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Identification of target genes of the NMD factor SMG7b

ABSTRACT: 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.

ORGANISM(S): Arabidopsis thaliana

PROVIDER: GSE32672 | GEO | 2011/10/07

SECONDARY ACCESSION(S): PRJNA147029

REPOSITORIES: GEO

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Identification of target genes of the NMD factor SMG7b

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

2011-10-06 | E-GEOD-32672 | biostudies-arrayexpress

Genes co-regulated by the NMD factors UPF2 and SMG5

Project description:Eukaryotic cells have evolved a mechanism called nonsense mediated mRNA decay (NMD) that detects and degrades aberrant mRNAs that contain premature termination codons (PTCs). NMD has recently acquired broader importance as it has been found to regulate not only aberrant mRNAs but also a great diversity of transcripts, including wild type genes in mammals, Drosophila and yeast. Seven proteins are the core of the NMD complex: SMG1, SMG2 (UPF1), SMG3 (UPF2), SMG4 (UPF3), SMG5, SMG6 and SMG7. Plants have orthologues of most of these proteins. We have identified and characterized a number of alleles of UPF1, UPF3 and SMG5 and made 35S:UPF2 RNAi (upf2i) transgenic plants, all of which share some phenotypic characteristics. Transcriptome analysis of upf1 and upf3 mutants has identified a subset of genes coregulated by UPF1 and UPF3 and, therefore, by NMD (unpublished data). By doing further transcriptome analysis on smg5 mutants and upf2i plants we aim to build a more robust subset of NMD targets in Arabidopsis. RNA will be extracted from 17 day-old mutant, transgenic and wild type seedlings grown at 22-24 C under constant light. 6 samples were used in this experiment

2011-10-06 | E-GEOD-32671 | biostudies-arrayexpress

Genes co-regulated by the NMD factors UPF2 and SMG5

2011-10-07 | GSE32671 | GEO

Nonsense-mediated mRNA decay relies on "two-factor authentication" by SMG5-SMG7

Project description:Eukaryotic gene expression is constantly regulated and controlled by the translation-coupled nonsense-mediated mRNA decay (NMD) pathway. Aberrant translation termination leads to NMD activation and robust clearance of NMD targets via two seemingly independent and redundant mRNA degradation branches. Here, we uncover that the loss of the first SMG5-SMG7-dependent pathway also inactivates the second SMG6-dependent branch, indicating an unexpected functional hierarchy of the final NMD steps. Transcriptome-wide analyses of SMG5-SMG7-depleted cells confirm complete NMD inhibition resulting in massive transcriptomic alterations. The NMD activity conferred by SMG5-SMG7 is determined to varying degrees by their interaction with the central NMD factor UPF1, heterodimer formation and the initiation of deadenylation. Surprisingly, we find that SMG5 functionally substitutes SMG7 and vice versa. Our data support an improved model for NMD execution that features two-factor authentication involving UPF1 phosphorylation and SMG5-SMG7 recruitment to access SMG6 activity.

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A post-translational regulatory switch on UPF1 controls targeted mRNA degradation.

Project description:Nonsense-mediated mRNA decay (NMD) controls the quality of eukaryotic gene expression and also degrades physiologic mRNAs. How NMD targets are identified is incompletely understood. A central NMD factor is the ATP-dependent RNA helicase UPF1. Neither the distance in space between the termination codon and the poly(A) tail nor the binding of steady-state, largely hypophosphorylated UPF1 is a discriminating marker of cellular NMD targets, unlike for PTC-containing reporter mRNAs when compared to their PTC-free counterparts. Here, we map phosphorylated UPF1 (p-UPF1) binding sites using transcriptome-wide footprinting or DNA oligonucleotide-directed mRNA cleavage to report that p-UPF1 provides the first reliable cellular NMD-target marker. p-UPF1 is enriched on NMD target 3'UTRs along with SMG5 and SMG7 but not SMG1 or SMG6. Immunoprecipitations of UPF1 variants deficient in various aspects of the NMD process in parallel with FRET experiments reveal that ATPase/helicase-deficient UPF1 manifests high levels of RNA binding and disregulated hyperphosphorylation, whereas wild-type UPF1 releases from nonspecific RNA interactions in an ATP hydrolysis-dependent mechanism until an NMD target is identified. 3'UTR-associated UPF1 undergoes regulated phosphorylation on NMD targets, providing a binding platform for mRNA degradative activities. p-UPF1 binding to NMD target 3'UTRs is stabilized by SMG5 and SMG7. Our results help to explain why steady-state UPF1 binding is not a marker for cellular NMD substrates and how this binding is transformed to induce mRNA decay.

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Genome-wide analysis of Human Upf1, SMG5, SMG7 and PNRC2 downregulated substrates in HeLa cell

2012-11-01 | GSE34876 | GEO

A post-translational regulatory switch on UPF1 controls targeted mRNA degradation.

2014-08-15 | E-GEOD-60045 | biostudies-arrayexpress

mRNA-Seq from control cells and two clones of Flp-In-T-REx-293 cells modified via CRISPR-Cas9 to knockout SMG7 in combination to knockdowns of control, SMG5, and SMG6

Project description:Mature mRNAs undergo quality control during translation that may lead to RNA degradation by triggering the nonsense mediated decay (NMD) pathway. Aberrant translation due to features such as the presence of a premature stop codon downstream on an exon-exon junction or an intron in the 3'UTR activates NMD. However, many of the features that lead to the activation of this pathway are unclear. UPF1, an RNA helicase, is the core NMD factor. UPF1 forms a multi-protein complex by recruiting a series of factors and other protein complexes in a process that depends on the UPF1 phosphorylation-dephosphorylation cycle. Among the factors recruited by UPF1, SMG5-SMG7 and SMG6 have critical importance in executing NMD. The SMG5-SMG7 heterodimer induces the exonucleolytic degradation of the mRNA, which depends on the recruitment of deadenylation factors. SMG6 has endonucleolytic activity and cleaves the targeted transcript close to the stop codon. The redundancy between the exonucleolytic and endonucleolytic paths to achieve degradation during NMD has been previously reported in the literature. To investigate the apparent redundancy between SMG5-SMG7 and SMG6 activity and to further understand the features that lead to the activation of NMD, we have generated two clones of SMG7 knockout human cells using CRISPR-Cas9. We generated mRNA-Sequencing data for control and both SMG7 KO clones with additional siRNA-mediated knockdown of Luciferase (Luc) as control, SMG5 or SMG6.

2021-05-07 | E-MTAB-9330 | biostudies-arrayexpress

Genome-wide analysis of Human Upf1, SMG5, SMG7 and PNRC2 downregulated substrates in HeLa cell

Project description:Analysis of cellular NMD (Nonsense-mediated mRNA decay) substrates that regulated by Upf1, SMG5, SMG7 and/or PNRC2 in HeLa cell. The hypothesis tested in the present study was that endogenous NMD substrates may co-regulated by Upf1, SMG5, SMG7 and PNRC2. Total RNA obtained from HeLa cells with downregulation of Upf1, SMG5, PNRC2 or SMG7 by siRNA. The up- or down-regulated transcripts were compare to control siRNA treated HeLa cell RNA extract. Significant transcripts were confirmed by replication

2012-11-01 | E-GEOD-34876 | biostudies-arrayexpress

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells

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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