Degradation of mRNAs that lack a stop codon: a decade of nonstop progress

Klauer, A. Alejandra; Hoof, Ambro van

doi:10.1002/wrna.1124

Cited by 128 publications

(116 citation statements)

References 100 publications

(144 reference statements)

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“…In animals and yeast, such RNAs (termed non-stop RNAs) are less stable than canonical mRNAs . The decay of non-stop RNAs is mediated by ribosome-associated factors that act to recognize stalled ribosomes and recruit the exosome so as to facilitate degradation of the associated RNA (Klauer and van Hoof, 2012). The results presented in this study confirm that mRNA isoforms derived from polyadenylation within protein-coding regions are generally less stable than other isoforms ( Figure 4) and are thus consistent with the presence of a quality control process in plants analogous to the non-stop decay pathway.…”

Section: Mrnas With 39 Ends That Lie Within Protein-coding Regionssupporting

confidence: 79%

Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia

et al. 2017

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Stresses from various environmental challenges continually confront plants, and their responses are important for growth and survival. One molecular response to such challenges involves the alternative polyadenylation of mRNA. In plants, it is unclear how stress affects the production and fate of alternative mRNA isoforms. Using a genome-scale approach, we show that in Arabidopsis thaliana, hypoxia leads to increases in the number of mRNA isoforms with polyadenylated 39 ends that map to 59-untranslated regions (UTRs), introns, and protein-coding regions. RNAs with 39 ends within protein-coding regions and introns were less stable than mRNAs that end at 39-UTR poly(A) sites. Additionally, these RNA isoforms were underrepresented in polysomes isolated from control and hypoxic plants. By contrast, mRNA isoforms with 39 ends that lie within annotated 59-UTRs were overrepresented in polysomes and were as stable as canonical mRNA isoforms. These results indicate that the generation of noncanonical mRNA isoforms is an important feature of the abiotic stress response. The finding that several noncanonical mRNA isoforms are relatively unstable suggests that the production of non-stop and intronic mRNA isoforms may represent a form of negative regulation in plants, providing a conceptual link with mechanisms that generate these isoforms (such as alternative polyadenylation) and RNA surveillance.

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Section: Mrnas With 39 Ends That Lie Within Protein-coding Regionssupporting

confidence: 79%

Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia

et al. 2017

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“…The degradation of these RNA substrates by the exosome requires Ski7 and its partner complex Ski2/3/8. Ski7 is thought to function in bridging the exosome with the ribosome complex in the nonstop decay pathway and bringing the Ski2/3/8 complex to the exosome to promote its RNA degradation activity [26,27]. Our current work isolated Ski7-bound exosomes from yeast cell lysates, showing that Ski7 directly and stably interacts with the cytoplasmic exosome.…”

Section: Discussionmentioning

confidence: 71%

CryoEM structure of yeast cytoplasmic exosome complex

Liu

Niu

et al. 2016

Cell Res

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The eukaryotic multi-subunit RNA exosome complex plays crucial roles in 3′-to-5′ RNA processing and decay. Rrp6 and Ski7 are the major cofactors for the nuclear and cytoplasmic exosomes, respectively. In the cytoplasm, Ski7 helps the exosome to target mRNAs for degradation and turnover via a through-core pathway. However, the interaction between Ski7 and the exosome complex has remained unclear. The transaction of RNA substrates within the exosome is also elusive. In this work, we used single-particle cryo-electron microscopy to solve the structures of the Ski7-exosome complex in RNA-free and RNA-bound forms at resolutions of 4.2 Å and 5.8 Å, respectively. These structures reveal that the N-terminal domain of Ski7 adopts a structural arrangement and interacts with the exosome in a similar fashion to the C-terminal domain of nuclear Rrp6. Further structural analysis of exosomes with RNA substrates harboring 3′ overhangs of different length suggests a switch mechanism of RNA-induced exosome activation in the through-core pathway of RNA processing.

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“…Since the polyadenylation sites for UL11 and UL22 are located close to the stop codon, the predicted outcome of these HFMs is a transcript of normal length lacking a stop codon. In eukaryotic cells, nonstop mRNAs such as these lead to ribosome stalling, poor translation, and non-stop-mediated mRNA decay (117,118). Recently, ribosomal frameshifting has been shown to allow the recovery of a low level of protein product from TK (UL23) transcripts that lack a stop codon due to HFM (119).…”

Section: Resultsmentioning

confidence: 99%

“…Despite the presence of other C homopolymers in UL11, the same C-terminal site is affected in strain R62, albeit with a longer extension of the homopolymer (C 6 to C 10 , resulting in MSDSE* to PHVR). Further work will be needed to determine whether the mutant UL11 transcripts are subject to nonstop mRNA decay or are rescued by ribosomal frameshifting (117)(118)(119). If UL11 is translated in these strains, it will be relevant to explore whether the altered C terminus affects UL11-gE protein interactions.…”

Section: Resultsmentioning

confidence: 99%

“…As with UL11, the close proximity of the polyadenylation site minimizes the effects of the frameshift, changing only the final few residues (WRRE* to LETRIK). The lack of a stop codon creates a potential target for nonstop mRNA decay or ribosomal frameshifting (117)(118)(119). The fusion machinery of gH lies in its extensive N-terminal ectodomain (800 amino acid residues), whereas the observed mutation is present in the short internal tail of 14 amino acid residues (77).…”

Section: Resultsmentioning

confidence: 99%

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Evolution and Diversity in Human Herpes Simplex Virus Genomes

Szpara

Gatherer

Ochoa

et al. 2014

J Virol

199

280

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gHerpes simplex virus 1 (HSV-1) causes a chronic, lifelong infection in >60% of adults. Multiple recent vaccine trials have failed, with viral diversity likely contributing to these failures. To understand HSV-1 diversity better, we comprehensively compared 20 newly sequenced viral genomes from China, Japan, Kenya, and South Korea with six previously sequenced genomes from the United States, Europe, and Japan. In this diverse collection of passaged strains, we found that one-fifth of the newly sequenced members share a gene deletion and one-third exhibit homopolymeric frameshift mutations (HFMs). Individual strains exhibit genotypic and potential phenotypic variation via HFMs, deletions, short sequence repeats, and single-nucleotide polymorphisms, although the protein sequence identity between strains exceeds 90% on average. In the first genome-scale analysis of positive selection in HSV-1, we found signs of selection in specific proteins and residues, including the fusion protein glycoprotein H. We also confirmed previous results suggesting that recombination has occurred with high frequency throughout the HSV-1 genome. Despite this, the HSV-1 strains analyzed clustered by geographic origin during whole-genome distance analysis. These data shed light on likely routes of HSV-1 adaptation to changing environments and will aid in the selection of vaccine antigens that are invariant worldwide. Herpes simplex virus 1 (HSV-1; species Human herpesvirus 1, genus Simplexvirus, subfamily Alphaherpesvirinae, family Herpesviridae, order Herpesvirales) is among the most successful human pathogens in terms of its global distribution, longevity in the host, and mild symptoms among the great majority of those exposed (1-4). HSV-1 is a large, enveloped DNA virus that infects lytically at epithelial surfaces and establishes a lifelong, latent infection in sensory neurons. HSV-1 infection produces a wide range of symptoms, ranging from few or none in many seropositive individuals to periodic lesions on epithelial surfaces in a significant proportion of people and to lethal encephalitis as an extreme manifestation in a few. There is no vaccine at present (5, 6). Studies in animal models have characterized the ways in which genetic variation between viral strains can influence the symptoms of pathology, including lesion severity and rates of reactivation from latency. The most recent phase III vaccine trial for HSV failed to provide protection from infection (7, 8), and one contributing factor to this failure may well be variation among HSV isolates found in the field.Based on early restriction fragment length polymorphism (RFLP) analyses, HSV-1 has been described as more diverse than HSV-2 (9-11). In contrast to both HSV-1 and HSV-2, the related human alphaherpesvirus, varicella-zoster virus (VZV), has relatively low interstrain diversity (12-15). Decades of research comparing RFLP bands, polypeptide size, and PCR-based sequence analysis have revealed that HSV-1 strains vary between individuals, over sequential isolates from the s...

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Degradation of mRNAs that lack a stop codon: a decade of nonstop progress

Cited by 128 publications

References 100 publications

Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia

Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia

CryoEM structure of yeast cytoplasmic exosome complex

Evolution and Diversity in Human Herpes Simplex Virus Genomes

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