inactivated by depleting the core EXOSC3/hRRP40 subunit, only minor increases in these RNAs are seen when a single catalytic subunit is depleted.85 Instead, simultaneous depletion of EXOSC10/hRRP6 and DIS3 is required to detect robust (15−30-fold) increases in PROMPTs, and depleting all three nucleases is required to raise PROMPT levels to that seen when a core subunit is depleted.85 In support of functional redundancy, levels of the DIS3L exoribonuclease increase when EXOSC10/hRRP6 is depleted, and EXOSC10/hRRP6 increases when DIS3L or DIS3 is depleted.85 4430


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3.5. MTR4-Containing Complexes in Human Cells

with the nucleoplasmic localization of ZCCHC8 and RBM7, support a model in which NEXT targets these ncRNAs for degradation by the nucleoplasmic form of the exosome. Recruitment of NEXT to its ncRNA targets occurs early in their biogenesis, with binding partly dependent on interactions with the cap-binding complex (CBC)151,160 (Figure 5B). The CBC, which is composed of the CBP20 and CBP80 proteins, associates with the ARS2 protein to promote 3′ end processing of cap-proximal short transcripts, such as PROMPTs and presnRNAs.161 Association of the CBC−ARS2 complex with NEXT is bridged by the zinc-finger-domain-containing protein ZC3H18, which interacts via protein−protein interactions with the ZCCHC8 component of NEXT.162 As both cap formation and CBC binding occurs when ∼20 nt of RNA have been synthesized, this coupling allows NEXT to be loaded onto nascent RNAs early in their biogenesis.160 Upon premature termination of RNA polymerase II transcripts to form PROMPTs, NEXT is positioned to target these ncRNAs for degradation by the exosome. 3.5.3. The PAXT Connection. In addition to NEXT, whose targets are largely short unprocessed cap-containing ncRNAs, human cells contain a SKIV2L2/hMTR4-containing adaptor that recognizes longer processed RNA polymerase II transcripts and targets them to the nuclear exosome. In this pathway, called the PAXT [poly(A) tail exosome targeting] connection, poly(A) tailed ncRNAs are recognized by the nuclear poly(A)-binding protein PABPN1.152,153,163 PABPN1 associates with the zinc finger protein ZFC3H1 through interactions that are partly RNase resistant, while ZFC3H1 binds SKIV2L2/hMTR4153 (Figure 5C). Thus, as in NEXT, a zinc finger protein (in this case, ZFC3H1) acts as a scaffold to bring a RNA binding protein and SKIV2L2/hMTR4 into proximity. Since the interaction between ZFC3H1 and PABPN1 partly depends on RNA,153 ZFC3H1 may also contribute to RNA recognition. Although the targets of NEXT and PAXT show considerable overlap, the RNAs that accumulate when PAXT components are depleted are, on average, longer than those detected when NEXT components are depleted. Prominent targets of PAXT include long noncoding RNAs (lncRNAs) such as NEAT1 and TUG1, spliced transcripts of noncoding snoRNA host genes, and prematurely terminated RNAs.152−154,163 These and other PAXT targets also differ from the RNAs targeted by NEXT in that they are more likely to be polyadenylated.153 Polyadenylation is required for recognition by PAXT, as PAPBN1 binding and exosome degradation of these lncRNA targets is reduced when cells are treated with cordycepin, an adenosine analogue that inhibits poly(A) polymerase.152,162,163 Polyadenylation is likely carried out by the canonical poly(A) polymerases PAPα and PAPγ, as the tails are longer than those added by TRAMP and codepletion of PAPα and PAPγ results in accumulation of many of the same lncRNAs.152 As a result, this degradation pathway has been named “PABPN1 and PAPα/γ-mediated decay” or PPD.152 How might PABPN1 and other components of the PAXT connection select ncRNAs for degradation? A possible clue comes from studies of the roles of polyadenylation and PABPN1 in the degradation of mRNAs lacking introns,152 a class of mRNAs that are exported more slowly than their intron-containing counterparts.164 In these studies, it was proposed that polyadenylated RNAs that are poorly exported to the cytoplasm are targets for PABPN1-mediated decay.152 Consistent with this hypothesis, a β-globin mRNA reporter

3.5.1. TRAMP. Human cells contain likely orthologs of all TRAMP subunits; however, the extent to which these proteins form a complex analogous to yeast TRAMP remains under investigation. Although a stable ternary complex has not been purified from mammalian cells, the Trf4 ortholog PAPD5/ hTRF4-2 and the Mtr4 ortholog SKIV2L2/hMTR4 are detected in immunoprecipitates when an epitope-tagged version of the Air1/2 ortholog ZCCHC7 is overexpressed in human cells.72,132 Moreover, as in yeast, where Trf4 and Mtr4 have reduced half-lives in air2 mutant strains, the levels of ZCCHC7 decrease when either PAPD5/hTRF4-2 or SKIV2L2/hMTR4 is depleted with siRNAs.72 To date, the best documented function for the putative human TRAMP is the polyadenylation and degradation of prematurely terminated rRNA precursors71,72 (Figure 5A). These transcripts accumulate when cells are treated with low concentrations of the transcription inhibitor actinomycin D and can also be detected in untreated cells.71 Consistent with polyadenylation by a TRAMP polymerase and subsequent degradation by the nuclear exosome, depletion of either PAPD5/hTRF4-2 or ZCCHC7 reduces levels of the poly(A)tailed rRNAs, while depleting SKIV2L2/hMTR4 or EXOSC10/hRRP6 results in increased levels of these RNAs.71,72 Another possible substrate for a TRAMP-like complex is the RNA component of telomerase, called hTR. Those hTR RNAs that fail to assemble with their core protein dyskerin (DKC1) are degraded, in part through polyadenylation by PAPD5/hTRF4-2 and degradation by the EXOSC10/ hRRP6-containing exosome.59,155,156 There is also evidence that PAPD5/hTRF4-2 can function independently of the Air1/2 ortholog ZCCHC7. Although yeast Trf4 and Trf5 lack RNA-binding modules and are inactive in polyadenylation without their Air1/2 partners,41 PAPD5/ hTRF4-2 contains a C-terminal RNA-binding domain and is active in polyadenylation in the absence of other proteins.157 Also, in contrast to yeast, where Trf4 and Air2 colocalize to nuclei, ZCCHC7 is nucleolar, while PAPD5/hTRF4-2 and SKIV2L2/hMTR4 are both nucleolar and nucleoplasmic.72 Since the only catalytic subunit of the nucleolar exosome is EXOSC10/hRRP6, the putative human TRAMP could target RNAs to this form of the exosome, while PAPD5/hTRF4-2 and SKIV2L2/hMTR4 may have additional substrates in the nucleoplasm. In this regard, it will be interesting to determine if ZCCHC7 is required for polyadenylation of unassembled forms of hTR RNA. 3.5.2. The NEXT Complex. In addition to its role in a putative TRAMP, SKIV2L2/hMTR4 is a component of other exosome adaptor complexes in human cells. Coimmunoprecipitation experiments, coupled with high-resolution mass spectrometry, revealed that SKIV2L2/hMTR4 associates with the zinc knuckle protein ZCCHC8 and the putative RNAbinding protein RBM7 to form the nuclear exosome targeting (NEXT) complex72 (Figure 5B). RBM7 carries out RNA recognition, showing some preference for polyuridines.151,158 ZCCHC8 functions as a scaffold, with separate binding sites for RBM7 and hMTR4, while hMTR4 likely contacts the exosome.159 Unlike SKIV2L2/hMTR4, which is both nucleoplasmic and nucleolar, ZCCHC8 and RBM7 are exclusively nucleoplasmic.72 The RNAs bound by NEXT are largely short newly synthesized RNA polymerase II transcripts, such as PROMPTs, enhancer RNAs, and 3′ extended small nuclear and small nucleolar RNAs.72,151,160 These ncRNA targets, together 4431


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Figure 6. Newly synthesized ncRNAs can be exported to the cytoplasm, uridylated, and degraded by DIS3L2. (A) In mouse and human embryonic stem cells, pre-let-7 miRNA is exported to the cytoplasm and bound by LIN28, which blocks cleavage by DICER1 and recruits TUT4 and TUT7 to the pre-miRNA. After uridylation, DIS3L2 degrades the pre-miRNA.183,185−188 (B) Unprocessed forms of many RNA polymerase transcripts, including pre-tRNAs and 3′extended forms of 7SL RNA, are exported to the cytoplasm, uridylated by TUT4 and TUT7, and degraded by DIS3L2.64,189−191 (C) 3′ Extended pre-snRNAs and pre-snoRNAs can also be exported to the cytoplasm, uridylated by TUT4 and TUT7, and degraded by DIS3L2.189−191

miRNAs.167 In a role that is separate from this function, DGCR8 binds directly to mature human snoRNAs and to the telomerase RNA (hTR), and also associates with the EXOSC10/hRRP6-containing form of the exosome.168 Consistent with a role as an exosome adaptor, DGCR8 is required for the association of mature snoRNAs and hTR with EXOSC10/hRRP6.168 As the levels of these ncRNAs increase when DGCR8 or EXOSC10/hRRP6 is depleted, DGCR8 likely targets these RNAs for exosome degradation.168 Similar experiments have implicated DGCR8 and the exosome in the degradation of ncRNAs called long intervening noncoding RNAs (lincRNAs) that initiate from their own promoters and do not overlap exons of protein-coding genes.169 The mechanism by which DGCR8 identifies ncRNAs for exosome degradation has not been determined. However, given the specificity of DGCR8 for RNA hairpins,170 coupled with the requirement of EXOSC10/hRRP6 for a single-stranded 3′ end, one possibility is that the ncRNAs targeted by DGCR8 for degradation by the nucleolar exosome contain protein-free RNA hairpins adjacent to single-stranded 3′ ends.

lacking introns undergoes PABPN1-mediated decay, while its intron-containing counterpart is exported efficiently and is stable.165 In support of the idea that nuclear ncRNAs with an accessible poly(A) tail are targeted for decay by PABPN1, several viral and cellular ncRNAs that accumulate to high levels in the nucleus possess short poly(A) tails that are sequestered within triple helical structures, rendering the tails inaccessible to PABPN1 and the exosome.49,50,166 Interestingly, a second complex, consisting of SKIV2L2/ hMTR4 and ZF3CH1, but lacking PABPN1, was described recently.154 These authors showed that when either SKIV2L2/ hMTR4 or ZF3CH1 is depleted, many target RNAs are exported to the cytoplasm and are found in polysome fractions.154 Depletion of SKIV2L2/hMTR4 or ZF3CH1 was also associated with a shift of bona fide mature mRNAs to lighter polysome fractions, a decrease in the overall population of heavy polysomes, and a reduction in overall translation.154 Since many of the normally unstable lncRNAs that reach the cytoplasm when either SKIV2L2/hMTR4 or ZF3CH1 is depleted are likely to contain short open reading frames, these lncRNAs may compete with bona fide mRNAs for ribosome binding, resulting in decreased protein synthesis. The relationship of this complex, called “polysome protector complex”,154 to PAXT remains to be investigated. 3.5.4. Other Nuclear Exosome Adaptors in Human Cells. Human cells contain additional adaptors that, similar to yeast Utp18 and Nop53, target specific ncRNAs to the nuclear exosome. One such adaptor is the DiGeorge syndrome critical region gene 8 (DGCR8) protein, a double-stranded RNAbinding protein best known for its role is assisting the RNase III endoribonuclease DROSHA in cleaving primary miRNAs (primiRNAs) to produce ∼70 nt stem-loop containing pre-

3.6. Role of the Cytoplasmic Exosome in ncRNA Surveillance

Although the cytoplasmic exosome largely functions in mRNA degradation,171 this form of the exosome functions in at least one ncRNA surveillance pathway in yeast, called nonfunctional rRNA decay (section 7.2), and may also participate in the decay of excess newly synthesized ncRNAs that undergo nuclear export and degradation in the mammalian cytoplasm.64,172 In yeast, the cytoplasmic exosome functions with the Ski complex, a heterotetramer consisting of the Mtr4-related helicase Ski2, two copies of the β-propeller protein Ski8, and the tetratricopeptide retreat protein Ski3.173−175 The tetrameric 4432


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ncRNAs from a surveillance pathway in which newly synthesized ncRNAs undergo nuclear export, poly(U) addition, and degradation by DIS3L2.64 Subsequent studies have established that a wide range of newly made ncRNAs undergo cytoplasmic uridylation and degradation by DIS3L2. Experiments in which the RNAs bound to catalytically inactive DIS3L2 mutants were immunoprecipitated from human, mouse, and Drosophila melanogaster cells revealed numerous ncRNAs, including RNase MRP, 5S rRNA, 7SL RNA, pre-tRNAs, snoRNAs, snRNAs, Y RNAs, vault RNAs, and pre-miRNAs.189,190,200 Consistent with newly made ncRNAs, many of these RNAs contained 3′ extensions. The 3′ extended RNAs included RNAs normally made as precursors (such as pre-tRNAs, pre-snRNAs, and pre-snoRNAs; Figure 6B,C) as well as ncRNAs, such as 7SL RNA, in which the 3′ trailer was generated by failure to terminate at the normal RNA polymerase III termination site.189,190,200 Many of these RNAs also contained short (less than 26 nt) U-tails.189,190,200 Consistent with a decay pathway, the uridylated forms of these RNAs increased when DIS3L2 was depleted or absent.189−191,200 Experiments in which TUT4 and TUT7 were depleted revealed that at least some uridylation was due to these enzymes.190,191 How conserved is ncRNA surveillance mediated by TUTases and DIS3L2? Although TUTases and DIS3L2 are absent in budding yeast, they are present in most eukaryotes,194,195,201 and DIS3L2 contributes to mRNA decay in both fission yeast and plants.201,202 Thus, the roles of TUTases and DIS3L2 in degrading newly synthesized aberrant ncRNAs may be widespread.

Ski complex, which unwinds RNA and funnels the resulting single-stranded RNA into the exosome channel,175 is tethered to the exosome via the Ski7 protein.176 Biochemical and structural studies have shown that Ski7 binds to the exosome via a domain near its N-terminus.92,176,177 This Ski7 domain wraps around the exosome, contacting the same surface formed by Csl4, Mtr3, and Rrp43 that is bound by the Rrp6 C-terminus in structures of the nuclear exosome.92,177 Although the mechanisms by which the Ski proteins and the cytoplasmic exosome contribute to ncRNA surveillance are largely unknown, the Ski complex was recently demonstrated to bind ribosomes that have stalled on mRNAs lacking stop codons.178 The Ski complex binds directly to the stalled 40S ribosomal subunits, with interactions both to the 18S rRNA and to ribosomal proteins.178 Conformational changes that occur upon Ski complex binding position the mRNA such that the 3′ end can enter the Ski2 helicase channel.178 The functions of the cytoplasmic exosome have been less studied in human cells; however, humans possess orthologs of all four SKI proteins177,179,180 and the human Ski2 ortholog SKIV2L has been demonstrated to associate with 40S ribosomal subunits.181

4. URIDYLATION FOLLOWED BY DIS3L2 DEGRADATION Although in budding yeast degradation of most newly made ncRNAs occurs in nuclei,182 recent studies in other species have revealed pathways in which these ncRNAs are exported to the cytoplasm for degradation. A prominent pathway in many organisms involves uridylation by terminal U transferases and degradation by DIS3L2, a 3′ to 5′ processive exoribonuclease, related in structure to DIS3 and DIS3L, that preferentially degrades uridylated RNAs183−185 (Table 1 and Figure 6). Early evidence for this pathway came from the discovery that let-7 miRNA levels were regulated post-transcriptionally in mouse and human embryonic stem cells. Specifically, while the primary transcript encoding let-7 miRNA (pri-let-7 miRNA) was abundant, the mature let-7 miRNA was undetectable.192,193 In these cells, after cleavage of pri-let-7 miRNA by the DROSHA endoribonuclease, the resulting pre-let-7 miRNA is exported to the cytoplasm and bound by LIN28, an RNAbinding protein that blocks processing and recruits two terminal uridyltransferases, TUT4 and TUT7.186−188 These enzymes are members of the same family of noncanonical poly(A) polymerases as yeast Trf4 and Trf5.194,195 Following uridylation, DIS3L2 degrades the pre-let-7 miRNA183−185 (Figure 6A). A second line of evidence came from studies of RNA packaging by retroviruses. Although retroviruses such as Moloney murine leukemia virus (MLV) and the human immunodeficiency virus HIV-1 assemble in the cytoplasm, numerous newly synthesized ncRNAs, including precursors to tRNAs, small nuclear RNAs, and small nucleolar RNAs, are highly enriched in virions.64,196,197 Several of these ncRNAs, such as the 7SL RNA component of the signal recognition particle and cytoplasmic vault and Y RNAs, appeared to be packaged shortly after synthesis, before assembling with their usual protein partners.64,198,199 Consistent with cytoplasmic recruitment, encapsidation of both pre-tRNAs and U6 snRNA by MLV was reduced when the nuclear export receptor Exportin-5 was depleted.64 Remarkably, uridylated forms of unprocessed tRNAs and U6 snRNA accumulated in cells and virions when DIS3L2 was depleted, either by itself or together with the exosome.64 Thus, retroviruses package some cellular

5. OTHER PATHWAYS THAT MAY INVOLVE 3′ TO 5′ EXORIBONUCLEASES 5.1. CCACCA Addition Targets Some tRNAs and tRNA-like ncRNAs for Decay

The CCA-adding enzyme, which adds CCA to tRNA 3′ ends, assists in identifying structurally unstable tRNAs and tRNA-like ncRNAs and marking them for degradation (Figure 4). Specifically, this enzyme adds CCACCA, rather than the usual CCA, to the 3′ ends of certain tRNAs and tRNA-like ncRNAs with weak acceptor stems. 203 Structural and biochemical studies revealed that, following CCA addition, nucleotide binding to the enzyme active site results in a conformational change that produces torque on the bound tRNA, leading to release of tRNAs with stable acceptor stems.204 For tRNAs with weak acceptor stems, the torque causes the stems to refold while the CCA-containing tRNA remains bound to the enzyme. For tRNAs that begin with 5′ GG, the two newly added C’s can base-pair with the two G’s, allowing another round of CCA addition.204 Although the enzymes that degrade the CCACCA end in vivo have not been identified, the CCACCA tail enhances degradation of tRNAs by 3′ to 5′ exoribonucleases in vitro.203

6. SURVEILLANCE PATHWAYS MEDIATED BY 5′ TO 3′ EXORIBONUCLEASES The major 5′ to 3′ exoribonucleases involved in ncRNA surveillance in eukaryotes are members of the XRN family.205 Because these highly processive enzymes preferentially degrade single-stranded RNAs containing 5′-terminal monophosphates,206 their substrates must undergo removal of either the 5′ triphosphate (RNA polymerase I and III transcripts) or the 4433


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sensitivity to RTD.220,221 In support of models in which ncRNA surveillance occurs in kinetic competition with ncRNA biogenesis,222 RTD occurs in competition with binding of proteins such as tRNA synthetases and EF1A to the mature tRNAs223,224 (Figure 4). As CCACCA has been detected at the 3′ end of several tRNAs that are RTD targets,203 the CCA-adding enzyme may also contribute to recognition of RTD substrates. Experiments in which tRNA degradation was studied in vitro revealed that, although the CCACCA tail enhanced degradation by 3′ to 5′ exoribonucleases, degradation was more efficient in the presence of Xrn1.203 Thus, it was proposed that the CCACCA tail may allow 3′ to 5′ exoribonucleases to initiate decay, while Xrn1 and Rat1 are important for efficient degradation of the tRNA body.203

5′ cap (RNA polymerase II transcripts) prior to degradation. In all studied organisms, distinct XRN family members carry out degradation in the nucleus and cytoplasm.205 For example, budding yeast Xrn1 is largely cytoplasmic207 while the XRN2 ortholog Rat1 is nuclear.208 Despite their disparate locations, these two enzymes are functionally similar, since expression of Rat1 in the cytoplasm is sufficient to alleviate the growth phenotypes of xrn1Δ strains, and targeting of Xrn1 to the nucleus complements the temperature sensitivity of a rat1-1 mutant strain.208 6.1. ncRNA Surveillance Mediated by Yeast Rat1

Noncoding RNAs that are targets of Rat1-mediated surveillance in S. cerevisiae include aberrant and excess pre-rRNA processing intermediates,31 rRNA precursors in misassembled preribosomes,209 antisense and intergenic lncRNAs,19 telomeric repeat containing ncRNAs,22 some hypomodified and/or structurally compromised tRNAs,210 and the noncoding transcripts that remain associated with RNA polymerase II following 3′ end cleavage of the nascent pre-mRNA211,212 (Table 1). Consistent with the requirement of Rat1 for a 5′ monophosphate, all these substrates undergo either decapping (in the case of lncRNAs19) or endonucleolytic cleavage (e.g., p r e - r R N A p r o c e s s i n g i n t er m e d i a t e s a n d m a t u r e tRNAs31,209,210) to generate this end. Indeed, for some yeast lncRNAs, degradation is regulated at the level of decapping.19 In both budding yeast and fission yeast, Rat1 copurifies with the Rai1 protein, which stabilizes Rat1 exonuclease activity and increases the ability of Rat1 to degrade structured RNAs.213,214 S. pombe Rai1, but not S. cerevisiae Rai1, also possesses pyrophosphohydrolase activity, which allows it to convert 5′ triphosphates to 5′ monophosphates.214,215 Moreover, all known fungal Rai1 enzymes possess a decapping endonuclease activity that allows them to remove the entire unmethylated cap (GpppN) from mRNAs.215,216 (This activity is distinct from that of classical cytoplasmic decapping enzymes, such as yeast Dcp2, which cleave the m7GpppN cap to form m7Gpp and 5′ phosphate containing mRNA. 217) The Rai1 decapping endonuclease activity is important for degrading immature mRNAs when S. cerevisiae is subjected to nutritional stress;218 however, a role has not been reported in ncRNA decay. Nonetheless, the decapping endonuclease activity could potentially assist Rat1 in degrading nascent RNA polymerase II transcribed ncRNAs, such as CUTs, telomeric repeat containing RNAs, and pre-snRNAs and pre-snoRNAs. Similarly, for species in which Rai1 is also a pyrophosphohydrolase, this activity could potentially convert newly made RNA polymerase III transcripts into Rat1 substrates.

6.3. Xrn1 Functions with Nonsense-Mediated Decay To Degrade Some lncRNAs

Some unstable lncRNAs resemble mRNAs in that they are transcribed by RNA polymerase II, polyadenylated, and exported to the cytoplasm, where they undergo decapping and degradation by Xrn1.15,225−227 This pathway has been best characterized in yeast, where intergenic and antisense ncRNAs that are Xrn1 targets are called XUTs (Xrn1-sensitive unstable transcripts).15 Although most XUTs do not encode functional proteins, degradation of many of these RNAs by Xrn1 requires nonsense mediated decay (NMD), a translation-dependent surveillance pathway that targets mRNAs containing premature stop codons for degradation.228 Most XUTs are stabilized in yeast deleted for one or more of the NMD factors UPF1, UPF2, and UPF3.225,227,229−231 Consistent with NMD, these XUTs contain one or more small open reading frames (ORFs) near the 5′ end of the RNA that are bound by ribosomes in ribosome-profiling experiments.229,231 These lncRNAs also contain long ribosome-free 3′ UTRs,229−231 consistent with findings that long 3′ UTRs contribute to targeting yeast and mammalian mRNAs for NMD.232,233 Some vertebrate lncRNAs may similarly be targeted for decay by NMD. As in yeast, many annotated zebrafish and mammalian lncRNAs are both ribosome-associated and contain long ribosome-free 3′ UTRs.231,234−237 Moreover, many ribosome-bound lncRNAs increase in levels when UPF1 is depleted or when translation inhibitors that block NMD are present.231,235,238,239 However, while XUTs are defined by their upregulation upon Xrn1 depletion,15 the enzymes that carry out cytoplasmic degradation of mammalian lncRNAs are largely undescribed. In addition, the finding that many lncRNAs are ribosome-bound in both yeast and human cells raises the question of whether the RNAs are truly noncoding. Attempts to determine if the only role of the small ORFs is to target the lncRNA for NMD, or whether some ORFs encode proteins with additional functions, have largely focused on ORF size and conservation.231,234,237,240

6.2. Xrn1 and Rat1 Monitor tRNA Integrity

A pathway that monitors the integrity of many mature tRNAs is rapid tRNA decay (RTD). Described primarily in budding yeast, RTD degrades mature tRNAs that contain mutations that destabilize structure and/or lack nucleotide modifications important for structural stability.219−221 Degradation is carried out largely by Rat1 and Xrn1,210 consistent with the fact that mature tRNAs contain 5′ monophosphates, making them substrates for these exonucleases. How are mature tRNAs recognized as aberrant? Comprehensive mutagenesis of a nonsense suppressor tRNA revealed that mutations throughout the tRNA can result in RTD.221 These data, together with experiments studying other tRNAs, are largely consistent with a model in which mutations that increase accessibility of the 5′ end to exoribonucleases confer

6.4. Roles of Human XRN2 in ncRNA Surveillance

Some ncRNAs that are targets of Rat1 in budding yeast are also degraded by its human ortholog XRN2, including aberrant prerRNAs241 and the transcripts attached to RNA polymerase II following pre-mRNA 3′ cleavage.212,242 XRN2 is also important for degrading some endogenous retrovirus transcripts,243 and for the production of transcription start site (TSS) RNAs, which are short RNAs protected by stalled RNA polymerase II from degradation.244 4434


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6.6. Other ncRNA Surveillance Pathways That May Involve 5′ to 3′ Exoribonucleases

As in yeast, XRN2 functions with cofactors. These partner proteins, which are unrelated to Rai1, contain a conserved domain called the XRN2 binding domain (XTBD).245,246 This domain was first described in the nematode Caenorhabditis elegans, where the XTBD-containing protein PAXT-1 (partner of XRN two) stabilizes correctly folded XRN2.245,246 Humans contain three proteins with predicted XTBD domains, two of which have been characterized functionally.245−250 Rather than stabilizing XRN2, both proteins influence its subnuclear location and substrate targeting. One protein, the nucleolar NF-κB repressing factor (NKRF), is required for localization of XRN2 to nucleoli and for its roles in maturing pre-rRNAs and degrading aberrant pre-rRNAs.249,250 NKRF acts as an adapter, as it also binds directly to pre-rRNAs and is required for association of XRN2 with pre-ribosomes.250 NKRF also regulates XRN2 localization, since both NKRF and XRN2 redistribute to the nucleoplasm during heat stress, with new synthesis of NKRF required for XRN2 to return to nucleoli.249 Interestingly, overexpression of a second XTBD-containing protein, nucleoplasmic CDKN2AIP/CARF, reduces the amount of XRN2 in nucleoli.247 Thus, CARF and NKRF may act in opposing ways to regulate the distribution of XRN2 between the nucleoplasm and nucleoli.

6.6.1. DUSP11-Dependent ncRNA Degradation. The triphosphate that is the initial 5′ end of all RNA polymerase III transcripts acts as a barrier to digestion by XRN1, the major cytoplasmic exonuclease.255 For some ncRNAs, such as tRNAs, the 5′ triphosphate-containing leader sequence is removed during maturation. However, for most polymerase III transcripts, including 5S rRNA, 7SL, Y RNAs, and vault RNAs, the mature ncRNAs retain the triphosphate. Recently, DUSP11 (dual specificity phosphatase 11), which removes the γ and β phosphates from triphosphate-containing transcripts,256 was shown to act on vault ncRNAs and Alu transcripts in vivo.257 As both vault and Alu RNAs increased by ∼2-fold when DUSP11 was depleted from HEK293T cells,257 these findings support a model in which, after removal of the 5′ triphosphate by DUSP11, these RNAs are degraded by a 5′ to 3′ exoribonuclease. DUSP11 is both nuclear and cytoplasmic,258,259 making the subcellular location of this pathway unclear.

7. ADDITIONAL MECHANISMS OF NONCODING RNA SURVEILLANCE 7.1. Retrograde tRNA Nuclear Import

6.5. The DXO/Rai1 Family of De-NADding Enzymes Regulates Levels of Some Mature snoRNAs and scaRNAs in Human Cells

Another mechanism by which defective tRNAs can be targeted for degradation and/or repair is retrograde nuclear import. In this pathway, cytosolic tRNAs undergo nuclear import, followed by reexport to the cytoplasm.260,261 Although the full extent to which this pathway contributes to tRNA biogenesis remains under investigation, retrograde nuclear import is required for modification of at least one tRNA.262 In budding yeast, retrograde nuclear import is important for removing nonfunctional tRNAs from the cytoplasm263 (Figure 4). All eukaryotic tRNAs are synthesized as precursors with 5′ leader and 3′ trailer sequences that must be removed by processing. Afterward, CCA is added to the 3′ end. Although the major tRNA export receptor in yeast, Los1/Exportin-t, preferentially binds end-matured, CCA-containing pretRNAs,264 a small fraction of tRNAs with 5′ and 3′ extensions are exported to the cytoplasm.263 The resulting pre-tRNAs cannot function in protein synthesis, since tRNAs with immature 3′ ends cannot undergo aminoacylation. As these aberrant tRNAs accumulate in the cytoplasm when nuclear reimport is blocked,263 their normal fate may be to undergo nuclear reimport, followed by 3′ end maturation or degradation. The retrograde tRNA nuclear import pathway also operates in mammalian cells;265 however, the extent to which this pathway contributes to tRNA quality control in these cells is unclear. Although pre-tRNAs containing 5′ and 3′ extensions access the cytoplasm of mammalian cells, at least some of these aberrant pre-tRNAs undergo uridylation by TUTases and degradation by DIS3L2, a pathway that is absent in budding yeast.64,189 Moreover, some misfolded pre-tRNAs that reach the cytoplasm undergo cleavage by the DICER1 endonuclease,266 an enzyme that is also absent in S. cerevisiae. Thus, mammalian cells have additional pathways to prevent nonfunctional tRNAs from accumulating in the cytoplasm.

A newly discovered class of 5′ to 3′ exoribonucleases that possess decapping activity are members of the DXO/Rai family. The founding member, S. cerevisiae Dxo1, is related in sequence to Rai1, the binding partner of Rat1. Similar to Rai1, Dxo1 exhibits decapping endonuclease activity on unmethylated capped RNAs.251 Dxo1 differs from Rai1 in that it lacks pyrophosphohydrolase activity and is capable of decapping RNAs with m7GpppN caps, albeit with lower efficiency than RNAs with unmethylated caps.251 Moreover, while Rai1 functions in the nucleus, Dxo1 is both nuclear and cytoplasmic.251 Finally, Dxo1, but not Rai1, possesses distributive 5′ to 3′ exoribonuclease activity.251 Human cells contain a single ortholog of Dxo1 and Rai1, called DXO1. DXO1 possesses all three catalytic activities exhibited collectively by yeast Rai1 and Dxo1: pyrophosphohydrolase, decapping endonuclease, and distributive 5′ to 3′ exoribonuclease activities.218 DXO1 can also remove a 5′ nicotinamide adenine dinucleotide (NAD+) cap, a modification that occurs in some bacterial, yeast, and human mRNAs252−254 and also in some snoRNAs and small Cajal body RNAs (scaRNAs).254 Upon DXO1 depletion, unprocessed mRNAs with unmethylated, immature caps accumulate, as do mRNAs and mature snoRNAs and scaRNAs with NAD+ caps.218,254 All the affected snoRNAs and scaRNAs, similar to most mammalian snoRNAs and scaRNAs, are encoded within premRNA introns and are matured from the excised debranched intron following splicing of the host pre-mRNA.254 The finding that some mature snoRNAs and scaRNAs contain NAD+ caps implies the existence of a pathway that adds these caps posttranscriptionally to already mature snoRNAs, targeting them for DXO1 degradation. S. pombe Rai1 and Kluveromyces lactis Dxo1 can also remove NAD+ caps from RNA in vitro; however, the cellular substrates of these enzymes were not identified.254

7.2. Nonfunctional rRNA Decay

In addition to degradation of aberrant pre-rRNAs by the TRAMP/exosome pathway38,127−129 and degradation of pre4435


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rRNAs in misassembled pre-60S ribosomes by Rat1,31,209 mature nonfunctional rRNAs are subject to surveillance. In this pathway, called nonfunctional rRNA decay (NRD), yeast 18S and 28S rRNAs containing point mutations that rendered them inactive in protein synthesis were found to be unstable.267 Surveillance occurred after the rRNAs were assembled into their respective ribosomal subunits.267 Degradation of the defective 40S subunits requires translation and involves the proteins Dom34 and Hbs1,268 which rescue stalled ribosomes by promoting their dissociation into individual subunits.269,270 Although the nucleases involved in degradation of the defective 18S rRNAs have not been fully identified, both Xrn1 and Ski7, which tethers the Ski complex to the cytoplasmic exosome,175,176 are important for decay.268 In contrast, degradation of the defective 60S ribosomal subunits requires the ubiquitination of 60S ribosomal subunits by a ubiquitin E3 ligase complex containing Rtt101 and its partner protein Mms1.271 Following degradation of one or more ubiquitinated proteins by the proteasome, degradation of the defective 28S rRNA is carried out by unknown RNase(s).272 Although NRD was uncovered by studying yeast containing rRNA mutations, this pathway may be important in wild-type cells when ribosomes are damaged by environmental stress. When yeast are treated with H2O2, many ribosomal proteins undergo oxidation and/or cross-linking to RNA.273 Interestingly, strains lacking the Ski8 component of the Ski complex are hypersensitive to H2O2 stress.274 Moreover, although yeast containing single deletions in Ski7, Dom34, or Hbs1 are similar to wild-type strains in their H2O2 sensitivity, yeast lacking both Ski7 and Dom34 or Ski7 and Hbs1 are hypersensitive.274 Levels of ubiquitinated ribosomal proteins also increase upon H2O2 treatment, although this ubiquitination does not require Rtt101.272 Although 40S subunits containing mutations that render them inactive in translation have not been assayed in mammalian cells, a similar pathway likely exists to release nonfunctional ribosomes from mRNAs and target them for degradation. The human Dom34 and Hbs1 homologues PELO and HBS1L are important for recycling ribosomes that accumulate in 3′ untranslated regions during differentiation of a leukemic cell line to erythroid lineages.275 Additionally, the mouse Dom34 homologue Pelota functions with the HBS1related protein GTPBP2 to release ribosomes that stall when a particular tRNA is limiting.276

Specifically, decreased DICER1 is associated with accumulation of Alu transcripts in the retinal pigment epithelial cells of patients with GA.32 These transcripts contribute to retinal pigment epithelial cell death, since introduction of oligonucleotides that target Alu sequences into DICER1-depleted retinal pigment epithelial cells increases cell viability.32 As purified DICER1 cleaves Alu RNAs in vitro,32 the data support a model in which DICER1, by cleaving Alu transcripts, prevents their accumulation in these cells. 7.4. Trafficking of Unneeded ncRNAs into Extracellular Vesicles

There is now evidence that some ncRNAs packaged within the small membrane-bound vesicles known as exosomes (no relation to the nuclease complex described above) consist of ncRNAs that have not complexed with their partner proteins. Similar to the cellular ncRNAs packaged by retroviruses,64,196,197 these vesicles are enriched in SRP RNA, Y RNAs, and repeat-derived RNAs and also contain ncRNAs that are normally confined to nuclei, such as snoRNAs and snRNAs.279−281 As is the case for the ncRNAs within retroviral virions,64,198 most protein partners of these ncRNAs are not detected within the vesicles. Since exosomes and retroviruses assemble using the same cellular machinery (ESCRT, the endosomal-sorting complex required for transport),282 they could potentially recruit their constituent ncRNAs from the same surveillance pathways. Although most attention has focused on the roles of extracellular vesicle ncRNAs in cell:cell communication,282 packaging of excess ncRNAs into vesicles could serve to rid cells of unneeded ncRNAs. Consistent with this possibility, both circular RNAs (circRNAs) and specific noncoding RNAs were found to be enriched in extracellular vesicles, compared to their concentration in cells.281,283,284 Since circRNAs cannot be degraded by exoribonucleases, it was suggested that packaging into extracellular vesicles may be a mechanism of removing these ncRNAs from cells.284 7.5. Noncoding RNA Surveillance Mediated by the Ro60 Autoantigen

In some animal cell nuclei, the Ro 60 kDa (Ro60) protein is found complexed with misfolded variant pre-5S rRNAs and U2 snRNAs.285−287 Structural studies have revealed that Ro60 folds to form a monomeric ring that binds the single-stranded 3′ ends of these RNAs in its central cavity and adjacent helices on its surface.288,289 Because binding of Ro60 to misfolded ncRNAs is not strongly sequence specific, it has been proposed that Ro60 scavenges RNAs that fail to bind their specific protein partners.289 In all cells that have been examined, Ro60 also binds and stabilizes Y RNAs.287,290,291 Although both the fate of the misfolded ncRNAs (refolding vs degradation) and the roles of Y RNAs are not well understood in animal cells, a bacterial Ro60 is tethered by Y RNA to the ring-shaped 3′ to 5′ exoribonuclease PNPase.43 In this bacterial RNA degradation machine, Ro60 is positioned such that RNA substrates can thread through the Ro60 ring into the PNPase cavity for degradation. Moreover, the presence of Ro60 and Y RNA increases the ability of PNPase to degrade structured RNAs.43 However, Ro60 has not been described to associate with nuclease(s) in metazoans, making it unclear if Ro60 functions similarly in animal cells.

7.3. Noncoding RNA Surveillance by Components of the RNA Interference Machinery

In addition to their roles in RNA interference, components of the miRNA processing machinery contribute to degrading some structured ncRNAs. DGCR8 and DROSHA, which together form the Microprocessor that cleaves pri-miRNAs to pre-miRNAs,167 cleave transcripts of long interspersed repetitive element 1 (LINE-1) retrotransposons to reduce their levels and activity in human cells.277 DICER1, which is best known for its role in cleaving pre-miRNAs to release mature miRNAs, also cleaves other ncRNAs in human cells and C. elegans to reduce their abundance.32,278 The ncRNAs whose levels are modulated by DICER1 include specific tRNAs, vault RNAs, Y RNAs, and transcripts from the Alu family of repetitive elements.278 Remarkably, reduced levels of DICER1 in human retinal pigment epithelium are reported to cause a form of age-related macular degeneration known as geographic atrophy (GA).32 4436


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recognition particle,311 telomerase RNA,312 Y RNAs,290 and vault RNAs313 are present at reduced levels in cells when their core proteins are mutated or absent. For those unassembled ncRNAs whose decay pathways have been elucidated, surveillance pathways have been found to be responsible. For example, unassembled forms of the yeast U1 snRNA are degraded both by the TRAMP/nuclear exosome pathway and by decapping and Xrn1 degradation,58 degradation of unassembled yeast 7SL RNAs requires TRAMP and the nuclear exosome,57 and degradation of unassembled forms of U1 snRNA and telomerase RNA in human cells involves the nuclear exosome as well as decapping and Xrn1 decay.58,59,172 Consistent with a model in which ncRNP assembly competes with surveillance, depletion of EXOSC10/hRRP6 and the decapping enzyme DCP2 restores telomerase activity in human cells depleted of dyskerin, a protein that stabilizes hTR RNA but is not required for activity.59 Similarly, human cells depleted of the survival of motor neuron (SMN) protein, which functions in a complex that assists loading of the Sm core proteins onto the spliceosomal U snRNAs, have reduced levels of these snRNAs and defects in pre-mRNA splicing.58,172 As codepletion of the decapping enzyme Dcp2 partially restores U snRNA levels and ameliorates the splicing defects,58 snRNP assembly occurs in competition with decapping of the unassembled RNPs.

8. COMPETITION WITH NONCODING RNA BIOGENESIS PATHWAYS For all surveillance pathways involving classical ncRNAs, the cofactors that target defective ncRNAs for degradation and the enzymes that degrade these ncRNAs compete with the normal biogenesis pathways for access to the ncRNAs. Some examples are described below. In addition, Figure 4 depicts some ways in which components involved in normal tRNA biogenesis compete with components that recognize and degrade the aberrant and nonfunctional tRNAs. 8.1. Competition with Chaperone Proteins That Bind Nascent ncRNAs

The La autoantigen functions as a chaperone for many newly synthesized ncRNAs. This ∼50 kDa phosphoprotein binds the 3′ end of all newly made RNA polymerase III transcripts, including pre-tRNAs,292 pre-5S rRNAs,292 pre-U6 snRNAs,293 7SL RNA,294 Y RNAs,295 vault RNAs,296 and Alu transcripts.297 La binds all these ncRNAs because its high affinity binding site is the UUUOH that is the initial 3′ end of all RNA polymerase III transcripts.298 In budding yeast, La also binds processing intermediates of spliceosomal snRNAs and snoRNAs that terminate with UUUOH.44,45,299 Because most of these ncRNAs undergo subsequent 3′ maturation, La binding is usually transient, such that La is not part of the mature ncRNP. Binding by La protects the 3′ ends of nascent ncRNAs from 3′ to 5′ exoribonucleases,44,45,52,57,300,301 and can assist their folding and assembly into RNPs.44,266,302,303 For pre-tRNAs, La can also influence the mechanism by which the 3′ leader sequence is matured, as La binding favors endonucleolytic removal of some pre-tRNA 3′ trailers by RNase Z.46,52,304 In cells lacking La, the 3′ end of these tRNAs is matured by exoribonucleases.46,52 Binding by La protects multiple nascent ncRNAs from surveillance pathways. Consistent with competition between binding of La to ncRNA 3′ ends and targeting of the RNAs for degradation, the levels of some ncRNAs are reduced in yeast and Trypanosoma brucei cells lacking La.55,305 In human cells, binding of La to specific pre-tRNAs prevents their folding into alternative structures that are cleaved by DICER to generate Argonaute 2 bound small RNAs.266 The roles of La have been best studied in budding yeast, where La becomes essential when yeast contain mutations that disrupt tRNA structure,52,302 eliminate nucleotide modifications important for stabilizing correctly folded tRNAs,53,55,306 or impair assembly of La-bound snRNAs into snRNPs.44,54,307 In many of the mutant strains, La binding allows the newly synthesized ncRNA to escape surveillance, enabling the ncRNA to undergo end maturation and/or assembly into functional RNPs.52,54,55,302 Consistent with competition between La binding and targeting of the nascent ncRNAs for degradation, overexpression of La in yeast results in increased levels of a hypomodified tRNA that is normally targeted for decay by the TRAMP/exosome pathway.53 Similarly, La overexpression results in increased U6 snRNA levels in yeast containing a mutation in a core U6 protein54 and increased levels of the 7SL RNA subunit of the signal recognition particle in cells deleted for SRP core proteins.57 La overexpression also results in decreased levels of aberrant tRNA processing intermediates that are normally TRAMP targets.46

8.3. Competition with Enzymes That Mature ncRNA 3′ Ends

Some ncRNAs acquire 3′ end modifications that protect the RNAs from surveillance. One such ncRNA is the U6 snRNA, a component of the spliceosome. After transcription by RNA polymerase III and La binding,54,293 U6 assembles with a heptameric ring complex comprised of the Lsm2−Lsm8 proteins,54,314−316 undergoes 3′ uridylation by a U6-specific TUTase,293,317 followed by 3′ trimming by the Usb1/Mpn1 exoribonuclease, which leaves a terminal cyclic 2′,3′ phosphate.60,61,318 This 3′ end modification is highly conserved, as U6 snRNAs from many metazoans, plants, and fission yeast all terminate with cyclic 2′,3′ phosphate.61,318 In budding yeast, an organism that lacks TUTases,194 the Usb1/Mpn1 exoribonuclease trims gene-encoded terminal uridylates, and most U6 terminates with a 3′ or 2′ monophosphate.318 These 3′ end modifications prevent both La rebinding and adenylation by TRAMP, which, like other poly(A) polymerases, requires that substrates contain 3′-OH.41 USB1/MPNI is disrupted in patients with the rare autosomal recessive disease poikiloderma with neutropenia, and in patient-derived cell lines, U6 is less stable and contains nontemplated oligo(A) tails.61−63 Consistent with competition between U6 end modification by Usb1/Mpn1 and targeting for decay, U6 is also less stable in budding and fission yeast depleted of Usb1/Mpn1.60,61,63 Other examples of end modifications that protect ncRNAs from surveillance include CCA addition and aminoacylation of tRNAs51 and the 3′ methylation that stabilizes germ-line specific ncRNAs called piRNAs.319

9. CONCLUSIONS AND PERSPECTIVES It is now clear that cells possess myriad ways to recognize and target aberrant ncRNAs for degradation. It is likely that most of the ribonucleases involved have been identified, and many of their adaptors are also known. High resolution structures exist for the most prominent nucleases involved in ncRNA surveillance, such as the RNA exosome, members of the XRN family, DIS3L2, and endoribonucleases such as DICER1.

8.2. Competition with ncRNP Assembly

Many ncRNAs, including U1, U4, and U6 snRNAs,44,54 snoRNAs,308−310 the 7SL RNA component of the signal 4437


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bioinformatics, may make it possible to formulate hypotheses that can be tested in model organisms and in patient-derived cell lines. Moreover, given reports that inappropriate activation of cytoplasmic innate immune sensors by endogenous ncRNAs contributes to both autoimmunity330 and cancer,280 identifying compounds that boost ncRNA surveillance pathways could be a therapeutic strategy.

Much progress has also been made in identifying the nuclease cofactors that recognize defective ncRNAs; however, less is known as to how they select their specific targets. For example, although there is good evidence that a protein-free accessible end is critical for recognition by both noncanonical poly(A) polymerases and exoribonucleases, it remains unclear whether other features of RNA structure, such as protein-free helices or single-stranded regions adjacent to the RNA end, contribute to recognition of specific ncRNAs by adaptor proteins. Since structural and biochemical investigations of most prominent nuclease cofactors, such as the TRAMP and NEXT complexes, are well underway, it should not be long before these studies, together with in vivo analyses, identify the exact requirements for binding. Some surveillance targets, such as the defective mature rRNAs that are subject to NRD, are targeted for degradation as RNPs, yet the ways in which the protein components are handled and removed from the ncRNAs are largely unaddressed. For example, although protein components of inactive 60S ribosomal subunits undergo ubiquitination and degradation by the proteasome,271,272 it is not known how the protein and rRNA degradation are coordinated, or if dedicated helicases exist that expose the rRNA for degradation. Although the defective rRNAs that assemble into inactive ribosomes267 are the clearest example of an RNP that must be dismantled for degradation, there may be other nonfunctional ncRNPs, such as snoRNPs and spliceosomal snRNPs, for which protein and RNA decay need to be coordinated. Moreover, although many ncRNAs that are targeted for surveillance are not bound by their normal protein partners,57−59 it is unknown if other protein(s) are bound to these RNAs. Other areas that are only beginning to be addressed are the ways in which damaged ncRNAs are targeted for degradation and how ncRNA repair systems interface with decay pathways. For example, ultraviolet light, reactive oxygen species, alkylating agents, and chemotherapeutic agents such as cisplatin and mitomycin C can all damage RNA,320,321 yet the full range of how these agents impact ncRNA function and how cells recognize and target the damaged RNAs for degradation remains poorly understood. Moreover, the widespread occurrence of RNA ligases,322 coupled with evidence that they can repair damaged RNAs,323 suggests that RNA repair systems may compete with degradation systems to handle ncRNAs rendered inactive by endonucleolytic cleavage. Lastly, a major challenge is to elucidate the ways in which failure to eliminate aberrant and excess ncRNAs impacts human disease. This is particularly challenging in mammalian cells, since the abundance of surveillance pathways in these cells results in numerous redundancies in the ways in which ncRNAs can be degraded. Moreover, the multitude of mRNAs and ncRNAs targeted by most surveillance pathways vastly increases the difficulties in elucidating how a specific mutation results in human disease. Yet, the fact that recessive mutations in the exosome core subunits EXOSC3/hRRP40324 and EXOSC8/ hRRP43,325 the NEXT component RBM7,326 and the DIS3L2 exoribonuclease327 all result in child-onset diseases with high mortality make deciphering the disease mechanisms a priority. Also, the finding that mutations that inactivate DIS3 are a common secondary event in the progression of multiple myeloma328 makes it important to understand how dysregulation of this exosome catalytic subunit contributes to cancer. The ongoing efforts to characterize large numbers of patient tumor transcriptomes,329 coupled with the appropriate

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Sandra L. Wolin: 0000-0001-6730-0399 Notes

The authors declare no competing financial interest. Biographies Cedric Belair obtained his B.S. in cell biology and physiology and his Ph.D. in microbiology/immunology from the University of Bordeaux, France. His doctoral project, performed under the supervision of Dr. Fabien Darfeuille, was to study the role of microRNAs in the response of gastric epithelial cells to infection by the bacterium Helicobacter pylori. In 2011, he became a postdoctoral associate in the laboratory of Dr. Sandra Wolin at Yale University in New Haven, CT, where he investigated the role of RNA surveillance pathways, most notably the RNA exosome, in human embryonic stem cell biology. He is currently a research fellow in the laboratory of Dr. Sandra Wolin at the National Cancer Institute in Frederick, MD, where he continues to investigate RNA surveillance pathways. Soyeong Sim received both her B.S. in chemistry and her Ph.D. in biochemistry from the Korea Advanced Institute of Science and Technology, where she studied bacterial RNA processing under the direction of Dr. Younghoon Lee. She joined the group of Dr. Sandra Wolin at the Yale School of Medicine in New Haven, CT, in 2003, where she was supported by a James Hudson Brown−Alexander Brown Coxe postdoctoral fellowship and by a postdoctoral fellowship from the Arthritis Foundation. In 2008, she became an associate research scientist in the same group. Currently, she is a staff scientist in the group of Dr. Sandra Wolin at the National Cancer Institute in Frederick, MD. Her research focuses on the function of ncRNAs and RNA binding proteins. Sandra L. Wolin is Chief of the RNA Biology Laboratory at the National Cancer Institute in Frederick, MD, and heads the Center for Cancer Research’s RNA Initiative. She received her undergraduate degree in biochemical sciences from Princeton University, her M.D. from the Yale School of Medicine, and her Ph.D. degree in molecular biophysics and biochemistry from Yale University, where she worked under the supervision of Dr. Joan Steitz. Her postdoctoral studies were carried out with Dr. Marc Kirschner and Dr. Peter Walter in the Department of Biochemistry and Biophysics at the University of California, San Francisco. She joined the faculty of Yale University in 1991, where she rose to become Professor of Cell Biology and Director of the Yale Center for RNA Science and Medicine. In 2017, she moved to the National Cancer Institute in Frederick, MD, to lead the newly established RNA Biology Laboratory.

ACKNOWLEDGMENTS The Wolin laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, the Center for Cancer Research. 4438


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Noncoding RNA Surveillance: The Ends Justify the Means - Chemical

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