How to get away with nonsense: Mechanisms and consequences of escape from nonsense‐mediated RNA decay

Dyle, Michael C.; Kolakada, Divya; Cortázar, Michael A.; Jagannathan, Sujatha

doi:10.1002/wrna.1560

Cited by 86 publications

(80 citation statements)

References 143 publications

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“…For the others, we see evidence of transcriptional or splicing regulation that could mask the stabilization of the transcript (including transcriptional down-regulation or a shift in splicing toward the productive isoform) and/or aspects that lead to increased uncertainty in the analysis (such as low sequencing coverage, incorrect transcript assembly or CDS definition, and complex alternative splicing patterns). PTC50nt-containing transcripts can escape NMD through secondary structure in the 3' UTR (Eberle et al 2008), alternative poly-adenylation sites (Gilat and Shweiki 2007), or differential deposition of the exon junction complex required for NMD (Alexandrov et al 2012;Saulière et al 2010), as well as other mechanisms (Dyle et al 2019;Hoek et al 2019;Kishor, Fritz, et al 2019;Neu-Yilik et al 2011;Peixeiro et al 2012). We conclude that while 3' UTR length may have an effect for a subset of genes, the 50nt rule is the major mechanism of targeting a transcript for NMD in humans with the caveat that our work is on 'natural' NMD targets and it is unclear what happens in 'unnatural' mutation cases.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of alternative splicing-coupled nonsense-mediated mRNA decay in human cells reveals broad regulatory potential

French

Wei

Lloyd

et al. 2020

Preprint

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AbstractTo explore the regulatory potential of nonsense-mediated mRNA decay (NMD) coupled with alternative splicing, we globally surveyed the transcripts targeted by this pathway via RNA-Seq analysis of HeLa cells in which NMD had been inhibited. We identified putative NMD-targeted transcripts as those with a termination codon more than 50 nucleotides upstream of an exon-exon junction (premature termination as defined by the ‘50nt rule’) and that significantly increased in abundance upon NMD inhibition. We additionally controlled for potential transcriptional up-regulation by requiring the putative NMD targets to increase in abundance substantially more than the isoforms from the same gene that do not contain a premature termination codon. This resulted in a conservative set of 2,793 transcripts derived from 2,116 genes as physiological NMD targets (9.2% of expressed transcripts and >20% of alternatively spliced genes). Our analysis identified previously inferred unproductive isoforms and numerous heretofore-uncharacterized ones. NMD-targeted transcripts were derived from genes involved in many functional categories, and are particularly enriched for RNA splicing genes as well as for those harboring ultraconserved elements. By investigating the features of all transcripts impacted by NMD, we find that the 50nt rule is a strong predictor of NMD degradation while 3’ UTR length on its own generally has only a small effect in this human cell line. Additionally, thousands more transcripts without a premature termination codon in the main coding sequence contain a uORF and display significantly increased abundance upon NMD inhibition indicating potentially widespread regulation through decay coupled with uORF translation. Our results support that alternative splicing coupled with NMD is a prevalent post-transcriptional mechanism in human cells with broad potential for biological regulation.

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Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of alternative splicing-coupled nonsense-mediated mRNA decay in human cells reveals broad regulatory potential

French

Wei

Lloyd

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…All known complete human transcripts of POLG that include ORF-Y also include several splice junctions 3′ of the ORF-Y stop codon, and thus one might expect that translation of ORF-Y would trigger Nonsense Mediated Decay (NMD), a cellular quality control pathway that is generally thought to degrade an mRNA if any Exon Junction Complexes (EJCs) are not removed by the ribosome the first time the mRNA molecule is translated [50]. However, the presence of two distinct overlapping translated ORFs on the same mRNA molecule might allow it to escape NMD.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon

et al. 2020

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“…Missense mutations may result in alterations of secondary structures, affecting protein stability or resulting in the loss of important catalytic domains. Two nonsense and one frameshift mutations were identified-these may result in premature termination of the encoded protein or in nonsense-mediated RNA decay [27]. A synonymous mutation in HNF1A (c.1623G>A, p.Gln541Gln), involving the last nucleotide of exon 8, was predicted to affect RNA splicing, although no RNA was available from the patient to demonstrate this experimentally.…”

Section: Discussionmentioning

confidence: 99%

Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations

Alvelos

Gonçalves

Coutinho

et al. 2020

JCM

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Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

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How to get away with nonsense: Mechanisms and consequences of escape from nonsense‐mediated RNA decay

Cited by 86 publications

References 143 publications

Transcriptome analysis of alternative splicing-coupled nonsense-mediated mRNA decay in human cells reveals broad regulatory potential

Transcriptome analysis of alternative splicing-coupled nonsense-mediated mRNA decay in human cells reveals broad regulatory potential

Evidence for a novel overlapping coding sequence in POLG initiated at a CUG start codon

Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations

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