Nonsense-mediated mRNA decay in humans at a glance (2024)

As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsem*nt of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more: PMC Disclaimer | PMC Copyright Notice

J Cell Sci. 2016 Feb 1; 129(3): 461–467.

doi:10.1242/jcs.181008

PMCID: PMC4760306

PMID: 26787741

Tatsuaki Kurosaki^1,² and Lynne E. Maquat^1,^2,^*

ABSTRACT

Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that typifies all eukaryotes examined to date. NMD surveys newly synthesized mRNAs and degrades those that harbor a premature termination codon (PTC), thereby preventing the production of truncated proteins that could result in disease in humans. This is evident from dominantly inherited diseases that are due to PTC-containing mRNAs that escape NMD. Although many cellular NMD targets derive from mistakes made during, for example, pre-mRNA splicing and, possibly, transcription initiation, NMD also targets ∼10% of normal physiological mRNAs so as to promote an appropriate cellular response to changing environmental milieus, including those that induce apoptosis, maturation or differentiation. Over the past ∼35 years, a central goal in the NMD field has been to understand how cells discriminate mRNAs that are targeted by NMD from those that are not. In this Cell Science at a Glance and the accompanying poster, we review progress made towards this goal, focusing on human studies and the role of the key NMD factor up-frameshift protein 1 (UPF1).

KEY WORDS: NMD, RNA quality control, mRNA surveillance, Superfamily 1 ATP-dependent RNA helicase, UPF1 protein

Summary: In humans, nonsense-mediated mRNA decay prevents the synthesis of potentially toxic proteins from mutated mRNAs, and also regulates 10% of physiological mRNAs that promote cellular adaptation to changing environments.

Introduction

Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA surveillance mechanism in eukaryotes that helps to maintain the quality of gene expression. NMD accelerates the degradation of aberrant mRNAs harboring a premature termination codon (PTC) and, in this capacity, is estimated to downregulate one-third of disease-causing mRNAs (Frischmeyer and Dietz, 1999; Mort et al., 2008). In humans, PTCs were first reported to reduce mRNA abundance in 1979 (Chang et al., 1979) and, shortly after, to reduce mRNA stability (Maquat et al., 1981) through studies of the β^o-thalassemias. PTCs that trigger NMD were also observed in patients with other diseases, including triose phosphate isomerase (TPI) deficiency (Daar and Maquat, 1988) and Marfan syndrome (Caputi et al., 2002), as well as in naturally occurring transcripts that encode certain selenoproteins, such as glutathione peroxidase 1 (GPx1), providing the first evidence that NMD sustains normal cellular metabolism (Moriarty et al., 1997, 1998).

Nonsense-mediated mRNA decay in humans at a glance (2)

Open in a separate window

It is now widely accepted that NMD functions in at least two distinct cellular processes: (1) to downregulate abnormal transcripts that are generated as a consequence of routine errors in gene expression, and (2) to maintain an appropriate level of gene expression by downregulating physiological mRNAs in response to cellular needs. Transcriptome-wide analyses have revealed that NMD modulates ∼10% of human cell mRNAs that, for example, harbor an upstream open reading frame (uORF) or an intron downstream of the normal termination codon (see, for example, Mendell et al., 2004). NMD also downregulates many alternatively spliced mRNAs that are largely mistakes (Lewis et al., 2003; Pan et al., 2006), but in some cases provide a means for RNA-binding proteins or ribosomal proteins to autoregulate their own levels (Cuccurese et al., 2005; Lareau and Brenner, 2015; Saltzman et al., 2008; Sureau et al., 2001; Tani et al., 2012). It is also likely that NMD might be used to eliminate aberrant transcripts that escape nuclear quality control, as was found to typify transcripts from 47% of expressed genes in Saccharomyces cerevisiae, largely because of non-specific transcription initiation (Malabat et al., 2015). Here, we present progress made towards the goal of understanding how human cells identify NMD targets by reviewing the roles of known NMD factors and features of mRNAs that are NMD targets. Outstanding questions in the field include: what yet-to-be-identified proteins contribute to the NMD mechanism? To what extent do different 5′-cap-binding proteins typify mRNAs undergoing NMD? How can we predict 3′-untranslated region (3′UTR) structures in 3D and define 3′UTR sequences that inhibit NMD so as to develop rules for which mRNA isoforms are NMD targets? And how is the efficiency of NMD regulated during cellular adaptation to changing environmental conditions?

Central NMD factors in human cells

The key human NMD factor, up-frameshift protein 1 (UPF1), was named after its ortholog in S. cerevisiae (Leeds et al., 1991). UPF1 is a ∼123–124 kDa RNA-dependent ATPase and ATP-dependent RNA helicase that hydrolyzes ATP and unwinds RNA in the 5′-to-3′ direction, one purpose of which is presumably to remove proteins that are associated with an NMD target during the process of mRNA decay (Bhattacharya et al., 2000; Chakrabarti et al., 2011; Chamieh et al., 2008; Fiorini et al., 2013; Franks et al., 2010; Shigeoka et al., 2012). At least in vitro, human UPF1 manifests high processivity, but slow unwinding and translocation rates, which are estimated to be no more than one nucleotide per second (Fiorini et al., 2015).

During NMD, UPF1 associates with a translation termination codon through the translation termination complex, which consists of eukaryotic release factor 1 (eRF1, also known as ETF1) and eRF3 (for which there are two isoforms, eRF3a and eRF3b, also known as GSPT1 and GSPT2) (Ivanov et al., 2008; Kashima et al., 2006; Singh et al., 2008), together with the NMD factors suppressor with morphogenic effect on genitalia 1 (SMG1), which is a phosphatidylinositol 3-kinase-related protein kinase, SMG8 and SMG9 (Yamash*ta et al., 2009) (see poster). In humans, two UPF3 paralogs, UPF3 and UPF3X (also called UPF3A and UPF3B, respectively), differently modulate NMD activity (Chan et al., 2009; Kunz et al., 2006; Lykke-Andersen et al., 2000; Serin et al., 2001) in ways that, like UPF1 and another NMD factor, UPF2, have been shown to be crucial for, for example, normal neuronal maturation and development (Colak et al., 2013; Jolly et al., 2013; Laumonnier et al., 2010; Lou et al., 2014; Nguyen et al., 2012, 2013; Tarpey et al., 2007). UPF3 or UPF3X are generally associated with exon junction complexes (EJCs; see below) that are deposited in the nucleus upstream of newly spliced exon–exon junctions, whereas UPF2 is generally associated with EJCs after newly synthesized mRNAs are exported to the cytoplasm (Kim et al., 2001; Lejeune et al., 2002; Lykke-Andersen et al., 2001). NMD is triggered upon the translation-dependent and highly regulated association of UPF1 with an EJC when translation terminates sufficiently upstream of an EJC so that the terminating ribosome does not physically displace the EJC (see below). UPF2 bound by UPF3 or UPF3X interacts directly with the cysteine- and histidine-rich domain of UPF1, so as to open and activate the UPF1 helicase domain, facilitating mRNA unwinding and protein remodeling, activities that appear to be crucial for mRNA decay (Chamieh et al., 2008; Chakrabarti et al., 2011); Franks et al., 2010; Lykke-Andersen et al., 2000; Mendell et al., 2000; Serin et al., 2001; Kurosaki et al., 2014).

Activation of NMD by EJCs

The idea that pre-mRNA splicing deposits a ‘mark’ on newly synthesized mRNA in the nucleoplasm and that this mark persists until at least the first round of translation was derived from data indicating that PTCs situated more than ∼50–55 nucleotides upstream of an exon–exon junction generally trigger NMD (Nagy and Maquat, 1998). This mark was renamed the EJC, which is deposited ∼20–24 nucleotides upstream of ∼80% of exon–exon junctions (Le Hir et al., 2000a,b, 2001; Saulière et al., 2012; Singh et al., 2012). EJCs consist of four core components: eukaryotic translation initiation factor 4A3 (eIF4A3), cancer susceptibility candidate 3 (CASC3), RNA-binding motif protein 8A (RBM8A or Y14), and either mago-nashi hom*olog (MAGOH) or MAGOHB (see poster). EJCs upstream of and within mRNA coding regions are removed by ribosomes during translation in the cytoplasm (Dostie and Dreyfuss, 2002; Gehring et al., 2009; Sato and Maquat, 2009). However, because PTCs shorten the length of the coding region, any downstream EJCs that normally reside within the coding region would fail to be removed from what becomes the 3′UTR.

After UPF1, together with SMG1, SMG8 and SMG9, forms a complex with eRF1 and eRF3 at a termination codon, a single 3′UTR EJC that is deposited at an exon–exon junction residing more than ∼50–55 nucleotides downstream of the termination codon (see poster) is sufficient to interact with the UPF1 complex, through EJC-bound UPF2 and UPF3 or UPF3X, and trigger NMD (Gehring et al., 2003; Hwang et al., 2010; Kim et al., 2001; Shibuya et al., 2004; Yamash*ta et al., 2009). mRNA decay requires SMG1-mediated UPF1 phosphorylation, which is tightly regulated by a conformational change in SMG1 that is mediated by SMG8 and SMG9 (Arias-Palomo et al., 2011; Deniaud et al., 2015; Melero et al., 2014; Yamash*ta et al., 2009) (see poster). SMG1 recognizes and phosphorylates serine and threonine residues that are situated adjacent to a glutamine residue (S/TQ motifs), which are enriched within the C-terminal end of human UPF1 (Kashima et al., 2006; Okada-Katsuhata et al., 2012; Yamash*ta et al., 2001). The 3′UTR EJC-promoted NMD pathway controls various cellular processes, given that it is triggered by a number of events, such as the introduction of a PTC due to a translational frameshift because of alternative splicing, the introduction of a 3′UTR EJC because of alternative splicing and/or alternative 3′-end formation, translation termination at an uORF or translation termination at some UGA selenocysteine codons (Mendell et al., 2004) (see poster).

There are also several variations of NMD. For example, some cellular NMD targets are less sensitive to a downregulation of UPF2 or UPF3X, suggesting that one of these two factors is sufficient for NMD in some instances (Chan et al., 2007; Gehring et al., 2005; Huang et al., 2011; Ivanov et al., 2008). Consistent with there being alternative or ‘branched’ NMD mechanisms, RBM8A, MAGOH, CASC3 and eIF4A3 have been reported to activate NMD in a UPF2-independent pathway, whereas NMD that involves the RNA-binding protein with serine-rich domain 1 (RNPS1) requires UPF2 (Gehring et al., 2005; Lykke-Andersen et al., 2001). Another alternative mechanism, which has been called ‘failsafe NMD’ or ‘3′UTR EJC-independent NMD’, has the general characteristic of a long 3′UTR (estimated to be ≥420 nucleotides, but exceptions exist) and appears to be less efficient than 3′UTR EJC-promoted NMD (Bühler et al., 2006; Eberle et al., 2008; Matsuda et al., 2007; Singh et al., 2008; Zhang et al., 1998a,b).

3′UTR EJC-independent NMD

The activation of NMD by a long mRNA 3′UTR presumably reflects the physical distance required between a termination codon and the mRNA 3′ poly(A) tail through its association with the cytoplasmic poly(A)-binding protein 1 (PABPC1), which can modulate NMD in the absence of a 3′UTR EJC (see below). However, genome-wide analyses of transcript levels or their half-lives suggest that 3′UTR length, as measured linearly by the number of its constituent nucleotides, does not strongly correlate with NMD activity (Hurt et al., 2013; Tani et al., 2012).

There are several reasons why predicting whether an mRNA is an NMD target cannot be made based on its 3′UTR length alone. For one, tethering PABPC1 or eIF4G, which interacts with PABPC1, to a position that resides between a termination codon and the 3′ poly(A) tail can inhibit NMD (Eberle et al., 2008; Fatscher et al., 2014; Joncourt et al., 2014; Peixeiro et al., 2012; Silva et al., 2008; Singh et al., 2008). Thus, NMD can be inhibited if PABPC1 is brought sufficiently close to the 3D environment of a termination codon, either by direct binding or through eIF4G-mediated recruitment, effectively shortening the 3′UTR length regardless of how many nucleotides constitute the 3′UTR. Another indication that the proximity between PABPC1 and a termination codon can inhibit NMD derives from the finding that most 5′ PTCs only inefficiently trigger 3′UTR EJC-promoted NMD, presumably because mRNAs form a ‘closed-loop’ that brings PABPC1 in proximity to the 5′-end of the mRNA through its eIF4G-mediated interaction with 5′-cap-binding proteins (Lejeune et al., 2004; Peixeiro et al., 2012; Silva et al., 2008) (see poster).

A second indication that mRNA 3′UTR length per se cannot be used to predict NMD targets derives from the discovery of naturally occurring but yet-to-be well characterized 3′UTR-stabilizing elements (Toma et al., 2015). These elements might recruit complexes that inhibit NMD, such as the RNA-binding cytidine deaminase (APOBEC1) and complementing specificity factor (ACF) complex that inhibits the NMD of apolipoprotein B (apoB) mRNA after a CAA codon has been edited to a UAA PTC (Chester et al., 2003). Notably, the 3′UTR RNA stability element in Rous sarcoma virus (Weil and Beemon, 2006; Weil et al., 2009) might represent a good system for characterizing host proteins and salient cis-acting features that a viral RNA has co-opted for defeating NMD in the host cell. The positioning of these stabilizing elements close to, but downstream of, the termination codon appears to be important for their function in inhibiting NMD.

Translation modulates binding of human UPF1 to cellular mRNAs

How does translation intersect with the activation of UPF1? Although the premature termination of translation enhances the binding of steady-state UPF1, which is largely hypo-phosphorylated (i.e. yet to be activated by SMG1-mediated phosphorylation), to the downstream 3′UTR (Kurosaki and Maquat, 2013; Lee et al., 2015), recent biochemical and transcriptome analyses have revealed that steady-state UPF1 associates with regions of cellular RNAs that are physically accessible to its binding, independently of translation. These RNAs include canonically defined NMD targets and also non-NMD targets, including long non-coding RNAs (Gregersen et al., 2014; Hogg and Goff, 2010; Hurt et al., 2013; Kurosaki and Maquat, 2013; Lee et al., 2015; Zünd et al., 2013). This promiscuous UPF1 binding is prevented or removed from 5′UTRs and coding regions by scanning and translationally active ribosomes, respectively, but is possible in 3′UTR regions and has been found to correlate with 3′UTR length (Gregersen et al., 2014; Hogg and Goff, 2010; Kurosaki and Maquat, 2013; Lee et al., 2015; Zünd et al., 2013). Steady-state UPF1 undergoes a transient interaction with any available RNA, from which it is released by its ATP-dependent RNA helicase activity (Kurosaki et al., 2014; Lee et al., 2015), and does not detectably form a complex with UPF2 or UPF3X (Kurosaki et al., 2014) (see poster). Importantly, because steady-state UPF1 binds to cellular RNAs promiscuously, and independently of NMD, cellular NMD targets cannot be predicted based on their co-immunoprecipitation with steady-state UPF1 (Gregersen et al., 2014; Zünd et al., 2013). Instead, cellular NMD targets can be identified based on their binding to phosphorylated UPF1 as discussed below (Kurosaki et al., 2014).

Role of human UPF1 phosphorylation in triggering NMD

The above-mentioned step of SMG1-mediated phosphorylation and thus activation of UPF1 represses any additional translation initiation events on an NMD target, and repression appears to be crucial for mRNA decay (Isken et al., 2008). Phosphorylation of UPF1 also enhances its interaction with SMG6 and/or the SMG5−SMG7 heterodimer (Franks et al., 2010; Kashima et al., 2006; Kurosaki et al., 2014; Ohnishi et al., 2003), although a phosphorylation-independent interaction between UPF1 and SMG6 has also been reported (Chakarabarti et al., 2014; Nicholson et al., 2014) (see poster). SMG5 and SMG6, which possess a PilT-N-terminal (PIN) domain that typifies some ribonucleases, bind to phosphorylated UPF1 and promote its dephosphorylation through the recruitment of protein phosphatase 2A, apparently after mRNA decay initiates (Anders et al., 2003; Boehm et al., 2014; Chiu et al., 2003; Kurosaki et al., 2014; Lee et al., 2015; Ohnishi et al., 2003; Schmidt et al., 2015) (see poster). Additionally, SMG6 is an active endonuclease that transiently associates with and cleaves NMD targets in the vicinity of the PTC, approximately where the interaction between phosphorylated UPF1 and the 3′UTR of mRNA occurs (Eberle et al., 2009; Gatfield and Izaurralde, 2004; Huntzinger et al., 2008; Kurosaki et al., 2014; Lykke-Andersen et al., 2014). In contrast, SMG5 and SMG7 lack any intrinsic nuclease activity and form a stable heterodimer on a NMD target (Jonas et al., 2013; Kurosaki et al., 2014; Loh et al., 2013; Ohnishi et al., 2003). This results in the recruitment of the CCR4–NOT deadenylase complex by SMG7 (Loh et al., 2013), whereas SMG5 recruits the mRNA-decapping protein DCP2 and its binding partner DCP1a (Cho et al., 2009, 2013). Given that mRNA decay intermediates lacking a 5′ cap or 3′ poly(A) tail are intrinsically unstable, the ultimate outcome is the exonucleolytic decay of the NMD target (see poster).

The cellular site of NMD and pioneer round of translation

For the majority of the mRNAs analyzed, NMD is associated with the nucleus, meaning that the observed reduction in mRNA abundance is found in nuclear fractions and is not attributable to their contamination with cytoplasmic content; early explanations posited that NMD degrades newly synthesized mRNAs as they exit the nuclear pore complex because these mRNAs could be co-purified with nuclei and simultaneously translated (Belgrader et al., 1994; Cheng and Maquat, 1993; Humphries et al., 1984; Urlaub et al., 1989). Consistent with this idea, a recent study has shown that NMD of PTC-containing β-globin mRNA occurs within 5–56 s of entering the cytoplasm and within ∼430 nm of the nuclear boundary, and there is no evidence for NMD taking place in the nucleoplasm or after newly synthesized PTC-containing β-globin mRNA is released into the cytoplasm (Trcek et al., 2013). Indeed, the decay of PTC-containing β-globin and TPI mRNAs is biphasic, with NMD occurring first, before the fraction of mRNA that escapes NMD is degraded with a half-life that is the same as that of its PTC-free counterpart (Belgrader et al., 1994; Cheng and Maquat, 1993; Trcek et al., 2013). Consistent with these findings, NMD appears to occur largely during the first or pioneer round of translation, which utilizes mRNAs that have yet to lose both the cap-binding protein (CBP) heterodimer CBP80−CBP20, which is deposited prior to its being replaced by eIF4E (Ishigaki et al., 2001), and the EJCs (Lejeune et al., 2002). Notably, this round can involve more than one ribosome, depending on the length of the coding region and efficiency of translation initiation (Isken et al., 2008). Although it has been shown that a proportion of the human PTC-containing mRNAs encoding β-globin, T-cell receptor β and immunoglobulin µ are targeted for NMD in their eIF4E-bound form (Durand and Lykke-Andersen, 2013; Rufener and Mühlemann, 2013), as is the case in yeast (Gao et al., 2005), it remains to be determined how much the decay of human eIF4E-bound mRNAs contributes to cellular NMD (see poster). Given that translation does not promote the replacement of CBP80−CBP20 by eIF4E on an mRNA (Sato and Maquat, 2009), it is possible that some newly synthesized eIF4E-bound mRNA could be targeted for NMD. However, EJC constituents are not detectable in immunoprecipitations of eIF4E-bound mRNAs (Kashima et al., 2006; Lejeune et al., 2002), raising uncertainty about the extent to which the NMD of eIF4E-bound mRNAs generally contributes to cellular metabolism, although, possibly, circ*mstances exist under which it does (Durand and Lykke-Andersen, 2013).

An exception to nucleus-associated NMD is provided by the selenoprotein-encoding GPx1 mRNA, which is targeted for NMD after it has been released from nuclei into the cytoplasm, but while it remains bound by CBP80−CBP20 (Ishigaki et al., 2001; Moriarty et al., 1998). In fact, CBP80 has been shown to activate NMD through its transient and/or weak interaction with UPF1, which promotes the regulated binding of the SMG1−UPF1 complex to eRF1–eRF3 and, subsequently, to a downstream EJC (Hosoda et al., 2005; Hwang et al., 2010) (see poster). It should be noted, however, that others have failed to detect an interaction between CBP80 and UPF1 (Rufener and Mühlemann, 2013).

Therapeutic approaches for PTC-associated diseases

One-third of inherited human diseases are due to PTCs that are introduced by nonsense mutations, frameshift mutations or splicing errors (Frischmeyer and Dietz, 1999; Linde and Kerem, 2008), and nonsense mutations account for ∼20% of the around 43,000 disease-associated single-base pair substitutions (Mort et al., 2008) and for 5 to 70% of genetic disorders (Lee and Dougherty, 2012). NMD functions to eliminate transcripts that harbor nonsense codons that would otherwise result in the production of truncated proteins that have the potential to increase disease severity. Indeed, PTCs that are unable to trigger NMD because they reside less than 50 nucleotides upstream of the last exon–exon junction or within the last exon cause dominantly inherited forms of, for example, β-thalassemia, spinal muscular atrophy, inherited blindness and neurocristopathic syndromes (Bhuvanagiri et al., 2010; Holbrook et al., 2004) (see poster).

One potential therapeutic treatment of diseases that are due to in-frame nonsense (but not frameshift) mutations is to suppress translation termination at a PTC and, therefore, allow some full-length protein to be produced. This can been achieved with the use of the nonsense-codon suppressors Ataluren, read-through compound (RTC)13, Amlexanox, synthetic aminoglycosides and nonaminoglycosides (Du et al., 2008, 2009; Gonzalez-Hilarion et al., 2012; Nakamura et al., 2012; Shalev and Baasov, 2014; Welch et al., 2007), although their lack of drug-target specificity is a great concern, given the large number of physiological cellular mRNAs that are NMD targets. Among these compounds, Ataluren (Translarna) is farthest along the drug-development pipeline, as it has shown the greatest effectiveness in treating duch*enne muscular dystrophy caused by nonsense mutations, but at doses that do not detectably inhibit NMD, consistent with its mild effects on cellular metabolism (Finkel et al., 2013; Welch et al., 2007). Even though results from the recent phase 3 clinical trial, which employed the 6-minute walk test for the treatment of duch*enne muscular dystrophy caused by nonsense mutations, failed to meet the pre-determined endpoint with statistical significance, the drug might be useful for a sub-group of patients (see, for example, http://www.raredr.com/news/ptc-therapeutics-phase-3-duch*enne-study-fails-to-meet-primary-endpoint). In contrast to Ataluren, cardiac glycosides, which elevate the level of intracellular Ca²⁺, are capable of inhibiting NMD at concentrations that reportedly do not affect cellular viability (Nickless et al., 2014). It might be possible to concomitantly use Ataluren and cardiac glycosides, or possibly a clinically effective nonsense suppressor with either another small reagent that has been reported to inhibit NMD (Bhuvanagiri et al., 2014; Martin et al., 2014; Dang et al., 2009; Feng et al., 2015; Gopalsamy et al., 2012; Usuki et al., 2004) or one or more antisense oligonucleotides that occlude deposition of the one or more EJCs that would normally reside downstream of a particular PTC (Nomakuchi et al., in press). Another approach that might be worthwhile for obtaining full-length protein from disease-associated mRNAs is site-directed pseudouridylation of in-frame PTCs (Karijolich and Yu, 2011); by providing a gene-specific therapeutic strategy, such a strategy would be expected to have only minimal toxic side effects.

Perspectives

NMD is a fundamental cellular mechanism utilized by eukaryotes to downregulate PTC-containing mRNAs that are routinely generated by cells through errors made during gene expression and that also naturally exist or are generated as part of autoregulatory mechanisms to maintain cellular homeostasis. Furthermore, NMD is intimately connected to human health and disease; PTCs that trigger NMD can give rise to disease by precluding the production of full-length protein, and PTCs that escape NMD can generate toxic levels of truncated proteins that can be detrimental. In fact, deficiencies in NMD activity lead to intellectual disabilities and developmental defects.

Although extensive studies on NMD over three decades have revealed details of the molecular mechanisms through which NMD occurs, developing molecular therapies for nonsense mutations that cause various inherited diseases remains challenging. The payoff, however, is that many different diseases with diverse physical symptoms can potentially be affected by modulating the activity of a single pathway, NMD. Revealing the full picture of how NMD operates will provide important insights into the treatment of associated diseases and aid in the development of effective and safe therapeutic strategies.

Acknowledgements

The authors thank Max Popp for reading this article and apologize to those authors whose work could not be cited due to space limitations.

Footnotes

Competing interests

The authors declare no competing or financial interests.

Funding

Work on NMD in the Maquat laboratory is supported by the National Insitutes of Health [grant number R01 GM59614]. T.K. is partially supported by a fellowship from the FRAXA Research Foundation. Deposited in PMC for release after 12 months.

Cell science at a glance

A high-resolution version of the poster is available for downloading at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.181008/-/DC1. Individual poster panels are available as JPEG files at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.181008/-/DC2.

References

Anders K. R., Grimson A. and Anderson P. (2003). SMG-5, required for C. elegans nonsense-mediated mRNA decay, associates with SMG-2 and protein phosphatase 2A. EMBO J.22, 641-650. 10.1093/emboj/cdg056 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Arias-Palomo E., Yamash*ta A., Fernández I. S., Nunez-Ramirez R., Bamba Y., Izumi N., Ohno S. and Llorca O. (2011). The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. Genes Dev.25, 153-164. 10.1101/gad.606911 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Belgrader P., Cheng J., Zhou X., Stephenson L. S. and Maquat L. E. (1994). Mammalian nonsense codons can be cis effectors of nuclear mRNA half-life. Mol. Cell. Biol.14, 8219-8228. 10.1128/MCB.14.12.8219 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Bhattacharya A., Czaplinski K., Trifillis P., He F., Jacobson A. and Peltz S. W. (2000). Characterization of the biochemical properties of the human Upf1 gene product that is involved in nonsense-mediated mRNA decay. RNA6, 1226-1235. 10.1017/S1355838200000546 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Bhuvanagiri M., Schlitter A. M., Hentze M. W. and Kulozik A. E. (2010). NMD: RNA biology meets human genetic medicine. Biochem. J.430, 365-377. 10.1042/BJ20100699 [PubMed] [CrossRef] [Google Scholar]
Bhuvanagiri M., Lewis J., Putzker K., Becker J. P., Leicht S., Krijgsveld J., Batra R., Turnwald B., Jovanovic B., Hauer C. et al. (2014). 5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion. EMBO Mol. Med.6, 1593-1609. 10.15252/emmm.201404461 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Boehm V., Haberman N., Ottens F., Ule J. and Gehring N. H. (2014). 3′ UTR length and messenger ribonucleoprotein composition determine endocleavage efficiencies at termination codons. Cell Rep.9, 555-568. 10.1016/j.celrep.2014.09.012 [PubMed] [CrossRef] [Google Scholar]
Bühler M., Steiner S., Mohn F., Paillusson A. and Mühlemann O. (2006). EJC-independent degradation of nonsense immunoglobulin-mu mRNA depends on 3′ UTR length. Nat. Struct. Mol. Biol.13, 462-464. 10.1038/nsmb1081 [PubMed] [CrossRef] [Google Scholar]
Caputi M., Kendzior R. J. and Beemon K. L. (2002). A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer. Genes Dev.16, 1754-1759. 10.1101/gad.997502 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Chakrabarti S., Jayachandran U., Bonneau F., Fiorini F., Basquin C., Domcke S., Le Hir H. and Conti E. (2011). Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2. Mol. Cell41, 693-703. 10.1016/j.molcel.2011.02.010 [PubMed] [CrossRef] [Google Scholar]
Chakrabarti S., Bonneau F., Schussler S., Eppinger E. and Conti E. (2014). Phospho-dependent and phospho-independent interactions of the helicase UPF1 with the NMD factors SMG5-SMG7 and SMG6. Nucleic Acids Res.42, 9447-9460. 10.1093/nar/gku578 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Chamieh H., Ballut L., Bonneau F. and Le Hir H. (2008). NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity. Nat. Struct. Mol. Biol.15, 85-93. 10.1038/nsmb1330 [PubMed] [CrossRef] [Google Scholar]
Chan W.-K., Huang L., Gudikote J. P., Chang Y.-F., Imam J. S., MacLean J. A. and Wilkinson M. F. (2007). An alternative branch of the nonsense-mediated decay pathway. EMBO J.26, 1820-1830. 10.1038/sj.emboj.7601628 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Chan W.-K., Bhalla A. D., Le Hir H., Nguyen L. S., Huang L., Gécz J. and Wilkinson M. F. (2009). A UPF3-mediated regulatory switch that maintains RNA surveillance. Nat. Struct. Mol. Biol.16, 747-753. 10.1038/nsmb.1612 [PubMed] [CrossRef] [Google Scholar]
Chang J., Temple G., Trecartin R. and Kan Y. (1979). Suppression of the nonsense mutation in hom*ozygous β⁰ thalassaemia. Nature281, 602-603. 10.1038/281602a0 [PubMed] [CrossRef] [Google Scholar]
Cheng J. and Maquat L. E. (1993). Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. Mol. Cell. Biol.13, 1892-1902. 10.1128/MCB.13.3.1892 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Chester A., Somasekaram A., Tzimina M., Jarmuz A., Gisbourne J., O'Keefe R., Scott J. and Navaratnam N. (2003). The apolipoprotein B mRNA editing complex performs a multifunctional cycle and suppresses nonsense-mediated decay. EMBO J.22, 3971-3982. 10.1093/emboj/cdg369 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Chiu S.-Y., Serin G., Ohara O. and Maquat L. E. (2003). Characterization of human Smg5/7a: a protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1. RNA9, 77-87. 10.1261/rna.2137903 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Cho H., Kim K. M. and Kim Y. K. (2009). Human proline-rich nuclear receptor coregulatory protein 2 mediates an interaction between mRNA surveillance machinery and decapping complex. Mol. Cell33, 75-86. 10.1016/j.molcel.2008.11.022 [PubMed] [CrossRef] [Google Scholar]
Cho H., Han S., Choe J., Park S. G., Choi S. S. and Kim Y. K. (2013). SMG5-PNRC2 is functionally dominant compared with SMG5-SMG7 in mammalian nonsense-mediated mRNA decay. Nucleic Acids Res.41, 1319-1328. 10.1093/nar/gks1222 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Colak D., Ji S.-J., Porse B. T. and Jaffrey S. R. (2013). Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay. Cell153, 1252-1265. 10.1016/j.cell.2013.04.056 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Cuccurese M., Russo G., Russo A. and Pietropaolo C. (2005). Alternative splicing and nonsense-mediated mRNA decay regulate mammalian ribosomal gene expression. Nucleic Acids Res.33, 5965-5977. 10.1093/nar/gki905 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Daar I. O. and Maquat L. E. (1988). Premature translation termination mediates triosephosphate isomerase mRNA degradation. Mol. Cell. Biol.8, 802-813. 10.1128/MCB.8.2.802 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Dang Y., Low W.-K., Xu J., Gehring N. H., Dietz H. C., Romo D. and Liu J. O. (2009). Inhibition of Nonsense-mediated mRNA decay by the natural product pateamine A through eukaryotic initiation factor 4AIII. J. Biol. Chem.284, 23613-23621. 10.1074/jbc.M109.009985 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Deniaud A., Karuppasamy M., Bock T., Masiulis S., Huard K., Garzoni F.,Kerschgens K., Hentze M. W., Kulozik A. E., Beck M. (2015). A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation. Nucleic Acids Res.43, 7600-7611. 10.1093/nar/gkv668 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Dostie J. and Dreyfuss G. (2002). Translation is required to remove Y14 from mRNAs in the cytoplasm. Curr. Biol.12, 1060-1067. 10.1016/S0960-9822(02)00902-8 [PubMed] [CrossRef] [Google Scholar]
Du M., Liu X., Welch E. M., Hirawat S., Peltz S. W. and Bedwell D. M. (2008). PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc. Natl. Acad. Sci. USA105, 2064-2069. 10.1073/pnas.0711795105 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Du L., Damoiseaux R., Nahas S., Gao K., Hu H., Pollard J. M., Goldstine J., Jung M. E., Henning S. M., Bertoni C. et al. (2009). Nonaminoglycoside compounds induce readthrough of nonsense mutations. J. Exp. Med.206, 2285-2297. 10.1084/jem.20081940 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Durand S. and Lykke-Andersen J. (2013). Nonsense-mediated mRNA decay occurs during eIF4F-dependent translation in human cells. Nat. Struct. Mol. Biol.20, 702-709. 10.1038/nsmb.2575 [PubMed] [CrossRef] [Google Scholar]
Eberle A. B., Stalder L., Mathys H., Orozco R. Z. and Mühlemann O. (2008). Posttranscriptional gene regulation by spatial rearrangement of the 3′ untranslated region. PLoS Biol.6, e92 10.1371/journal.pbio.0060092 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Eberle A. B., Lykke-Andersen S., Mühlemann O. and Jensen T. H. (2009). SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells. Nat. Struct. Mol. Biol.16, 49-55. 10.1038/nsmb.1530 [PubMed] [CrossRef] [Google Scholar]
Fatscher T., Boehm V., Weiche B. and Gehring N. H. (2014). The interaction of cytoplasmic poly(A)-binding protein with eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay. RNA20, 1579-1592. 10.1261/rna.044933.114 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Feng D., Su R.-C., Zou L., Triggs-Raine B., Huang S. and Xie J. (2015). Increase of a group of PTC+ transcripts by curcumin through inhibition of the NMD pathway. Biochim. Biophys. Acta1849, 1104-1115. 10.1016/j.bbagrm.2015.04.002 [PubMed] [CrossRef] [Google Scholar]
Finkel R. S., Flanigan K. M., Wong B., Bönnemann C., Sampson J., Sweeney H. L., Reha A., Northcutt V. J., Elfring G., Barth J. et al. (2013). Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation duch*enne muscular dystrophy. PLoS ONE8, e81302 10.1371/journal.pone.0081302 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Fiorini F., Boudvillain M. and Le Hir H. (2013). Tight intramolecular regulation of the human Upf1 helicase by its N- and C-terminal domains. Nucleic Acids Res.41, 2404-2415. 10.1093/nar/gks1320 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Fiorini F., Bagchi D., Le Hir H. and Croquette V. (2015). Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities. Nat. Commun.6, 7581 10.1038/ncomms8581 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Franks T. M., Singh G. and Lykke-Andersen J. (2010). Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay. Cell143, 938-950. 10.1016/j.cell.2010.11.043 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Frischmeyer P. A. and Dietz H. C. (1999). Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet.8, 1893-1900. 10.1093/hmg/8.10.1893 [PubMed] [CrossRef] [Google Scholar]
Gao Q., Das B., Sherman F. and Maquat L. E. (2005). Cap-binding protein 1-mediated and eukaryotic translation initiation factor 4E-mediated pioneer rounds of translation in yeast. Proc. Natl. Acad. Sci. USA102, 4258-4263. 10.1073/pnas.0500684102 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Gatfield D. and Izaurralde E. (2004). Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila. Nature429, 575-578. 10.1038/nature02559 [PubMed] [CrossRef] [Google Scholar]
Gehring N. H., Neu-Yilik G., Schell T., Hentze M. W. and Kulozik A. E. (2003). Y14 and hUpf3b form an NMD-activating complex. Mol. Cell11, 939-949. 10.1016/S1097-2765(03)00142-4 [PubMed] [CrossRef] [Google Scholar]
Gehring N. H., Kunz J. B., Neu-Yilik G., Breit S., Viegas M. H., Hentze M. W. and Kulozik A. E. (2005). Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements. Mol. Cell20, 65-75. 10.1016/j.molcel.2005.08.012 [PubMed] [CrossRef] [Google Scholar]
Gehring N. H., Lamprinaki S., Kulozik A. E. and Hentze M. W. (2009). Disassembly of exon junction complexes by PYM. Cell137, 536-548. 10.1016/j.cell.2009.02.042 [PubMed] [CrossRef] [Google Scholar]
Gonzalez-Hilarion S., Beghyn T., Jia J., Debreuck N., Berte G., Mamchaoui K., Mouly V., Gruenert D. C., Déprez B. and Lejeune F. (2012). Rescue of nonsense mutations by amlexanox in human cells. Orphanet J. Rare Dis.7, 58 10.1186/1750-1172-7-58 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Gopalsamy A., Bennett E. M., Shi M., Zhang W.-G., Bard J. and Yu K. (2012). Identification of pyrimidine derivatives as hSMG-1 inhibitors. Bioorg. Med. Chem. Lett.22, 6636-6641. 10.1016/j.bmcl.2012.08.107 [PubMed] [CrossRef] [Google Scholar]
Gregersen L. H., Schueler M., Munschauer M., Mastrobuoni G., Chen W., Kempa S., Dieterich C. and Landthaler M. (2014). MOV10 is a 5′ to 3′ RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3′ UTRs. Mol. Cell54, 573-585. 10.1016/j.molcel.2014.03.017 [PubMed] [CrossRef] [Google Scholar]
Hogg J. R. and Goff S. P. (2010). Upf1 senses 3′UTR length to potentiate mRNA decay. Cell143, 379-389. 10.1016/j.cell.2010.10.005 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Holbrook J. A., Neu-Yilik G., Hentze M. W. and Kulozik A. E. (2004). Nonsense-mediated decay approaches the clinic. Nat. Genet.36, 801-808. 10.1038/ng1403 [PubMed] [CrossRef] [Google Scholar]
Hosoda N., Kim Y. K., Lejeune F. and Maquat L. E. (2005). CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells. Nat. Struct. Mol. Biol.12, 893-901. 10.1038/nsmb995 [PubMed] [CrossRef] [Google Scholar]
Huang L., Lou C.-H., Chan W., Shum E. Y., Shao A., Stone E., Karam R., Song H.-W. and Wilkinson M. F. (2011). RNA homeostasis governed by cell type-specific and branched feedback loops acting on NMD. Mol. Cell43, 950-961. 10.1016/j.molcel.2011.06.031 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Humphries R. K., Ley T. J., Anagnou N. P., Baur A. W. and Nienhuis A. W. (1984). β⁰-Thalassemia gene: a premature termination codon caused β-mRNA deficiency without affecting cytoplasmic β-mRNA stability. Blood64, 23-32. [PubMed] [Google Scholar]
Huntzinger E., Kashima I., Fauser M., Saulière J. and Izaurralde E. (2008). SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA14, 2609-2617. 10.1261/rna.1386208 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Hurt J. A., Robertson A. D. and Burge C. B. (2013). Global analyses of UPF1 binding and function reveal expanded scope of nonsense-mediated mRNA decay. Genome Res.23, 1636-1650. 10.1101/gr.157354.113 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Hwang J., Sato H., Tang Y., Matsuda D. and Maquat L. E. (2010). UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps. Mol. Cell39, 396-409. 10.1016/j.molcel.2010.07.004 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Ishigaki Y., Li X., Serin G. and Maquat L. E. (2001). Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell106, 607-617. 10.1016/S0092-8674(01)00475-5 [PubMed] [CrossRef] [Google Scholar]
Isken O., Kim Y. K., Hosoda N., Mayeur G. L., Hershey J. W. B. and Maquat L. E. (2008). Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay. Cell133, 314-327. 10.1016/j.cell.2008.02.030 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Ivanov P. V., Gehring N. H., Kunz J. B., Hentze M. W. and Kulozik A. E. (2008). Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. EMBO J.27, 736-747. 10.1038/emboj.2008.17 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Jolly L. A., Homan C. C., Jacob R., Barry S. and Gecz J. (2013). The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth. Hum. Mol. Genet.22, 4673-4687. 10.1093/hmg/ddt315 [PubMed] [CrossRef] [Google Scholar]
Jonas S., Weichenrieder O. and Izaurralde E. (2013). An unusual arrangement of two 14-3-3-like domains in the SMG5-SMG7 heterodimer is required for efficient nonsense-mediated mRNA decay. Genes Dev.27, 211-225. 10.1101/gad.206672.112 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Joncourt R., Eberle A. B., Rufener S. C. and Mühlemann O. (2014). Eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay by two genetically separable mechanisms. PLoS ONE9, e104391 10.1371/journal.pone.0104391 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Karijolich J. and Yu Y.-T. (2011). Converting nonsense codons into sense codons by targeted pseudouridylation. Nature474, 395-398. 10.1038/nature10165 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Kashima I., Yamash*ta A., Izumi N., Kataoka N., Morish*ta R., Hoshino S., Ohno M., Dreyfuss G. and Ohno S. (2006). Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev.20, 355-367. 10.1101/gad.1389006 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Kim V. N., Kataoka N. and Dreyfuss G. (2001). Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon-exon junction complex. Science293, 1832-1836. 10.1126/science.1062829 [PubMed] [CrossRef] [Google Scholar]
Kunz J. B., Neu-Yilik G., Hentze M. W., Kulozik A. E. and Gehring N. H. (2006). Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA12, 1015-1022. 10.1261/rna.12506 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Kurosaki T. and Maquat L. E. (2013). Rules that govern UPF1 binding to mRNA 3′ UTRs. Proc. Natl. Acad. Sci. USA110, 3357-3362. 10.1073/pnas.1219908110 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Kurosaki T., Li W., Hoque M., Popp M. W.-L., Ermolenko D. N., Tian B. and Maquat L. E. (2014). A post-translational regulatory switch on UPF1 controls targeted mRNA degradation. Genes Dev.28, 1900-1916. 10.1101/gad.245506.114 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Lareau L. F. and Brenner S. E. (2015). Regulation of splicing factors by alternative splicing and NMD is conserved between kingdoms yet evolutionarily flexible. Mol. Biol. Evol.32, 1072-1079. 10.1093/molbev/msv002 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Laumonnier F., Shoubridge C., Antar C., Nguyen L. S., Van Esch H., Kleefstra T., Briault S., Fryns J. P., Hamel B., Chelly J. et al. (2010). Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism. Mol. Psychiatry15, 767-776. 10.1038/mp.2009.14 [PubMed] [CrossRef] [Google Scholar]
Le Hir H., Izaurralde E., Maquat L. E. and Moore M. J. (2000a). The spliceosome deposits multiple proteins 20-24 nucleotides upstream of mRNA exon-exon junctions. EMBO J.19, 6860-6869. 10.1093/emboj/19.24.6860 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Le Hir H., Moore M. J. and Maquat L. E. (2000b). Pre-mRNA splicing alters mRNP composition: evidence for stable association of proteins at exon-exon junctions. Genes Dev.14, 1098-1108. [PMC free article] [PubMed] [Google Scholar]
Le Hir H., Gatfield D., Izaurralde E. and Moore M. J. (2001). The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J.20, 4987-4997. 10.1093/emboj/20.17.4987 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Lee H.-L. R. and Dougherty J. P. (2012). Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacol. Ther.136, 227-266. 10.1016/j.pharmthera.2012.07.007 [PubMed] [CrossRef] [Google Scholar]
Lee S. R., Pratt G. A., Martinez F. J., Yeo G. W. and Lykke-Andersen J. (2015). Target Discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity. Mol. Cell59, 413-425. 10.1016/j.molcel.2015.06.036 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Leeds P., Peltz S. W., Jacobson A. and Culbertson M. R. (1991). The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev.5, 2303-2314. 10.1101/gad.5.12a.2303 [PubMed] [CrossRef] [Google Scholar]
Lejeune F., Ishigaki Y., Li X. and Maquat L. E. (2002). The exon junction complex is detected on CBP80-bound but not eIF4E-bound mRNA in mammalian cells: dynamics of mRNP remodeling. EMBO J.21, 3536-3545. 10.1093/emboj/cdf345 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Lejeune F., Ranganathan A. C. and Maquat L. E. (2004). eIF4G is required for the pioneer round of translation in mammalian cells. Nat. Struct. Mol. Biol.11, 992-1000. 10.1038/nsmb824 [PubMed] [CrossRef] [Google Scholar]
Lewis B. P., Green R. E. and Brenner S. E. (2003). Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl. Acad. Sci. USA100, 189-192. 10.1073/pnas.0136770100 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Linde L. and Kerem B. (2008). Introducing sense into nonsense in treatments of human genetic diseases. Trends Genet.24, 552-563. 10.1016/j.tig.2008.08.010 [PubMed] [CrossRef] [Google Scholar]
Loh B., Jonas S. and Izaurralde E. (2013). The SMG5-SMG7 heterodimer directly recruits the CCR4-NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2. Genes Dev.27, 2125-2138. 10.1101/gad.226951.113 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Lou C. H., Shao A., Shum E. Y., Espinoza J. L., Huang L., Karam R. and Wilkinson M. F. (2014). Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway. Cell Rep.6, 748-764. 10.1016/j.celrep.2014.01.028 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Lykke-Andersen J., Shu M.-D. and Steitz J. A. (2000). Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell103, 1121-1131. 10.1016/S0092-8674(00)00214-2 [PubMed] [CrossRef] [Google Scholar]
Lykke-Andersen J., Shu M.-D. and Steitz J. A. (2001). Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1. Science293, 1836-1839. 10.1126/science.1062786 [PubMed] [CrossRef] [Google Scholar]
Lykke-Andersen S., Chen Y., Ardal B. R., Lilje B., Waage J., Sandelin A. and Jensen T. H. (2014). Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes. Genes Dev.28, 2498-2517. 10.1101/gad.246538.114 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Malabat C., Feuerbach F., Ma L., Saveanu C. and Jacquier A. (2015). Quality control of transcription start site selection by nonsense-mediated-mRNA decay. eLife4, e06722 10.7554/eLife.06722 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Maquat L. E., Kinniburgh A. J. and Ross J. (1981). Unstable β-globin mRNA in mRNA-deficient β⁰-thalassemia. Cell27, 543-553. 10.1016/0092-8674(81)90396-2 [PubMed] [CrossRef] [Google Scholar]
Martin L., Grigoryan A., Wang D., Wang J., Breda L., Rivella S., Cardozo T. and Gardner L. B. (2014). Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense p53 mutations. Cancer Res.74, 3104-3113. 10.1158/0008-5472.CAN-13-2235 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Matsuda D., Hosoda N., Kim Y. K. and Maquat L. E. (2007). Failsafe nonsense-mediated mRNA decay does not detectably target eIF4E-bound mRNA. Nat. Struct. Mol. Biol.14, 974-979. 10.1038/nsmb1297 [PubMed] [CrossRef] [Google Scholar]
Melero R., Uchiyama A., Castaño R., Kataoka N., Kurosawa H., Ohno S., Yamash*ta A. and Llorca O. (2014). Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD. Structure22, 1105-1119. 10.1016/j.str.2014.05.015 [PubMed] [CrossRef] [Google Scholar]
Mendell J. T., Medghalchi S. M., Lake R. G., Noensie E. N. and Dietz H. C. (2000). Novel Upf2p orthologues suggest a functional link between translation initiation and nonsense surveillance complexes. Mol. Cell. Biol.20, 8944-8957. 10.1128/MCB.20.23.8944-8957.2000 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Mendell J. T., Sharifi N. A., Meyers J. L., Martinez-Murillo F. and Dietz H. C. (2004). Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat. Genet.36, 1073-1078. 10.1038/ng1429 [PubMed] [CrossRef] [Google Scholar]
Moriarty P. M., Reddy C. C. and Maquat L. E. (1997). The presence of an intron within the rat gene for selenium-dependent glutathione peroxidase 1 is not required to protect nuclear RNA from UGA-mediated decay. RNA3, 1369-1373. [PMC free article] [PubMed] [Google Scholar]
Moriarty P. M., Reddy C. C. and Maquat L. E. (1998). Selenium deficiency reduces the abundance of mRNA for Se-dependent glutathione peroxidase 1 by a UGA-dependent mechanism likely to be nonsense codon-mediated decay of cytoplasmic mRNA. Mol. Cell. Biol.18, 2932-2939. 10.1128/MCB.18.5.2932 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Mort M., Ivanov D., Cooper D. N. and Chuzhanova N. A. (2008). A meta-analysis of nonsense mutations causing human genetic disease. Hum. Mutat.29, 1037-1047. 10.1002/humu.20763 [PubMed] [CrossRef] [Google Scholar]
Nagy E. and Maquat L. E. (1998). A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem. Sci.23, 198-199. 10.1016/S0968-0004(98)01208-0 [PubMed] [CrossRef] [Google Scholar]
Nakamura K., Du L., Tunuguntla R., Fike F., Cavalieri S., Morio T., Mizutani S., Brusco A. and Gatti R. A. (2012). Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia. Hum. Mutat.33, 198-208. 10.1002/humu.21632 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Nguyen L. S., Jolly L., Shoubridge C., Chan W. K., Huang L., Laumonnier F., Raynaud M., Hackett A., Field M., Rodriguez J. et al. (2012). Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol. Psychiatry17, 1103-1115. 10.1038/mp.2011.163 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Nguyen L. S., Kim H.-G., Rosenfeld J. A., Shen Y., Gusella J. F., Lacassie Y., Layman L. C., Shaffer L. G. and Gécz J. (2013). Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders. Hum. Mol. Genet.22, 1816-1825. 10.1093/hmg/ddt035 [PubMed] [CrossRef] [Google Scholar]
Nicholson P., Josi C., Kurosawa H., Yamash*ta A. and Mühlemann O. (2014). A novel phosphorylation-independent interaction between SMG6 and UPF1 is essential for human NMD. Nucleic Acids Res.42, 9217-9235. 10.1093/nar/gku645 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Nickless A., Jackson E., Marasa J., Nugent P., Mercer R. W., Piwnica-Worms D. and You Z. (2014). Intracellular calcium regulates nonsense-mediated mRNA decay. Nat. Med.20, 961-966. 10.1093/nar/gku645 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Nomakuchi T. T., Rigo F., Aznarez I. and Krainer A. R. (2015). Antisense oligonucleotide -directed inhibition of nonsense-mediated mRNA decay. Nat. Biotechnol.3, in press [EPub] 10.1038/nbt.3427 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Ohnishi T., Yamash*ta A., Kashima I., Schell T., Anders K. R., Grimson A., Hachiya T., Hentze M. W., Anderson P. and Ohno S. (2003). Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7. Mol. Cell12, 1187-1200. 10.1016/S1097-2765(03)00443-X [PubMed] [CrossRef] [Google Scholar]
Okada-Katsuhata Y., Yamash*ta A., Kutsuzawa K., Izumi N., Hirahara F. and Ohno S. (2012). N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD. Nucleic Acids Res.40, 1251-1266. 10.1093/nar/gkr791 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Pan Q., Saltzman A. L., Kim Y. K., Misquitta C., Shai O., Maquat L. E., Frey B. J. and Blencowe B. J. (2006). Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression. Genes Dev.20, 153-158. 10.1101/gad.1382806 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Peixeiro I., Inácio Â., Barbosa C., Silva A. L., Liebhaber S. A. and Romão L. (2012). Interaction of PABPC1 with the translation initiation complex is critical to the NMD resistance of AUG-proximal nonsense mutations. Nucleic Acids Res.40, 1160-1173. 10.1093/nar/gkr820 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Rufener S. C. and Mühlemann O. (2013). eIF4E-bound mRNPs are substrates for nonsense-mediated mRNA decay in mammalian cells. Nat. Struct. Mol. Biol.20, 710-717. 10.1038/nsmb.2576 [PubMed] [CrossRef] [Google Scholar]
Saltzman A. L., Kim Y. K., Pan Q., fa*gnani M. M., Maquat L. E. and Blencowe B. J. (2008). Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay. Mol. Cell. Biol.28, 4320-4330. 10.1128/MCB.00361-08 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Sato H. and Maquat L. E. (2009). Remodeling of the pioneer translation initiation complex involves translation and the karyopherin importin beta. Genes Dev.23, 2537-2550. 10.1101/gad.1817109 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Saulière J., Murigneux V., Wang Z., Marquenet E., Barbosa I., Le Tonquèze O., Audic Y., Paillard L., Crollius H. C. and Le Hir H. (2012). CLIP-seq of eIF4AIII reveals transcriptome-wide mapping of the human exon junction complex. Nat. Struct. Mol. Biol.19, 1124-1131. 10.1038/nsmb.2420 [PubMed] [CrossRef] [Google Scholar]
Schmidt S. A., Foley P. L., Jeong D.-H., Rymarquis L. A., Doyle F., Tenenbaum S. A., Belasco J. G. and Green P. J. (2015). Identification of SMG6 cleavage sites and a preferred RNA cleavage motif by global analysis of endogenous NMD targets in human cells. Nucleic Acids Res.43, 309-323. 10.1093/nar/gku1258 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Serin G., Gersappe A., Black J. D., Aronoff R. and Maquat L. E. (2001). Identification and characterization of human orthologues to Saccharomyces cerevisiae Upf2 protein and Upf3 protein (Caenorhabditis elegans SMG-4). Mol. Cell. Biol.21, 209-223. 10.1128/MCB.21.1.209-223.2001 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Shalev M. and Baasov T. (2014). When proteins start to make sense: fine-tuning of aminoglycosides for PTC suppression therapy. MedChemComm.5, 1092-1105. 10.1039/C4MD00081A [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Shibuya T., Tange T. Ø., Sonenberg N. and Moore M. J. (2004). eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay. Nat. Struct. Mol. Biol.11, 346-351. 10.1038/nsmb750 [PubMed] [CrossRef] [Google Scholar]
Shigeoka T., Kato S., Kawaichi M. and Ishida Y. (2012). Evidence that the Upf1-related molecular motor scans the 3′-UTR to ensure mRNA integrity. Nucleic Acids Res.40, 6887-6897. 10.1093/nar/gks344 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Silva A. L., Ribeiro P., Inácio Â., Ina N. and Romão S. A. (2008). Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay. RNA14, 563-576. 10.1261/rna.815108 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Singh G., Rebbapragada I. and Lykke-Andersen J. (2008). A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. PLoS Biol.6, e111 10.1371/journal.pbio.0060111 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Singh G., Kucukural A., Cenik C., Leszyk J. D., Shaffer S. A., Weng Z. and Moore M. J. (2012). The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell151, 750-764. 10.1016/j.cell.2012.10.007 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Sureau A., Gattoni R., Dooghe Y., Stévenin J. and Soret J. (2001). SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs. EMBO J.20, 1785-1796. 10.1093/emboj/20.7.1785 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Tani H., Imamachi N., Salam K. A., Mizutani R., Ijiri K., Irie T., Yada T., Suzuki Y. and Akimitsu N. (2012). Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability. RNA Biol.9, 1370-1379. 10.4161/rna.22360 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Tarpey P. S., Raymond F. L., Nguyen L. S., Rodriguez J., Hackett A., Vandeleur L., Smith R., Shoubridge C., Edkins S., Stevens C. et al. (2007). Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat. Genet.39, 1127-1133. 10.1038/ng2100 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Toma K. G., Rebbapragada I., Durand S. and Lykke-Andersen J. (2015). Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay. RNA21, 887-897. 10.1261/rna.048637.114 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Trcek T., Sato H., Singer R. H. and Maquat L. E. (2013). Temporal and spatial characterization of nonsense-mediated mRNA decay. Genes Dev.27, 541-551. 10.1101/gad.209635.112 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Urlaub G., Mitchell P. J., Ciudad C. J. and Chasin L. A. (1989). Nonsense mutations in the dihydrofolate reductase gene affect RNA processing. Mol. Cell. Biol.9, 2868-2880. 10.1128/MCB.9.7.2868 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Usuki F., Yamash*ta A., Higuchi I., Ohnishi T., Shiraishi T., Osame M. and Ohno S. (2004). Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich's disease. Ann. Neurol.55, 740-744. 10.1002/ana.20107 [PubMed] [CrossRef] [Google Scholar]
Weil J. E. and Beemon K. L. (2006). A 3′ UTR sequence stabilizes termination codons in the unspliced RNA of Rous sarcoma virus. RNA12, 102-110. 10.1261/rna.2129806 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Weil J. E., Hadjithomas M. and Beemon K. L. (2009). Structural characterization of the Rous sarcoma virus RNA stability element. J. Virol.83, 2119-2129. 10.1128/JVI.02113-08 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Welch E. M., Barton E. R., Zhuo J., Tomizawa Y., Friesen W. J., Trifillis P., Paushkin S., Patel M., Trotta C. R., Hwang S. et al. (2007). PTC124 targets genetic disorders caused by nonsense mutations. Nature447, 87-91. 10.1038/nature05756 [PubMed] [CrossRef] [Google Scholar]
Yamash*ta A., Ohnishi T., Kashima I., Taya Y. and Ohno S. (2001). Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev.15, 2215-2228. 10.1101/gad.913001 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Yamash*ta A., Izumi N., Kashima I., Ohnishi T., Saari B., Katsuhata Y., Muramatsu R., Morita T., Iwamatsu A., Hachiya T. et al. (2009). SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes Dev.23, 1091-1105. 10.1101/gad.1767209 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Zhang J., Sun X., Qian Y. and Maquat L. E. (1998a). Intron function in the nonsense-mediated decay of beta-globin mRNA: indications that pre-mRNA splicing in the nucleus can influence mRNA translation in the cytoplasm. RNA4, 801-815. 10.1017/S1355838298971849 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Zhang J., Sun X., Qian Y., LaDuca J. P. and Maquat L. E. (1998b). At least one intron is required for the nonsense-mediated decay of triosephosphate isomerase mRNA: a possible link between nuclear splicing and cytoplasmic translation. Mol. Cell. Biol.18, 5272-5283. 10.1128/MCB.18.9.5272 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Zünd D., Gruber A. R., Zavolan M. and Mühlemann O. (2013). Translation-dependent displacement of UPF1 from coding sequences causes its enrichment in 3′ UTRs. Nat. Struct. Mol. Biol.20, 936-943. 10.1038/nsmb.2635 [PubMed] [CrossRef] [Google Scholar]

Articles from Journal of Cell Science are provided here courtesy of Company of Biologists