DHX34 and NBAS form part of an autoregulatory NMD circuit that regulates endogenous RNA targets in human cells, zebrafish and Caenorhabditis elegans

Longman, Dáša; Hug, Nele; Keith, Marianne; Anastasaki, Corina; Patton, E. Elizabeth; Grimes, Graeme R.; Cáceres, Javier F.

doi:10.1093/nar/gkt585

Cited by 81 publications

(112 citation statements)

References 67 publications

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“…These studies point to a feedback loop where components of the NMD machinery are also regulated by the pathway (34). The regulation of NMD factors by the pathway has also been observed in zebrafish and C. elegans, further supporting the notion of a conserved NMD feedback loop (74).…”

Section: Atypically Long 3= Utrs Can Target Mrnas To the Nmd Pathwaysupporting

confidence: 55%

Regulation of Natural mRNAs by the Nonsense-Mediated mRNA Decay Pathway

Peccarelli

Kebaara

2014

Eukaryot Cell

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The nonsense-mediated mRNA decay (NMD) pathway is a specialized mRNA degradation pathway that degrades select mRNAs. This pathway is conserved in all eukaryotes examined so far, and it triggers the degradation of mRNAs that prematurely terminate translation. Originally identified as a pathway that degrades mRNAs with premature termination codons as a result of errors during transcription, splicing, or damage to the mRNA, NMD is now also recognized as a pathway that degrades some natural mRNAs. The degradation of natural mRNAs by NMD has been identified in multiple eukaryotes, including Saccharomyces cerevisiae, Drosophila melanogaster, Arabidopsis thaliana, and humans. S. cerevisiae is used extensively as a model to study natural mRNA regulation by NMD. Inactivation of the NMD pathway in S. cerevisiae affects approximately 10% of the transcriptome. Similar percentages of natural mRNAs in the D. melanogaster and human transcriptomes are also sensitive to the pathway, indicating that NMD is important for the regulation of gene expression in multiple organisms. NMD can either directly or indirectly regulate the decay rate of natural mRNAs. Direct NMD targets possess NMD-inducing features. This minireview focuses on the regulation of natural mRNAs by the NMD pathway, as well as the features demonstrated to target these mRNAs for decay by the pathway in S. cerevisiae. We also compare NMD-targeting features identified in S. cerevisiae with known NMDtargeting features in other eukaryotic organisms.

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Section: Atypically Long 3= Utrs Can Target Mrnas To the Nmd Pathwaysupporting

confidence: 55%

Regulation of Natural mRNAs by the Nonsense-Mediated mRNA Decay Pathway

Peccarelli

Kebaara

2014

Eukaryot Cell

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Section: Discussionmentioning

confidence: 80%

“…Therefore the situation appears analogous to what occurs in higher eukaryotes in which such introns can trigger EJC-mediated NMD. NMD control of N. crassa upf1 mRNA stability might be exerted through recognition of its uORF stop codons as PTCs, as is the case for N. crassa arg-2 ( Figure 5A) and S. cerevisiae CPA1 (Gaba et al 2005), or through its relatively long 39-UTR ( Figure 1A) as is reported for metazoan UPF1 (Huang et al 2011;Longman et al 2013), but this remains to be determined.To our knowledge, this work represents the first demonstration of circuits that enables regulation at the level of mRNA stability for eRF1, eIF4a3, and Y14. Autoregulation of mRNA levels for NMD factors has been reported for metazoans (Huang et al 2011;Yepiskoposyan et al 2011; reviewed in Karam et al 2013;Longman et al 2013) and autoregulation of NMD and EJC factors has been reported for plants (Nyiko et al 2013).…”

mentioning

confidence: 80%

“…Autoregulation of mRNA levels for NMD factors has been reported for metazoans (Huang et al 2011;Yepiskoposyan et al 2011; reviewed in Karam et al 2013;Longman et al 2013) and autoregulation of NMD and EJC factors has been reported for plants (Nyiko et al 2013). Measurements of mRNA stability in mammalian cells established that UPF2 and SMG1 (a kinase that phosphorylates UPF1) are stabilized in UPF1-depleted cells and that UPF1 is stabilized in SMG1 depleted cells; furthermore the UPF1 39-UTR conferred UPF1-dependent mRNA stability to a reporter (Huang et al 2011).…”

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confidence: 98%

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Control of mRNA Stability in Fungi by NMD, EJC and CBC Factors Through 3′UTR Introns

Zhang¹,

Sachs

2015

Genetics

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In higher eukaryotes the accelerated degradation of mRNAs harboring premature termination codons is controlled by nonsense-mediated mRNA decay (NMD), exon junction complex (EJC), and nuclear cap-binding complex (CBC) factors, but the mechanistic basis for this quality-control system and the specific roles of the individual factors remain unclear. Using Neurospora crassa as a model system, we analyzed the mechanisms by which NMD is induced by spliced 39-UTR introns or upstream open reading frames and observed that the former requires NMD, EJC, and CBC factors whereas the latter requires only the NMD factors. The transcripts for EJC components eIF4A3 and Y14, and translation termination factor eRF1, contain spliced 39-UTR introns and each was stabilized in NMD, EJC, and CBC mutants. Reporter mRNAs containing spliced 39-UTR introns, but not matched intronless controls, were stabilized in these mutants and were enriched in mRNPs immunopurified from wild-type cells with antibody directed against human Y14, demonstrating a direct role for spliced 39-UTR introns in triggering EJC-mediated NMD. These results demonstrate conclusively that NMD, EJC, and CBC factors have essential roles in controlling mRNA stability and that, based on differential requirements for these factors, there are branched mechanisms for NMD. They demonstrate for the first time autoregulatory control of expression at the level of mRNA stability through the EJC/CBC branch of NMD for EJC core components, eIF4A3 and Y14, and for eRF1, which recognizes termination codons. Finally, these results show that EJC-mediated NMD occurs in fungi and thus is an evolutionarily conserved quality-control mechanism.KEYWORDS nonsense-mediated mRNA decay (NMD); RNA stability; exon junction complex (EJC); cap-binding complex (CBC); spliced 39-UTR intron; post-transcriptional control; ribosome; translation; Neurospora crassa T HE nonsense-mediated mRNA decay (NMD) pathway targets mRNA for degradation through the recognition of translated termination codons determined to be premature (Nicholson et al. 2009;Kervestin and Jacobson 2012;Popp and Maquat 2013). The NMD pathway can degrade mRNAs that contain upstream open reading frames (uORFs) or long 39-UTRs. The termination-related processes that trigger uORFmediated or long 39-UTR-mediated NMD are considered to be similar (Amrani et al. 2004(Amrani et al. , 2006Nicholson et al. 2009) in that termination events occurring far from the context created by the mRNA poly(A) tail can result in mRNA degradation (the "faux-UTR" model). In higher eukaryotes, NMD can also act on mRNAs that contain an intron downstream of a termination codon, such as aberrantly spliced transcripts or 39-UTR introncontaining transcripts (Sauliere et al. 2010;Bicknell et al. 2012). When a spliced intron is positioned at least 50-55 nt downstream of a termination codon, the exon junction complex (EJC) positioned near the exon-exon junction is not displaced by translating ribosomes and its continued association with mRNA targets the mRNA for deg...

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“…Figure 4 depicts the molecular architecture of the core NMD factors and summarizes their functions and interaction sites, both of which are discussed in detail below. A number of additional NMD factors have been identified in different organisms, including SMG8, SMG9, PNRC2, DHX34, NBAS, RUVBL1, RUVBL2, MOV10, GNL2 and SEC13 for the human system [107][108][109][110][111][112][113].…”

Section: Nmd Factors and Their Role In Substrate Recognition And Degrmentioning

confidence: 99%

Mechanism, factors, and physiological role of nonsense-mediated mRNA decay

Fatscher

Boehm

Gehring

2015

Cell. Mol. Life Sci.

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Nonsense-mediated mRNA decay (NMD) is a translation-dependent, multistep process that degrades irregular or faulty messenger RNAs (mRNAs). NMD mainly targets mRNAs with a truncated open reading frame (ORF) due to premature termination codons (PTCs). In addition, NMD also regulates the expression of different types of endogenous mRNA substrates. A multitude of factors are involved in the tight regulation of the NMD mechanism. In this review, we focus on the molecular mechanism of mammalian NMD. Based on the published data, we discuss the involvement of translation termination in NMD initiation. Furthermore, we provide a detailed overview of the core NMD machinery, as well as several peripheral NMD factors, and discuss their function. Finally, we present an overview of diseases associated with NMD factor mutations and summarize the current state of treatment for genetic disorders caused by nonsense mutations.

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DHX34 and NBAS form part of an autoregulatory NMD circuit that regulates endogenous RNA targets in human cells, zebrafish and Caenorhabditis elegans

Cited by 81 publications

References 67 publications

Regulation of Natural mRNAs by the Nonsense-Mediated mRNA Decay Pathway

Regulation of Natural mRNAs by the Nonsense-Mediated mRNA Decay Pathway

Control of mRNA Stability in Fungi by NMD, EJC and CBC Factors Through 3′UTR Introns

Mechanism, factors, and physiological role of nonsense-mediated mRNA decay

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