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Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression

ABSTRACT: Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178759 | GEO | 2021/06/29

REPOSITORIES: GEO

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Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression

Project description:Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated.

2021-06-29 | GSE178760 | GEO

Identification of genes regulated by NMD in Arabidopsis

Project description:The nonsense-mediated mRNA decay pathway (NMD) is a quality control mechanism that detects and degrades mRNAs that contain premature translation termination codons (PTCs), thus preventing the production of potentially harmful truncated proteins. NMD has been studied in a number of organisms including humans, yeast, Drosophila, C. elegans and recently Arabidopsis. Recently the NMD process has been shown to have a wider significance in regulating the levels of mRNA expression for a wide range of genes in yeast and Drosophila. Several genes have been found to be required for NMD in a variety of organisms, including UPF1 and UPF3. We have identified and characterised a number of alleles of UPF1 and UPF3 in Arabidopsis that are defective in NMD. By doing a transcriptomic analysis of two NMD mutants, upf1-1 and upf3-1, and wild type plants we aim to identify the subset of genes that are co-regulated by UPF1 and UPF3 and, therefore, by NMD in Arabidopsis. RNA will be extracted from 17-day-old mutant and wild type seedlings grown at 22-24 C under constant light. 7 samples were used in this experiment.

2010-07-09 | E-GEOD-19253 | biostudies-arrayexpress

Truncated protein isoforms generate diversity of protein localization and function in yeast

Project description:Genome-wide measurements of ribosome occupancy on mRNA transcripts have enabled global empirical identification of translated regions. These approaches have revealed an unexpected diversity of protein products, but high-confidence identification of new coding regions that entirely overlap annotated coding regions – including those that encode truncated protein isoforms – has remained challenging. Here, we develop a sensitive and robust algorithm focused on identifying N-terminally truncated proteins genome-wide, identifying 388 truncated protein isoforms, a more than 30-fold increase in the number known in budding yeast. We perform extensive experimental validation of these truncated proteins and define two general classes. The first set lack large portions of the annotated protein sequence and tend to be produced from a truncated transcript. We show two such cases, Yap5truncation and Pus1truncation, to have condition-specific regulation and functions that appear distinct from their respective annotated isoforms. The second set of N-terminally truncated proteins lack only a small region of the annotated protein and are less likely to be regulated by an alternative transcript isoform. Many localize to different subcellular compartments than their annotated counterpart, representing a common strategy for achieving dual localization of otherwise functionally identical proteins.

2024-04-16 | GSE235852 | GEO

RNAi knock down of known nonsense-mediated mRNA decay (NMD) factors in Drosophila cells

Project description:All eukaryotes studied to date have the capacity to detect and degrade mRNAs harboring premature translation termination codons (PTCs) in a process called nonsense-mediated mRNA decay (NMD) (reviewed in Wagner E & Lykke-Andersen J, 2002). This surveillance system allows the cell to prevent the expression of potentially harmful truncated proteins. trans-acting factors required for NMD in Drosophila are the proteins UPF1, UPF2, UPF3, SMG-1, SMG-5 and SMG-6. To identify mRNAs naturally regulated by NMD, we analyzed expression profiles in Drosophila cells RNAi-depleted of known NMD factors using high-density oligonucleotide arrays.

2005-11-01 | E-MEXP-202 | biostudies-arrayexpress

Genome-wide analysis of gene expression in human macrophages in response to infection with influenza A viruses expressing full length or truncated non-structural protein NS1.

Project description:Analysis of gene expression in human macrophages infected with influenza A viruses expressing full length or truncated NS1 protein. The hypothesis tested was that C-terminal truncations of viral NS1 protein attenuate the capability of NS1 to limit activation of host antiviral and immune response genes. Cells were infected with influenza A/WSN/33 viruses expressing wild type NS1 protein (WSN-230), NS1 protein of 220 aa long (WSN-220) and NS1 protein of 202 aa long (WSN-202) on non-infected (Mock)

2014-10-08 | GSE62127 | GEO

Identification of genes regulated by NMD in Arabidopsis

2010-07-09 | GSE19253 | GEO

Genome-wide analysis of gene expression in human macrophages in response to infection with influenza A viruses expressing full length or truncated non-structural protein NS1.

2014-10-08 | E-GEOD-62127 | biostudies-arrayexpress

Truncated titin detection in TTNtv positive DCM human myocardium via patient and allele specific proteomics.

Project description:Premature termination codons in the gene coding for titin are known to cause dilated cardiomyopathy in humans, but it has been unclear whether or not the expected truncated protein is expressed in the human heart, potentially causing DCM. We have shown using per patient allele specific proteomics that truncated titin is expressed in human myocardium in patients with truncations in those exons retained in the spliced titin transcript. Proteomics were run at Taplin Mass Spectrometry Facility, Harvard University. Filename denotes patient number-gel slice-enzyme-fileID See: Q. McAfee et al., Sci. Transl. Med.10.1126/scitranslmed.abd7287 for a complete description of the experiment.

2021-10-27 | MSV000088275 | MassIVE

The myopathic transcription factor DUX4 induces the production of truncated RNA-binding proteins in human muscle cells

Project description:The myopathic transcription factor DUX4 induces the production of truncated RNA-binding proteins in human muscle cells

| PRJNA740298 | ENA

Identification of NMD regulated genes in Nicotiana benthamiana

Project description:Nonsense mediated decay (NMD) is a translation termination coupled quality control system. NMD identifies and degrades aberrant mRNAs containing premature termination codons, thereby preventing the accumulation of detrimental truncated proteins. NMD also controls the expression of several normal mRNAs and non-coding transcripts. RNA-seq assays were conducted to identify the NMD regulated genes in Arabidopsis. However, NMD targets have not been studied in other plants. To identify the conserved NMD targets, we wanted to identify the NMD regulated genes in Nicotiana benthamiana model species. Virus induced gene silencing was used to inactivate UPF1 NMD key factor in N. benthamiana, and then comparative RNA-seq experiment was carried out using UPF1-silenced and control–silenced plants. We found that in N. benthamiana significantly more genes are controlled by NMD than in Arabidopsis and that, surprisingly few conserved NMD targets can be recognized. These results suggest that while the mechanism of NMD is highly conserved, the set of NMD controlled genes can be quickly changed in plants.

2019-07-01 | GSE109130 | GEO

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