SMG1, a Nonsense-Mediated mRNA Decay (NMD) regulator, as a therapeutic target in multiple myeloma
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ABSTRACT:
PROVIDER: PRJNA588638 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10425900_1.fastq.gz | Fastqsanger.gz | |||
| SRR10425900_2.fastq.gz | Fastqsanger.gz | |||
| SRR10425901_1.fastq.gz | Fastqsanger.gz | |||
| SRR10425901_2.fastq.gz | Fastqsanger.gz | |||
| SRR10425902_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA stability is meticulously controlled. Here, we sought to determine if an essential post-transcriptional regulatory mechanism plays a role in pain. Nonsense-mediated decay (NMD ) safeguards against translation of mRNAs that harbor premature termination codons and controls the stability of roughly 10% of typical protein-coding mRNAs. It hinges on the activity of the conserved kinase SMG1. Both SMG1 and its target UPF1 are expressed in sensory neurons throughout the dorsal root ganglion (DRG). SMG1 protein is present in DRG neurons and their fibers in the sciatic nerve. Using high-throughput sequencing, we examined changes in mRNA abundance following inhibition of SMG1. Among the characteristics of NMD substrates, the most prominent is structure specifically in the 3′UTR. We confirmed multiple NMD stability targets in sensory neurons including ATF4. AFT4 is preferentially translated during the integrated stress response (ISR). This led us to ask if suspension of NMD induces the ISR. Indeed, blockade of NMD increases eIF2-alpha phosphorylation, a key marker of the integrated stress response. Next, we examined the effects of SMG1 inhibition on pain-associated behaviors. Peripheral inhibition of SMG1 result in mechanical hypersensitivity that persists for several days and priming to a subthreshold dose of PGE2. Priming was fully rescued by a small molecule inhibitor of the ISR. Collectively, our results indicate that suspension of NMD promotes pain through activation of the ISR.
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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
Project description:Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA degradation pathway that targets for degradation faulty mRNAs with premature termination codons as well as many physiological mRNAs encoding full-length proteins. Consequently, NMD functions in both, quality control and post-transcriptional regulation of gene expression, and it has been implicated in the modulation of cancer progression. To investigate the role of NMD in cancer, we knocked out SMG7 in the HT1080 human fibrosarcoma cell line. SMG7 is involved in deadenylation-coupled exonucleolytic mRNA decay, one of the two main degradation pathways in mammalian NMD. Genome-wide proteomic and transcriptomic analyses confirmed that NMD is severely compromised in these SMG7-knockout HT1080 cells. We compared the oncogenic properties between the parental, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. In parallel, we tested the effect of a drug inhibiting the NMD factor SMG1 on the HT1080 cells to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays as well as a mouse xenograft tumor model, we show that the oncogenic properties of the parental HT1080 cells areseverely compromised when NMD is inhibited. Molecular pathway analysis revealed a strong reduction of the matrix metalloprotease 9 (MMP9) gene expression in NMD-suppressed cells. Since MMP9 expression promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation in NMD-suppressed cells explains, at least partially, their reduced tumorigenicity. Collectively, our findings emphasize the therapeutic potential of NMD inhibition for the treatment ofcertain types of cancer.
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Project description:We blocked nonsense-mediated mRNA decay (NMD) pathway and used a custom alternative transcript sensitive Affymetrix microarray to seek alternatively spliced RNAs whose levels increased compared to controls. Keywords: Nonsense Mediated Decay (NMD)
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Project description:Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA degradation pathway that targets for degradation faulty mRNAs with premature termination codons as well as many physiological mRNAs encoding full-length proteins. Consequently, NMD functions in both, quality control and post-transcriptional regulation of gene expression, and it has been implicated in the modulation of cancer progression. To investigate the role of NMD in cancer, we knocked out SMG7 in the HT1080 human fibrosarcoma cell line. SMG7 is involved in deadenylation-coupled exonucleolytic mRNA decay, one of the two main degradation pathways in mammalian NMD. Genome-wide proteomic and transcriptomic analyses confirmed that NMD is severely compromised in these SMG7-knockout HT1080 cells. We compared the oncogenic properties between the parental, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. In parallel, we tested the effect of a drug inhibiting the NMD factor SMG1 on the HT1080 cells to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays as well as a mouse xenograft tumor model, we show that the oncogenic properties of the parental HT1080 cells are severely compromised when NMD is inhibited. Molecular pathway analysis revealed a strong reduction of the matrix metalloprotease 9 (MMP9) gene expression in NMD-suppressed cells. Since MMP9 expression promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation in NMD-suppressed cells explains, at least partially, their reduced tumorigenicity. Collectively, our findings emphasize the therapeutic potential of NMD inhibition for the treatment of certain types of cancer.
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Project description:Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA degradation pathway that targets for degradation faulty mRNAs with premature termination codons as well as many physiological mRNAs encoding full-length proteins. Consequently, NMD functions in both, quality control and post-transcriptional regulation of gene expression, and it has been implicated in the modulation of cancer progression. To investigate the role of NMD in cancer, we knocked out SMG7 in the HT1080 human fibrosarcoma cell line. SMG7 is involved in deadenylation-coupled exonucleolytic mRNA decay, one of the two main degradation pathways in mammalian NMD. Genome-wide proteomic and transcriptomic analyses confirmed that NMD is severely compromised in these SMG7-knockout HT1080 cells. We compared the oncogenic properties between the parental, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. In parallel, we tested the effect of a drug inhibiting the NMD factor SMG1 on the HT1080 cells to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays as well as a mouse xenograft tumor model, we show that the oncogenic properties of the parental HT1080 cells are severely compromised when NMD is inhibited. Molecular pathway analysis revealed a strong reduction of the matrix metalloprotease 9 (MMP9) gene expression in NMD-suppressed cells. Since MMP9 expression promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation in NMD-suppressed cells explains, at least partially, their reduced tumorigenicity. Collectively, our findings emphasize the therapeutic potential of NMD inhibition for the treatment of certain types of cancer.
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Project description:Nonsense-mediated mRNA decay (NMD) controls gene expression by eliminating mRNAs with premature or aberrant translation termination. Degradation of NMD substrates is initiated by the central NMD factor UPF1, which recruits the endonuclease SMG6 and the deadenylation-promoting SMG5/7 complex. Here we map transcriptome-wide sites of SMG6-mediated endocleavage via 3′ fragment capture and degradome sequencing.
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Project description:Nonsense-mediated mRNA decay (NMD) is a conserved mRNA quality control mechanism that identifies and destroys aberrant mRNAs that contain premature termination codons (PTCs). The NMD core comprises seven proteins, from SMG1 to SMG7. Arabidopsis has orthologues of most of these proteins. Studies on yeast, Drosophila, Humans and Arabidopsis reveal that NMD not only functions to target PTC-containing mRNAs but also acts as a global regulator of gene expression. It has also been reported that the NMD pathway branches with some target genes being dependent on specific NMD factors. In order to determine the extent to which different NMD factors co-regulate or independently regulate Arabidopsis genes, transcriptome analysis of smg7b-1 mutants will be carried out and added to existent data of upf1, upf3 and smg5 NMD mutants for comparison. RNA will be extracted from 17 day-old mutant and wild type seedlings grown at 22-24 C under constant light. 4 samples were used in this experiment
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Project description:Nonsense-mediated RNA decay (NMD) is regulated by a variety of cellular stresses. We expose U2OS cells to several stresses and assess RNA expression in the absence of transcription (i.e. stability). These studies identify transcripts that are stabilized by the physiological inhibition of NMD.
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Project description:Nonsense-mediated mRNA decay (NMD) is a conserved mRNA quality control mechanism that identifies and destroys aberrant mRNAs that contain premature termination codons (PTCs). The NMD core comprises seven proteins, from SMG1 to SMG7. Arabidopsis has orthologues of most of these proteins. Studies on yeast, Drosophila, Humans and Arabidopsis reveal that NMD not only functions to target PTC-containing mRNAs but also acts as a global regulator of gene expression. It has also been reported that the NMD pathway branches with some target genes being dependent on specific NMD factors. In order to determine the extent to which different NMD factors co-regulate or independently regulate Arabidopsis genes, transcriptome analysis of smg7b-1 mutants will be carried out and added to existent data of upf1, upf3 and smg5 NMD mutants for comparison. RNA will be extracted from 17 day-old mutant and wild type seedlings grown at 22-24 C under constant light.
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