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Published in final edited form as: Trends Cell Biol. 2013 Jun 4;23(10):504–510. doi: 10.1016/j.tcb.2013.05.001

Emerging roles for RNP modification and remodeling in controlling RNA fate

Suzanne R Lee 1,*, Jens Lykke-Andersen 1,*
PMCID: PMC3983964  NIHMSID: NIHMS478409  PMID: 23756094

Abstract

In the cell, mRNAs and non-coding RNAs exist in association with proteins to form ribonucleoprotein (RNP) complexes. Regulation of RNP stability and function is achieved by alterations to the RNP through poorly understood mechanisms into which recent studies have now begun to provide insight. This emerging body of work identifies chemical modifications of RNPs at the RNA or protein level and ATP-dependent RNP remodeling by RNA helicases/RNA-dependent ATPases as central events that dictate RNA fate. Some RNP modifications serve as tags for recruitment of regulatory proteins, with RNP modifiers and recruited proteins analogous to the writers and readers of chromatin modification, respectively. This review highlights examples of in which RNP modification and ATP-dependent remodeling play key roles in the control of eukaryotic RNA fate, suggesting that we are only at the beginning of uncovering the multitude of ways in which RNP modification and remodeling impact RNA regulation.

Keywords: RNA tailing, uridylation, ribonucleotidyltransferase, RNA modification, RNP modification, post-translational modification, RNA helicase, RNA decay

RNAs function in, and are regulated as, RNPs

Life depends on the proper decoding of information contained within DNA into the creation of functional molecules, and maintenance of those molecules at levels that meet cellular needs and changing environmental stimuli. The immediate product of DNA decoding is RNA, which serves critical cellular and developmental functions either directly, as non-coding RNAs, or indirectly, as protein-coding messenger (m)RNAs. Each step in the life of a eukaryotic RNA - from transcriptional birth to processing to function - involves the dynamic organization and reorganization of RNA structures with proteins to form ribonucleoprotein (RNP) complexes [1]. The biological importance of RNA-binding proteins (RBPs) is underscored by the fact that many human diseases result from RBP malfunction [2–4].

It is within the context of structured RNPs that the activity and stability of many RNAs are regulated post-transcriptionally. The composition of an RNP dictates RNA fate, reflecting aberrations that subject the RNA to quality control degradation pathways [5] or enabling the specific recognition of an RNA as a target by regulatory machineries. The latter is perhaps best understood for RNP complexes containing mRNAs (mRNPs), in which different RNA binding proteins mediate the initiation of translation, translational repression and storage, or the recruitment of RNA degradation enzymes, and fate switches for a given mRNA are the result of changes to the complement of associated RNA binding proteins [6]. In RNA decay, restructuring an RNP is not only important for the recruitment of degradation machineries, but also critical to permit nuclease access to the RNA itself. For example, it is known that proteins bound to the 5′ mRNA cap are inhibitory to decapping factors that remove the cap during mRNA degradation [7], while the poly(A)-binding protein inhibits some deadenylases that degrade the poly(A) tail while activating others [8].

Thus, an important, and poorly understood, question is how these fate-determining RNP transitions – between an active state and an inactive state, from stability to instability – are mediated. Here we review key examples that are beginning to highlight RNP modification – the covalent addition of a chemical moiety to RNA or protein components of RNPs (Figure 1) - and ATP-dependent RNP remodeling (Figure 2) as important mechanisms that alter RNP composition and thereby regulate RNA fate.

Figure 1. Modification of RNA and protein components of RNPs controls RNA fate.

Figure 1

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The RNA within RNPs is represented by a black line and proteins are represented by spheres. The terms writer, reader, and eraser are borrowed from the chromatin field [70] and refer to proteins that add, bind to, and remove RNP modifications, respectively. m6A, N6-methyl-adenosine; CH3, methyl group, Ac; acetyl group, P, phosphate group; UUU, oligouridylation.

Figure 2. RNP remodeling by ATP-dependent RNA helicases regulates RNA function.

Figure 2

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ATP, adenosine triphosphate; ADP, adenosine diphosphate; Pi, inorganic phosphate.

Complexes that combine RNP modification and remodeling activities are key players in RNA degradation pathways in bacteria and eukaryotic nuclei

In bacteria, it has long been known that RNP modification and remodeling activities come bundled as one package in the degradosome, which is a multisubunit complex that targets mRNAs and misfolded structural RNAs for decay [9]. Within the degradosome, there exists a poly(A) polymerase, which tails RNA with a string of 3′ adenosines, and an RNA helicase, which resolves RNP structures. Together, these RNP modifying and remodeling activities render the targeted RNAs unstable by creating a single-stranded RNA tail that serves as a tag accessible to the 3-to-5′ exonucleases which carry out RNA degradation.

It has only been in the past decade that a conserved multisubunit complex similar in composition to the bacterial degradosome was identified in eukaryotic nuclei [10]. What is now known as the Trf4p/Air2p/Mtr4p polyadenylation (TRAMP) complex contributes to a nuclear quality control pathway responsible for degrading a broad range of RNA species that are aberrantly processed, in excess, or are otherwise nonfunctional. Like it’s bacterial counterpart, eukaryotic TRAMP contains Trf4p, an adenosine-specific ribonucleotidyltransferase (rNTr), and Mtr4, an RNA helicase [11–14]. Promotion of nuclear decay is achieved at least in part by increasing the accessibility of 3′ RNA ends to 3′-to-5′ exonucleases through RNP structure resolution and/or the addition a 3′ oligoadenosine tail [12–18]. In addition, 3′ tailing may stimulate the activity of the helicase component of TRAMP itself by creating an optimal RNA tag for helicase binding [19–21].

Interestingly, given the huge variety of RNPs degraded by nuclear quality control, RNP modification and remodeling activities by TRAMP may be employed “on-demand”, modulated in response to a given target RNP or the degree of local structure encountered during degradation of a single RNP. Consistent with this, some RNA species and degradation intermediates do not require ATP-dependent RNA nucleotide tagging or helicase activity for efficient TRAMP-dependent decay [14,17,18]. Moreover, recent high-throughput sequencing studies have uncovered oligoadenylated fragments with 3′ ends corresponding to multiple sites across TRAMP-target RNAs [22,23], which may reflect alternating rounds of TRAMP-mediated RNA tailing and 3′-to-5′ degradation.

Thus, the bacterial degradosome and the TRAMP complex of eukaryotic nuclei exemplify complexes that carry out tagging and ATP-dependent remodeling of RNPs to determine RNA fate.

RNP modification by RNA tailing

Observations in recent years suggest that RNA tailing outside of TRAMP-mediated quality control or normal nuclear polyadenylation during mRNA biogenesis may be a widespread modification that alters RNP fate. In the cytoplasm, the extension of mRNA poly(A) tails serves to stabilize and/or activate repressed mRNAs under certain conditions, including oocyte maturation, neuronal stimulation and inflammation [24]. In contrast, the appending of short RNA tails composed of uridine, or both uridine and cytosine, to RNA targets has emerged to be linked to RNA instability or repression. Both poly(A) tail extensions and uridine-rich tails are added by nucleotide-specific rNTrs in the same family as the TRAMP rNTr [25–27]. In mammals, known RNA targets of uridylation-associated repression include mRNA cleavage fragments generated by RNAi targeting [28], histone mRNAs [29], pre-micro (mi)RNAs, and mature miRNAs [30,31]. In addition, the instability of a tRNA-like small RNA has been linked to 3′ extension by the CCA-adding enzyme through a proposed tRNA quality control pathway [32]. However, it is likely that this represents just a small fraction of tailed RNAs in mammalian cells, with many more RNA targets of uridylation or other nucleotide tailing left to uncover. In fact, studies in Saccharomyces pombe and Aspergillus nidulans have reported that apparently normal polyadenylated mRNAs [33–35], as well as targets for the nonsense-mediated mRNA decay (NMD) pathway [35], are subject to uridylation.

While the molecular details of how RNA tailing contributes to RNA repression and decay have not been fully elucidated, closer study of certain uridylated RNAs suggests that RNA tailing may trigger RNA repression in at least a few different ways. Synthetic RNAs bearing 3′ uridine tails stimulate decapping in human leukemia cell extracts, in a manner dependent on Lsm1 [36]. In yeast, Lsm1 is part of a complex that functions as an enhancer of decapping, with strong intrinsic affinity for oligoadenylated and deadenylated mRNAs with a 3′ U tract [37]. In vivo support that 3′ U tails serve as a tag for Lsm1 binding to stimulate decapping and 5′-to-3′ degradation comes from S. pombe, in which strains lacking Lsm1 or bearing a mutant decapping activator accumulate both capped and decapped mRNAs with U-tails to higher levelsthan in the corresponding wild-type strain [33]. It has also been suggested that uridylation-induced Lsm1 binding may stimulate 3′-to-5′ decay as well, by recruiting the 3′-to-5′ exonuclease Eri1 in the decay of replication-dependent histone mRNAs in mouse embryonic fibroblasts [38]. Finally, a very recent study found that S. pombe Dis3l2, a cytoplasmic 3′-to-5′ exonuclease, exhibits an intrinsic preference in vitro for degrading RNA substrates with 3′ U tracts over those lacking 3′ U under competitive conditions [39]. This activity may target mRNA substrates in vivo that have undergone 3′-to-5′ trimming and U tailing, as mutant strains lacking both Dis3l2 and Lsm1 accumulate 3′ truncated mRNAs with oligoU tails of longer length and to higher levels than strains lacking only Lsm1 [39].

mRNA tailing in the cytoplasm may also contribute to translational repression. In the filamentous fungus Aspergillus nidulans, the tailing of mRNAs with a mixture of uridine and cytidine not only contributes to the decay of normal mRNAs, but also plays a role in the liberation of mRNAs targeted by NMD from polyribosomes [34,35]. Translational repression is proposed to precede the RNA tailing-dependent ribosome release step. It remains to be determined whether this activity is mediated by Lsm1, which forms a complex with the translational repressor Pat1 [40,41].

A very recent study implicated Dis3l2 in the degradation of oligouridylated pre-let-7 in mouse embryonic stem cells [44], while it remains unclear how uridylation leads to the destabilization and/or repression of mature small (s)RNAs [30,31,42,43]. However, it is worth noting that monoadenylation was recently found to stabilize mature miRNAs in mammalian cells [45–47]. Thus, RNA tailing appears to be a means for mediating RNP transitions in activity or stability for both mRNAs and functional non-coding RNAs alike.

Collectively, these studies reveal an emerging, yet poorly understood, role for RNA tailing in controlling RNP fate, not only as a mechanism for ridding the cell of aberrant RNAs, but also for regulating the function and levels of normal RNAs.

RNP modification by RNA nucleotide modification

Over a hundred RNA modifications are known to exist, affecting stable non-coding RNAs such as transfer RNAs and ribosomal RNAs, as well as mRNAs and other non-coding RNAs, yet knowledge of their function and potential for influencing RNP fate is limited [48,49]. For example, modification of sRNAs functioning in RNA interference pathways by 2′-O-methylation provides a protective role against sRNA tailing and degradation [31], yet it is unknown if methylation is reversible or otherwise regulated, or simply part of normal biogenesis. A-to-I editing [50] and 5-methyl-cytosine (m5C) modification [51] have been detected in both mRNAs and non-coding RNAs. Though the small fraction of A-to-I editing that occurs in mRNA coding regions can cause protein recoding, the function of the vast majority of A-to-I and m5C modifications is unknown.

Interest in the RNA modification N6-methyl-adenosine (m6A) was revived recently with the discovery of tens of thousands of m6A-modified segments in mRNA and non-coding RNAs in mice and human cultured cells [52–54]. The level of m6A appears to vary by tissue and stage of development in mice, and a subset of modified sites was found to be dynamically modified in response to various stimuli in human cells, indicating that m6A modification is subject to regulation. Further support for m6A regulation comes from studies that have revealed that methylation of a given mRNA species only affects a fraction of its transcripts at a given site [55] and that demethylases with specificity for the m6A tag exist [56,57].

m6A-modified RNA segments appear to be conserved through evolution, suggesting that an important function is served by this modification [52,53]. Proposed functions have included mRNA splicing, nuclear export, stability and translational control [54,58], yet direct involvement of RNA methylation in the biogenesis, function and/or fate of the vast majority of modified RNAs has yet to be demonstrated. Curiously, in the case of modified mRNAs, m6A is enriched in coding and 3′ UTR regions near the translation termination codon [52,53], suggestive of possible roles in translation or translation-dependent processes. Although it is tempting to speculate that this modification alters RNA structure, as suggested by in vitro studies [59], or impacts RNA-protein interactions, perhaps by acting as a tag specifically recognized by binding effector proteins, more research into the function and regulation of m6A in vivo is needed. An important question for future studies is whether this and possibly other RNA nucleotide modifications represent a new layer of gene regulation.

RNP modification at the protein component level

Like RNA modification, there is emerging evidence that modification of proteins in RNPs can also have profound effects on RNP stability and activity. These effects can be mediated indirectly by the creation of binding sites for proteins that act on the RNP, or by direct modulation of protein-protein or protein-RNA interactions within the RNP. As an example of the former, Upf1, the key effector of NMD, undergoes a phosphorylation-dephosphorylation cycle [60,61]. Phosphorylated sites in Upf1 promote Upf1 decay function by serving as tags that are recognized and bound by the endonuclease Smg6 and other proteins that physically associate with decapping and 5′-to-3′ degradation machineries [62,63]. In addition, phosphorylated Upf1 has been reported to repress translation initiation through interaction with initiation factor eIF3 [64].

Phosphorylation can also have an RNA stabilizing function, as seen for decay-promoting AU-rich element (ARE)-binding proteins (AUBPs), which negatively regulate mRNAs containing AREs in their 3′ UTRs. In this case, phosphorylation interferes with mRNA decay by disrupting AUBP RNA binding or preventing the recruitment of degradation enzymes [65,66]. In an intriguing model for the dynamic control of mRNPs by protein modification, it is thought that the transient inactivation of the AUBP TTP through phosphorylation contributes to the initial stabilization and expression of ARE mRNAs encoding proteins important for the inflammatory response upon macrophage stimulation. As TTP phosphorylation prevents its recruitment of deadenylases, rapid revival of TTP-dependent mRNA decay upon dissipation of the inflammatory response trigger may be achieved by TTP dephosphorylation, which would be expected to limit the destructive potential of an unchecked inflammatory response [67,68].

Other types of protein modifications impacting RNPs include lysine acetylation and arginine methylation, both of which impact protein-RNA interactions in known cases. For example, a recent report described developmentally regulated lysine acetylation of MVH, an RNA helicase that localizes in germline-specific RNA granules associated with translational repression [69]. MVH lysine acetylation was found to interfere with RNA-binding in vitro, and during spermatogenesis, MVH lysine acetylation correlates with the selective release of a target mRNA from MVH-RNPs. Loss of MVH-mediated translational repression due to acetylation was inferred from the increase in target mRNA protein expression that followed.

Arginine methylation of the mRNA stabilizing factor HuR appears important to its regulation of SIRT1 deacetylase mRNA [70]. Decreased mRNA stability partly accounts for a decrease in SIRT1 protein levels during differentiation of human embryonic stem cells. This reduction in mRNA stability parallels a decrease in HuR-modifying methyltransferase levels, resulting in loss of HuR methylation and HuR-SIRT1 mRNA association. That HuR methylation stabilizes HuR binding to SIRT1 mRNA is supported by the finding that a methylation-resistant version of HuR is compromised in SIRT1 mRNA binding compared to wild-type HuR. In contrast, phosphorylation of HuR under oxidative stress in cancer cells causes a release of SIRT1 mRNA, resulting in mRNA destabilization [71].

The above examples of regulatory protein modifications in RNPs seem likely to be followed by many more that underlie important RNP transitions in activity and stability. In fact, a recent study of human cytoplasmic poly(A) binding protein PABP1 revealed 14 novel post-translational modifications, including methylation of glutamate, aspartate, lysine and arginine, as well as acetylation of lysine, the latter of which appears to be regulated in an cell cycle-dependent manner [72]. As PABP1 plays central roles in mRNA translation and stability, an important question is whether these modifications make significant contributions to PABP1-dependent gene regulation. In addition, a number of conserved proteins containing arginine-glycine rich motifs (RGG) were found recently to inhibit mRNA translation through interaction with translation initiation factor eIF4G in yeast [73,74]. Notably, RGG motifs are often targeted by methyltransferases for arginine methylation [73,75].

Taken together, the above examples indicate that RNP modification by different means - RNA tailing, attachment of chemical moieties to RNP protein components, and possibly RNA nucleotide modification – contribute to the control of RNP function and stability (Figure 1). In the case of RNA tailing and some protein modifications, it appears that RNP modification creates a tag that is recognized and bound by RNA regulatory proteins that contribute to RNP fate. Borrowing terms established in the chromatin field for histone modifying enzymes and the proteins that bind histone modifications [76], RNP modification enzymes may act as writers, marking RNPs with tags that are recognized by regulatory protein readers. Other modifications may directly cause the remodeling of RNPs, by physically disrupting interactions within the RNP or altering RNA structure.

RNP regulation by ATP-dependent RNP remodeling

Exposure of RNA to regulatory proteins and/or RNP remodeling can also take place without chemical modification of the RNP, but rather through the ATP-dependent activity of members of the RNA helicase/RNA-dependent ATPase family (Figure 2). In fact, Ski2 helicase is considered the cytoplasmic equivalent of the TRAMP helicase component Mtr4, bearing similarity in amino acid sequence and structure, and functioning in conjunction with 3′-to-5′ degradation machinery in cytoplasmic decay pathways [77,78]. However, whether Ski2 functions molecularly in the same manner proposed for Mtr4, through target binding and exposure of a 3′ single-stranded RNA end to 3′-to-5′ nucleases, remains to be determined. In addition, recent studies suggest that RNA helicase/RNA-dependent ATPase family members may impact RNP stability or function through RNP complex remodeling, which may also include release of the RNA helicase itself.

The core NMD factor Upf1 serves as an example of an RNA helicase/RNA-dependent ATPase which may enable 5′-to-3′ RNA degradation through protein displacement [79]. Mutations disrupting Upf1 ATP binding or ATP hydrolysis activities are inhibitory to NMD [79,80]. ATPase-deficient human Upf1 causes the accumulation of 3′ degradation intermediates of NMD substrates bearing a premature termination codon [79]. As NMD factors are also retained on the 3′ RNA fragments under these conditions, it has been suggested that Upf1 ATP hydrolysis is required for the removal of the NMD complex in order to grant degradation machinery access to the RNA and recycle NMD factors. This Upf1-catalyzed RNP transition is likely under tight regulation, with activation triggered only after the NMD complex has been fully assembled and decay enzymes recruited. In support of this model, the NMD complex component Upf2 has been found to stimulate Upf1 ATPase activity in vitro through interaction with and displacement of an autoinhibitory domain of Upf1 [81,82].

Use of ATP hydrolysis for RNP component release and recycling may also be exemplified by the widely conserved RNA-dependent ATPase Dhh1, which functions as a translational repressor [83]. Recent studies in yeast have demonstrated that the translational repression and subsequent 5′-to-3′ decay induced by Dhh1-tethering to mRNAs is retained in a putative ATPase-deficient mutant [84,85]. However, rescue of Dhh1-dependent decay of some endogenous mRNAs by untethered Dhh1 is compromised by the ATPase mutation [84,86]. These seemingly contradictory data may be explained by the finding that Dhh1 mutant expression causes the accumulation of cytoplasmic RNP granules containing decapping machinery in which the Dhh1 mutant itself is trapped [84,86]. Thus, while Dhh1 ATP hydrolysis is not required for its mRNA repression activities, it may be required to release Dhh1 itself and possibly other factors from repressed RNP complexes targeted for decay for reuse in the repression of additional RNPs.

Examination of another broadly conserved RNA helicase, Ded1, suggests that members of this enzyme class may also have the potential to contribute to opposing RNP states, with ATP binding- or hydrolysis-dependent remodeling triggering the switch between states. Ded1 has long been implicated in both translational initiation and repression [87], but only recently was Ded1-mediated initiation, and not repression, found to be dependent on ATP-binding [88]. Although the underlying molecular outcome of Ded1-ATPase activity has yet to be determined, it is tempting to speculate, given the examples of Upf1 and Dhh1, that Ded1 ATP hydrolysis is required for remodeling mRNP complexes from a translationally inactive state into one that is active, perhaps by releasing inhibitory factors that could include Ded1 itself.

The examples above indicate a common, critical role for RNA helicases in ATP-driven remodeling of RNPs to control RNA function and/or stability. Such remodeling could occur by changes in RNA structure and/or the assembly, remodeling or disassembly of protein components of the RNP. An intriguing area for future research is whether RNP tagging is coupled to ATP-dependent RNP remodeling to control RNA fate in the cytoplasm of eukaryotic cells, as has been found for the degradosome of bacteria and for the TRAMP complex of eukaryotic nuclei.

Concluding remarks

The activity and stability of RNPs are significantly affected by covalent modification at both the RNA and protein levels and by ATP-dependent remodeling. In some cases, these RNP alterations have been found to directly impact the accessibility of RNA components to nucleases and the recruitment or binding of other proteins. However, for many alterations, the precise biochemical and molecular changes that ultimately result in changes to RNP activity or stability have yet to be described.

As our understanding of the above pathways grows, an important area for future study is how the enzymes involved are regulated. How are RNP modification and ATP-dependent remodeling enzymes recruited to their RNP targets in the first place? How are the biochemical functions of these enzymes activated or repressed in response to cellular needs? How common is the coupling between RNP modifiers and remodelers as exemplified by the bacterial degradosome and nuclear TRAMP complexes? Will the creation of RNP tags through RNP modification by writer enzymes for recognition by reader proteins emerge as a general theme in RNA regulation as it has in chromatin?

The processes and factors described above likely represent only a small fraction of the activities that influence the activity and stability of RNPs. In principle, RNP modification and remodeling could impact RNPs of any flavor, whether these bear mRNAs, sRNAs, or functional noncoding RNAs. In addition, recently identified mRNP-associated enzymes with potential RNA and protein modifying or remodeling activities represent tantalizing avenues for further research [89,90]. Such studies are predicted to reveal exciting new layers in the regulation of RNP stability and function.

Highlights.

  • RNAs function in, and are regulated as, ribonucleoprotein complexes (RNPs)

  • Chemical modification and ATP-dependent remodeling of RNPs regulate RNA fate

  • RNP modifications can serve as tags for the binding of regulatory proteins

Acknowledgments

The authors wish to thank Marcos Arribas-Layton for thought-provoking discussions on RNP remodeling. Research on mRNP remodeling in the JL-A laboratory is supported by grant R01 GM099717 from the National Institutes of Health. SRL was supported by a fellowship from the Helen Hay Whitney foundation.

Glossary terms

AUBPs

AU-rich mRNA element-binding proteins

NMD

Nonsense-mediated decay, a cytoplasmic RNA degradation pathway that targets certain mRNAs, such as those bearing a premature stop codon or a long 3′ untranslated region, for destruction

RNA helicases/RNA-dependent ATPases

RNA-binding enzymes that couple ATP binding and hydrolysis to the disruption of protein-RNA or RNA-RNA interactions in RNPs

RNAi

RNA interference

RNPs

ribonucleoprotein complexes composed of RNA and associated proteins

rNTRs

ribonucleotidyltranferases, RNA tailing enzymes capable of appending one or more nucleotides to the 3′ end of target RNAs

TRAMP

A protein complex involved in nuclear RNA quality control consisting of Trf4 (a A-specific rNTR), Mtr4 (an RNA helicase), and either Air1 or 2 (RNA binding proteins)

Footnotes

Disclosure Statement

The authors have no conflicts of interest to declare.

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