Cutting the nonsense: the degradation of PTC-containing mRNAs

Nicholson, Pamela; Mühlemann, Oliver

doi:10.1042/bst0381615

Cited by 102 publications

(87 citation statements)

References 61 publications

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“…Previously, mRNA 3= tagging has been linked to mRNA degradation, being coincident with decapping and the initiation of transcript degradation (60,76). NMD is a well-conserved degradation process, which rapidly eliminates transcripts containing a PTC, thus preventing accumulation of truncated proteins (69). Previously, we have shown that uaZ14, a mutant allele of the urate oxidaseencoding gene, is subject to NMD and that this is dependent on the fidelity of NmdA/Upf2 (63).…”

Section: Resultsmentioning

confidence: 99%

mRNA 3′ Tagging Is Induced by Nonsense-Mediated Decay and Promotes Ribosome Dissociation

Morozov

Jones

Gould

et al. 2012

Molecular and Cellular Biology

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For a range of eukaryote transcripts, the initiation of degradation is coincident with the addition of a short pyrimidine tag at the 3= end. Previously, cytoplasmic mRNA tagging has been observed for human and fungal transcripts. We now report that Arabidopsis thaliana mRNA is subject to 3= tagging with U and C nucleotides, as in Aspergillus nidulans. Mutations that disrupt tagging, including A. nidulans cutA and a newly characterized gene, cutB, retard transcript degradation. Importantly, nonsensemediated decay (NMD), a major checkpoint for transcript fidelity, elicits 3= tagging of transcripts containing a premature termination codon (PTC). Although PTC-induced transcript degradation does not require 3= tagging, subsequent dissociation of mRNA from ribosomes is retarded in tagging mutants. Additionally, tagging of wild-type and NMD-inducing transcripts is greatly reduced in strains lacking Upf1, a conserved NMD factor also required for human histone mRNA tagging. We argue that PTC-induced translational termination differs fundamentally from normal termination in polyadenylated transcripts, as it leads to transcript degradation and prevents rather than facilitates further translation. Furthermore, transcript deadenylation and the consequent dissociation of poly(A) binding protein will result in PTC-like termination events which recruit Upf1, resulting in mRNA 3= tagging, ribosome clearance, and transcript degradation. Modulation of mRNA function within the cytoplasm is critical to the control of gene expression, function being determined primarily by the balance between transcript degradation and translation. Two cotranscriptional modifications, the 5= cap and the 3= poly(A) tail, are essential to both mRNA transcript stability and translation (15,81,83), and integral to this is their association mediated by an array of proteins which modulate function (6, 71).The poly(A) tail, a homopolymeric sequence at the 3= end of transcripts, is added by the canonical poly(A) polymerase in the nucleus. Within the cytoplasm, controlled deadenylation of this tail to ϳA15 in fungi and ϳA15 to A25 in mammals generally precedes decapping and subsequent 5=-3= and/or exosome-dependent 3=-5= decay (17,20,60,64,66). In specific instances, e.g., during embryonic development, deadenylated transcripts remain translationally dormant and can be reactivated by cytoplasmic adenylation (45). Deadenylation is a key control point through which rapid physiological change can occur. However, the mechanisms that underlie this switch between translation and mRNA turnover remain poorly understood.It has recently been discovered that poly(A) tails in Aspergillus nidulans and Schizosaccharomyces pombe are modified in the cytoplasm with the addition of nontemplated U or C/U-rich tags at the point of mRNA decapping, and this increases the rate of transcript degradation (60, 76). Human H2a and H3.3 mRNAs, which are not polyadenylated, also undergo 3= uridylation prior to decapping and degradation (67). This 3= tagging of mRNA is conducted by noncanon...

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Section: Resultsmentioning

confidence: 99%

mRNA 3′ Tagging Is Induced by Nonsense-Mediated Decay and Promotes Ribosome Dissociation

Morozov

Jones

Gould

et al. 2012

Molecular and Cellular Biology

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“…6), which could be explained by nonsense-mediated mRNA decay of the tva r3 transcript with retained intron 1 (reviewed in reference 27). This kind of mRNA decay generally requires that translation terminate sufficiently upstream of an exon-exon junction (29,30), and the premature stop codon in the longer transcript positioned 76 nucleotides upstream of the exon 4-exon 5 junction can be a proper target. Sometimes, in retroviral full-length transcripts, the stop codon can be masked by highly structured stability elements (42).…”

Section: Discussionmentioning

confidence: 99%

Intronic Deletions That Disrupt mRNA Splicing of the tva Receptor Gene Result in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroup A

Reinišová

Plachý

Trejbalová

et al. 2012

J Virol

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The group of closely related avian sarcoma and leukosis viruses (ASLVs) evolved from a common ancestor into multiple subgroups, A to J, with differential host range among galliform species and chicken lines. These subgroups differ in variable parts of their envelope glycoproteins, the major determinants of virus interaction with specific receptor molecules. Three genetic loci, tva, tvb, and tvc, code for single membrane-spanning receptors from diverse protein families that confer susceptibility to the ASLV subgroups. The host range expansion of the ancestral virus might have been driven by gradual evolution of resistance in host cells, and the resistance alleles in all three receptor loci have been identified. Here, we characterized two alleles of the tva receptor gene with similar intronic deletions comprising the deduced branch-point signal within the first intron and leading to inefficient splicing of tva mRNA. As a result, we observed decreased susceptibility to subgroup A ASLV in vitro and in vivo. These alleles were independently found in a close-bred line of domestic chicken and Indian red jungle fowl (Gallus gallus murghi), suggesting that their prevalence might be much wider in outbred chicken breeds. We identified defective splicing to be a mechanism of resistance to ASLV and conclude that such a type of mutation could play an important role in virus-host coevolution. Retroviruses enter the host cell through specific receptors, cell surface proteins with high affinity to viral envelope glycoproteins. The interaction between receptors and viral glycoproteins is very complex and includes the initial attachment of the virion, profound conformational changes in the structure of the viral glycoprotein, exposure of fusion peptides, and, ultimately, the fusion of viral and cellular membranes (5, 47). Despite the strict structural requirements for these interactions, hypervariability of retroviral glycoproteins can change the receptor usage and broaden the host range. Indeed, closely related families of retroviruses have evolved into multiple subgroups that utilize different cellular surface proteins as receptors. For example, the group of avian alpharetroviruses avian sarcoma and leukosis viruses (ASLVs) comprise 10 related subgroups, A to J, which either do not interfere at all with each other or interfere only nonreciprocally in infecting chicken cells. The susceptibility of chicken cells to highly related ASLV subgroups A to E is determined by three genetic loci, tva, tvb, and tvc (5, 41). The Tva protein belongs to the family of low-density lipoprotein receptors (LDLRs) (6, 48) and determines susceptibility to the subgroup A ASLVs. The tumor necrosis factor receptor-related protein Tvb confers susceptibility to subgroup B, D, and E ASLVs by three nonoverlapping binding sites (2,3,8), and the Tvc protein, closely related to the mammalian butyrophilins, serves as receptor for C subgroup ASLV (14).The rapid evolution of novel retrovirus envelopes is compelled by the appearance of host entry restrictions. Gen...

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“…First, AS can regulate transcript levels by the introduction of premature termination codons (PTCs), which commit the transcript isoform to degradation by the nonsense-mediated decay (NMD) pathway. Linked AS-NMD thus regulates the level of functional mRNA transcripts (which encode protein) via targeted degradation of alternative splice forms (McGlincy and Smith, 2008;Nicholson and Mühlemann, 2010), and in Arabidopsis thaliana, at least 13% of genes undergo AS-NMD . The second main consequence of AS is where transcript isoforms give rise to proteins that differ in their sequence and domain arrangement and thus may widely differ in subcellular localization, stability, or function (Syed et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Alternative Splicing at the Intersection of Biological Timing, Development, and Stress Responses

2013

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High-throughput sequencing for transcript profiling in plants has revealed that alternative splicing (AS) affects a much higher proportion of the transcriptome than was previously assumed. AS is involved in most plant processes and is particularly prevalent in plants exposed to environmental stress. The identification of mutations in predicted splicing factors and spliceosomal proteins that affect cell fate, the circadian clock, plant defense, and tolerance/sensitivity to abiotic stress all point to a fundamental role of splicing/AS in plant growth, development, and responses to external cues. Splicing factors affect the AS of multiple downstream target genes, thereby transferring signals to alter gene expression via splicing factor/AS networks. The last two to three years have seen an ever-increasing number of examples of functional AS. At a time when the identification of AS in individual genes and at a global level is exploding, this review aims to bring together such examples to illustrate the extent and importance of AS, which are not always obvious from individual publications. It also aims to ensure that plant scientists are aware that AS is likely to occur in the genes that they study and that dynamic changes in AS and its consequences need to be considered routinely.

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Cutting the nonsense: the degradation of PTC-containing mRNAs

Cited by 102 publications

References 61 publications

mRNA 3′ Tagging Is Induced by Nonsense-Mediated Decay and Promotes Ribosome Dissociation

mRNA 3′ Tagging Is Induced by Nonsense-Mediated Decay and Promotes Ribosome Dissociation

Intronic Deletions That Disrupt mRNA Splicing of the tva Receptor Gene Result in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroup A

Alternative Splicing at the Intersection of Biological Timing, Development, and Stress Responses

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