Nonsense-mediated mRNA decay (NMD) in animal embryogenesis: to die or not to die, that is the question

Hwang, Jungwook; Maquat, Lynne E.

doi:10.1016/j.gde.2011.03.008

Cited by 119 publications

(122 citation statements)

References 81 publications

(104 reference statements)

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“…The NMD pathway is required for organismal development as well as in several tissue-and condition-specific contexts, suggesting a regulatory role extending beyond a general surveillance mechanism (Hwang and Maquat 2011). Several recent studies have highlighted the specific contribution of AS-NMD to the regulation of gene expression.…”

Section: Discussionmentioning

confidence: 99%

Rbfox2 controls autoregulation in RNA-binding protein networks

Boutz²,

et al. 2014

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The tight regulation of splicing networks is critical for organismal development. To maintain robust splicing patterns, many splicing factors autoregulate their expression through alternative splicing-coupled nonsensemediated decay (AS-NMD). However, as negative autoregulation results in a self-limiting window of splicing factor expression, it is unknown how variations in steady-state protein levels can arise in different physiological contexts. Here, we demonstrate that Rbfox2 cross-regulates AS-NMD events within RNA-binding proteins to alter their expression. Using individual nucleotide-resolution cross-linking immunoprecipitation coupled to highthroughput sequencing (iCLIP) and mRNA sequencing, we identified >200 AS-NMD splicing events that are bound by Rbfox2 in mouse embryonic stem cells. These ''silent'' events are characterized by minimal apparent splicing changes but appreciable changes in gene expression upon Rbfox2 knockdown due to degradation of the NMDinducing isoform. Nearly 70 of these AS-NMD events fall within genes encoding RNA-binding proteins, many of which are autoregulated. As with the coding splicing events that we found to be regulated by Rbfox2, silent splicing events are evolutionarily conserved and frequently contain the Rbfox2 consensus UGCAUG. Our findings uncover an unexpectedly broad and multilayer regulatory network controlled by Rbfox2 and offer an explanation for how autoregulatory splicing networks are tuned.

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Section: Discussionmentioning

confidence: 99%

Rbfox2 controls autoregulation in RNA-binding protein networks

Boutz²,

et al. 2014

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“…However, the NMD-specific function of PABP has proven to be difficult to study separately from its other important functions in mRNA translation and stabilization. Furthermore, human NMD is characterized by different signals for NMD activation and multiple pathways for degradation, contrary to many other organisms that use one main NMD mechanism (Hwang and Maquat 2011).…”

Section: Discussionmentioning

confidence: 99%

“…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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“…[14][15][16] The malfunction of NMD factors results in serious consequences for the development of various organisms. 17 Genome-wide analysis using DNA microarrays suggested that NMD regulates 3-20% of transcripts in yeast, 18 nematode, 19 fruitfly, 20 plants 21 and mammals. [22][23][24][25][26][27] Genome-wide RNA half-life analysis also identified the transcripts dysregulated in response UpF1 eliminates aberrant mRNAs harboring premature termination codons, and regulates the steady-state levels of normal physiological mRNAs.…”

Section: Introductionmentioning

confidence: 99%