High-resolution profiling of NMD targets in yeast reveals translational fidelity as a basis for substrate selection

Çelik, Alper; Baker, Richard E.; He, Feng; Jacobson, Andrew D.

doi:10.1261/rna.060541.116

Cited by 102 publications

(171 citation statements)

References 80 publications

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“…Consistently, previous studies have shown that UPF genes are involved in more than just the degradation of nonsense messages, but rather target a wide range of mRNAs, including aberrant and normal ones (He et al 2003;Hug et al 2015). In line with this, substrates of Upf proteins have lower codon optimality (Celik et al 2017). Furthermore, we did not observe any change of effect upon knockout of DOM34 and HBS1 (Fig.…”

Section: Several Sequence Features In Thesupporting

confidence: 92%

“…2D). These observations are consistent with a single-gene study demonstrating that translation of upstream ORFs can lead to RNA degradation by NMD (Gaba et al 2005) and that uORFs are enriched in NMD substrates (Celik et al 2017). Altogether, these results show that uAUGs are mRNA destabilizing elements as they almost surely match with cognate premature stop codons, which, whether in frame or not with the gene, and within the UTR or in the coding region, trigger NMD.…”

Section: Upstream Augs Destabilize Mrnas By Triggering Nonsense-mediasupporting

confidence: 89%

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Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Cheng

Maier

Avsec

et al. 2017

RNA

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The stability of mRNA is one of the major determinants of gene expression. Although a wealth of sequence elements regulating mRNA stability has been described, their quantitative contributions to half-life are unknown. Here, we built a quantitative model for Saccharomyces cerevisiae based on functional mRNA sequence features that explains 59% of the half-life variation between genes and predicts half-life at a median relative error of 30%. The model revealed a new destabilizing 3 ′ ′ ′ ′ ′ UTR motif, ATATTC, which we functionally validated. Codon usage proves to be the major determinant of mRNA stability. Nonetheless, single-nucleotide variations have the largest effect when occurring on 3 ′ ′ ′ ′ ′ UTR motifs or upstream AUGs. Analyzing mRNA half-life data of 34 knockout strains showed that the effect of codon usage not only requires functional decapping and deadenylation, but also the 5 ′ ′ ′ ′ ′ -to-3 ′ ′ ′ ′ ′ exonuclease Xrn1, the nonsense-mediated decay genes, but not no-go decay. Altogether, this study quantitatively delineates the contributions of mRNA sequence features on stability in yeast, reveals their functional dependencies on degradation pathways, and allows accurate prediction of half-life from mRNA sequence.

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Section: Several Sequence Features In Thesupporting

confidence: 92%

Section: Upstream Augs Destabilize Mrnas By Triggering Nonsense-mediasupporting

confidence: 89%

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Cheng

Maier

Avsec

et al. 2017

RNA

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“…In lower eukaryotes such as yeast, short (< 200 nt), homogenous 3 0 UTRs make surveillance of 3 0 UTR length an effective strategy to identify PTCs (Jan et al, 2011;Celik et al, 2017). In contrast, mammalian mRNAs are subject to extensive post-transcriptional regulatory mechanisms that combine to determine their stability, translation efficiency, localization, and function.…”

Section: Introductionmentioning

confidence: 99%

hnRNP L‐dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma

Kishor

Hogg

2018

The EMBO Journal

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The human nonsense‐mediated mRNA decay pathway (NMD) performs quality control and regulatory functions within complex post‐transcriptional regulatory networks. In addition to degradation‐promoting factors, efficient and accurate detection of NMD substrates involves proteins that safeguard normal mRNAs. Here, we identify hnRNP L as a factor that protects mRNAs with NMD‐inducing features including long 3′UTRs. Using biochemical and transcriptome‐wide approaches, we provide evidence that the susceptibility of a given transcript to NMD can be modulated by its 3′UTR length and ability to recruit hnRNP L. Integrating these findings with the previously defined role of polypyrimidine tract binding protein 1 in NMD evasion enables enhanced prediction of transcript susceptibility to NMD. Unexpectedly, this system is subverted in B cell lymphomas harboring translocations that produce BCL2:IGH fusion mRNAs. CRISPR/Cas9 deletion of hnRNP L binding sites near the BCL2 stop codon reduces expression of the fusion mRNAs and induces apoptosis. Together, our data indicate that protection by hnRNP L overrides the presence of multiple 3′UTR introns, allowing these aberrant mRNAs to evade NMD and promoting BCL2 overexpression and neoplasia.

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“…Page 6, third paragraph: More recent investigations of yeast NMD have not uncovered evidence for a downstream sequence element that contributes significantly to decay target discrimination 8 , 15 . …”

mentioning

confidence: 99%

“…The author should also mention a recent paper in yeast describing that poor translation efficiency is a major criteria for NMD targeting (Celik et al, 2017 2 ). This major result could potentially explain not yet understood deregulations observed in several other species upon NMD knockdown.…”

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confidence: 99%

The evolution and diversity of the nonsense-mediated mRNA decay pathway

Lloyd¹

2018

F1000Res

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Nonsense-mediated mRNA decay is a eukaryotic pathway that degrades transcripts with premature termination codons (PTCs). In most eukaryotes, thousands of transcripts are degraded by NMD, including many important regulators of development and stress response pathways. Transcripts can be targeted to NMD by the presence of an upstream ORF or by introduction of a PTC through alternative splicing. Many factors involved in the recognition of PTCs and the destruction of NMD targets have been characterized. While some are highly conserved, others have been repeatedly lost in eukaryotic lineages. Here, I outline the factors involved in NMD, our current understanding of their interactions and how they have evolved. I outline a classification system to describe NMD pathways based on the presence/absence of key NMD factors. These types of NMD pathways exist in multiple different lineages, indicating the plasticity of the NMD pathway through recurrent losses of NMD factors during eukaryotic evolution. By classifying the NMD pathways in this way, gaps in our understanding are revealed, even within well studied organisms. Finally, I discuss the likely driving force behind the origins of the NMD pathway before the appearance of the last eukaryotic common ancestor: transposable element expansion and the consequential origin of introns.

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High-resolution profiling of NMD targets in yeast reveals translational fidelity as a basis for substrate selection

Cited by 102 publications

References 80 publications

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast

hnRNP L‐dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma

The evolution and diversity of the nonsense-mediated mRNA decay pathway

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