Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

Tani, Hidenori; Imamachi, Naoto; Salam, Kazi Abdus; Mizutani, Ryuta; Ijiri, Kenichi; Irie, Takuma; Yada, Tetsushi; Suzuki, Yutaka; Akimitsu, Nobuyoshi

doi:10.4161/rna.22360

Cited by 153 publications

(202 citation statements)

References 73 publications

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“…1B), which was consistent with findings in previous global studies (Mendell et al 2004;Yepiskoposyan et al 2011). These observations are consistent with the notion that many endogenous mRNAs with long 3 ′ UTRs are not targeted by the NMD pathway despite artificial long 3 ′ UTRs activating NMD (Singh and Lykke-Andersen 2003;Mendell et al 2004;Tani et al 2012;Hurt et al 2013).…”

Section: Many Human Longsupporting

confidence: 80%

“…NMD thereby prevents production of truncated proteins that could interfere with cell function via gain-of-function or dominant-negative effects (Frischmeyer and Dietz 1999;Kuzmiak and Maquat 2006;Schweingruber et al 2013). In addition, evidence suggests that NMD participates in regulation of normal gene expression by targeting a subset of normally processed mRNAs (Mendell et al 2004;Wittmann et al 2006;Viegas et al 2007;Huang et al 2011;Yepiskoposyan et al 2011;Tani et al 2012;Hurt et al 2013). Consistent with this, NMD contributes to important biological processes such as neuronal differentiation, myogenesis, T lymphocyte maturation, and inhibition of viral replication (Weischenfeldt et al 2008;Gong et al 2009;Bruno et al 2011;Frischmeyer-Guerrerio et al 2011;Balistreri et al 2014;Lou et al 2014).…”

Section: Introductionmentioning

confidence: 72%

“…This raises the question of whether this large subset of mRNAs is targeted by NMD, or whether these mRNAs instead have acquired mechanisms to evade the NMD pathway. Global and mRNA-specific analyses have indicated that while a subset of endogenous long 3 ′ UTR mRNAs are indeed substrates of NMD, many are insensitive to depletion of NMD factors (Mendell et al 2004;Wittmann et al 2006;Viegas et al 2007;Singh et al 2008;Hogg and Goff 2010;Yepiskoposyan et al 2011;Tani et al 2012;Hurt et al 2013). However, the mechanism by which a subset of long 3 ′ UTR mRNAs evades the NMD pathway is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

Toma

Rebbapragada

Durand

et al. 2015

RNA

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The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3 ′ UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion. Here, we analyzed a set of human long 3 ′ UTR mRNAs and found that many are indeed resistant to NMD. By dissecting the 3 ′ UTR of one such mRNA, TRAM1 mRNA, we identified a cis element located within the first 200 nt that inhibits NMD when positioned in downstream proximity of the translation termination codon and is sufficient for repressing NMD of a heterologous reporter mRNA. Investigation of other NMD-evading long 3 ′ UTR mRNAs revealed a subset that, similar to TRAM1 mRNA, contains NMDinhibiting cis elements in the first 200 nt. A smaller subset of long 3 ′ UTR mRNAs evades NMD by a different mechanism that appears to be independent of a termination-proximal cis element. Our study suggests that different mechanisms have evolved to ensure NMD evasion of human mRNAs with long 3 ′ UTRs.

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Section: Many Human Longsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

Toma

Rebbapragada

Durand

et al. 2015

RNA

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“…The core NMD factors are present in all eukaryotes and their activity prevents the synthesis of C-terminally truncated proteins with potentially dominant negative effects (Bhuvanagiri et al 2010). Furthermore, NMD directly or indirectly regulates the expression of many physiological mRNAs, although only some of them contain PTCs, for example, as a result of alternative splicing or upstream open reading frames (Yepiskoposyan et al 2011;Tani et al 2012). The function of NMD as a general regulator of gene expression explains why NMD factors are essential for normal animal development (Hwang and Maquat 2011).…”

Section: Introductionmentioning

confidence: 99%

The interaction of cytoplasmic poly(A)-binding protein with eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay

Fatscher

Boehm

Weiche

et al. 2014

RNA

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Nonsense-mediated mRNA decay (NMD) eliminates different classes of mRNA substrates including transcripts with long 3 ′ UTRs. Current models of NMD suggest that the long physical distance between the poly(A) tail and the termination codon reduces the interaction between cytoplasmic poly(A)-binding protein (PABPC1) and the eukaryotic release factor 3a (eRF3a) during translation termination. In the absence of PABPC1 binding, eRF3a recruits the NMD factor UPF1 to the terminating ribosome, triggering mRNA degradation. Here, we have used the MS2 tethering system to investigate the suppression of NMD by PABPC1. We show that tethering of PABPC1 between the termination codon and a long 3 ′ UTR specifically inhibits NMDmediated mRNA degradation. Contrary to the current model, tethered PABPC1 mutants unable to interact with eRF3a still efficiently suppress NMD. We find that the interaction of PABPC1 with eukaryotic initiation factor 4G (eIF4G), which mediates the circularization of mRNAs, is essential for NMD inhibition by tethered PABPC1. Furthermore, recruiting either eRF3a or eIF4G in proximity to an upstream termination codon antagonizes NMD. While tethering of an eRF3a mutant unable to interact with PABPC1 fails to suppress NMD, tethered eIF4G inhibits NMD in a PABPC1-independent manner, indicating a sequential arrangement of NMD antagonizing factors. In conclusion, our results establish a previously unrecognized link between translation termination, mRNA circularization, and NMD suppression, thereby suggesting a revised model for the activation of NMD at termination codons upstream of long 3 ′ UTR.

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“…NMD affects the half-life of many physiological mRNAs and at the same time serves as a quality-control process that recognizes and degrades aberrant mRNAs with truncated open reading frames (for review, see Nicholson et al 2010;Huang and Wilkinson 2012). Up to 10% of all mRNAs in Homo sapiens (Mendell et al 2004;Wittmann et al 2006;Chan et al 2007;Huang et al 2011;Yepiskoposyan et al 2011;Tani et al 2012), Saccharomyces cerevisiae (Lelivelt and Culbertson 1999;He et al 2003;Guan et al 2006;Johansson et al 2007), Caenorhabditis elegans (Ramani et al 2009), and Drosophila melanogaster (Rehwinkel et al 2005) are regulated by NMD. The exact mechanism of substrate selection is not yet fully understood, but several mRNA features have been identified that can trigger NMD.…”

Section: Introductionmentioning

confidence: 99%

Comparison of EJC-enhanced and EJC-independent NMD in human cells reveals two partially redundant degradation pathways

Metze

Herzog

Ruepp

et al. 2013

RNA

116

122

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Nonsense-mediated mRNA decay (NMD) is a eukaryotic post-transcriptional gene regulation mechanism that eliminates mRNAs with the termination codon (TC) located in an unfavorable environment for efficient translation termination. The best-studied NMD-targeted mRNAs contain premature termination codons (PTCs); however, NMD regulates even many physiological mRNAs. An exon-junction complex (EJC) located downstream from a TC acts as an NMD-enhancing signal, but is not generally required for NMD. Here, we compared these "EJC-enhanced" and "EJC-independent" modes of NMD with regard to their requirement for seven known NMD factors in human cells using two well-characterized NMD reporter genes (immunoglobulin μ and β-Globin) with or without an intron downstream from the PTC. We show that both NMD modes depend on UPF1 and SMG1, but detected transcript-specific differences with respect to the requirement for UPF2 and UPF3b, consistent with previously reported UPF2-and UPF3-independent branches of NMD. In addition and contrary to expectation, a higher sensitivity of EJC-independent NMD to reduced UPF2 and UPF3b concentrations was observed. Our data further revealed a redundancy of the endo-and exonucleolytic mRNA degradation pathways in both modes of NMD. Moreover, the relative contributions of both decay pathways differed between the reporters, with PTC-containing immunoglobulin μ transcripts being preferentially subjected to SMG6-mediated endonucleolytic cleavage, whereas β-Globin transcripts were predominantly degraded by the SMG5/SMG7-dependent pathway. Overall, the surprising heterogeneity observed with only two NMD reporter pairs suggests the existence of several mechanistically distinct branches of NMD in human cells.

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Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

Cited by 153 publications

References 73 publications

Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

The interaction of cytoplasmic poly(A)-binding protein with eukaryotic initiation factor 4G suppresses nonsense-mediated mRNA decay

Comparison of EJC-enhanced and EJC-independent NMD in human cells reveals two partially redundant degradation pathways

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