Regulation of hepatocellular carcinoma growth by UPF1 variants not through nonsense-mediated mRNA decay
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ABSTRACT:
PROVIDER: PRJNA770285 | ENA |
REPOSITORIES: ENA
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Project description:Multiple studies showed that overexpression of UPF1 reduced the growth of HCC. However, it remains unanswered how UPF1 expression retarded HCC proliferation. Thus, this study employed UPF1 variants to evaluate the UPF1 function in HCC growth inhibition. Transcriptome analysis indicated that the level of DUSP1, dual specificity phosphatase 1, was upregulated by UPF1 variants by posttranscriptional regulation. The increase of DUPS1 by UPF1 overexpression repressed the downstream signaling, inhibiting cell growth.
2021-10-13 | GSE185655 | GEO
Project description:We have HA-tagged two nonsense-mediated decay proteins, UPF1 and UPF2, in the malaria parasite Plasmodium falciparum. We then performed co-immunoprecipitation experiments to determine the protein-protein interactions of these nonsense-mediated decay components.
2021-04-16 | PXD023910 | Pride
Project description:RNA quality control pathways serve to get rid of faulty RNAs and therefore must be able to discriminate these RNAs from those that are normal. Here we present evidence that the ATPase cycle of SF1 Helicase Upf1 is required for mRNA discrimination during Nonsense-Mediated Decay (NMD). Mutations affecting the Upf1 ATPase cycle disrupt the mRNA selectivity of Upf1, leading to indiscriminate accumulation of NMD complexes on both NMD target and non-target mRNAs. In addition, two modulators of NMD - translation and termination codon-proximal poly(A) binding protein - depend on Upf1 ATPase to limit Upf1-non-target association. Preferential ATPase-dependent dissociation of Upf1 from non-target mRNAs in vitro suggests that selective release of Upf1 contributes to the ATPase-dependence of Upf1 target discrimination. Given the prevalence of helicases in RNA regulation, ATP hydrolysis may be an underappreciated, yet widely employed, activity in target RNA discrimination. CLIP and RIP-seq against Wild Type and Mutant Upf1 in HEK293-T cell lines
2015-07-06 | E-GEOD-69584 | biostudies-arrayexpress
Project description:RNA quality control pathways serve to get rid of faulty RNAs and therefore must be able to discriminate these RNAs from those that are normal. Here we present evidence that the ATPase cycle of SF1 Helicase Upf1 is required for mRNA discrimination during Nonsense-Mediated Decay (NMD). Mutations affecting the Upf1 ATPase cycle disrupt the mRNA selectivity of Upf1, leading to indiscriminate accumulation of NMD complexes on both NMD target and non-target mRNAs. In addition, two modulators of NMD - translation and termination codon-proximal poly(A) binding protein - depend on Upf1 ATPase to limit Upf1-non-target association. Preferential ATPase-dependent dissociation of Upf1 from non-target mRNAs in vitro suggests that selective release of Upf1 contributes to the ATPase-dependence of Upf1 target discrimination. Given the prevalence of helicases in RNA regulation, ATP hydrolysis may be an underappreciated, yet widely employed, activity in target RNA discrimination. CLIP and RIP-seq against Wild Type and Mutant Upf1 in HEK293-T cell lines
2015-07-06 | E-GEOD-69585 | biostudies-arrayexpress
Project description:RNA quality control pathways serve to get rid of faulty RNAs and therefore must be able to discriminate these RNAs from those that are normal. Here we present evidence that the ATPase cycle of SF1 Helicase Upf1 is required for mRNA discrimination during Nonsense-Mediated Decay (NMD). Mutations affecting the Upf1 ATPase cycle disrupt the mRNA selectivity of Upf1, leading to indiscriminate accumulation of NMD complexes on both NMD target and non-target mRNAs. In addition, two modulators of NMD - translation and termination codon-proximal poly(A) binding protein - depend on Upf1 ATPase to limit Upf1-non-target association. Preferential ATPase-dependent dissociation of Upf1 from non-target mRNAs in vitro suggests that selective release of Upf1 contributes to the ATPase-dependence of Upf1 target discrimination. Given the prevalence of helicases in RNA regulation, ATP hydrolysis may be an underappreciated, yet widely employed, activity in target RNA discrimination.
2015-07-06 | GSE69585 | GEO
Project description:RNA quality control pathways serve to get rid of faulty RNAs and therefore must be able to discriminate these RNAs from those that are normal. Here we present evidence that the ATPase cycle of SF1 Helicase Upf1 is required for mRNA discrimination during Nonsense-Mediated Decay (NMD). Mutations affecting the Upf1 ATPase cycle disrupt the mRNA selectivity of Upf1, leading to indiscriminate accumulation of NMD complexes on both NMD target and non-target mRNAs. In addition, two modulators of NMD - translation and termination codon-proximal poly(A) binding protein - depend on Upf1 ATPase to limit Upf1-non-target association. Preferential ATPase-dependent dissociation of Upf1 from non-target mRNAs in vitro suggests that selective release of Upf1 contributes to the ATPase-dependence of Upf1 target discrimination. Given the prevalence of helicases in RNA regulation, ATP hydrolysis may be an underappreciated, yet widely employed, activity in target RNA discrimination.
2015-07-06 | GSE69584 | GEO
Project description:Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a core nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein levels, or NMD efficiency. We subsequently discovered that ~40% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that UPF1 is not a common functional driver of PASC and motivate further attempts to identify unique genetic features defining these malignancies.
2020-12-19 | GSE163517 | GEO
Project description:Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance pathway that is an important modulator of disease pathology and is required for embryonic development. Despite significant research effort, the rules that govern NMD remain incompletely understood. Here we used a combined¬ approach, integrating RNA-Seq, ribosome footprinting, and CLIP-Seq analysis of the essential NMD factor Upf1, to provide a more complete picture of the role of NMD in modulating gene expression in murine embryonic stem cells (mESCs). We show that presence of an exon-exon junction ?50 nucleotides (nt) downstream of a termination codon (dEJ) contributes to NMD independently of 3' UTR length, but has stronger effects in genes with shorter 3' UTRs. We also map translated upstream open reading frames (uORFs) in mESCs and show that they are associated with NMD regulation, especially of genes encoding transcription factors, and we find that lowly translated mRNAs can escape NMD. Finally, we identify over 200 direct binding targets of Upf1 and describe a pathway of Upf1-dependent gene regulation reliant on Upf1 binding to the 3' UTR and independent of presence of a dEJ. Together, these analyses characterize known and discover novel determinants of NMD and establish a broader role in mESC gene regulation for Upf1. mRNA-Seq analysis of wildtype (2 samples), translationally inhibited (by cycloheximide treatment, 2 samples), control-depleted (2 samples), and Upf1-depleted (4 samples) mouse embryonic stem cells (mESCs); CLIP-Seq analysis of Upf1 (5 samples, and 5 samples of IgG control CLIP-Seq); Ribosome footprint profiling of wildtype (1 sample), control-depleted (1 sample), and Upf1-depleted (1 sample) mESCs
2013-06-12 | E-GEOD-41785 | biostudies-arrayexpress
Project description:Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance pathway that is an important modulator of disease pathology and is required for embryonic development. Despite significant research effort, the rules that govern NMD remain incompletely understood. Here we used a combined¬ approach, integrating RNA-Seq, ribosome footprinting, and CLIP-Seq analysis of the essential NMD factor Upf1, to provide a more complete picture of the role of NMD in modulating gene expression in murine embryonic stem cells (mESCs). We show that presence of an exon-exon junction ≥50 nucleotides (nt) downstream of a termination codon (dEJ) contributes to NMD independently of 3' UTR length, but has stronger effects in genes with shorter 3' UTRs. We also map translated upstream open reading frames (uORFs) in mESCs and show that they are associated with NMD regulation, especially of genes encoding transcription factors, and we find that lowly translated mRNAs can escape NMD. Finally, we identify over 200 direct binding targets of Upf1 and describe a pathway of Upf1-dependent gene regulation reliant on Upf1 binding to the 3' UTR and independent of presence of a dEJ. Together, these analyses characterize known and discover novel determinants of NMD and establish a broader role in mESC gene regulation for Upf1.
2013-06-12 | GSE41785 | GEO
Project description:Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that recognizes aberrant transcripts arising from mutations and transcriptional mistakes. Moreover, differential transcript processing such as alternative precursor mRNA splicing (AS) can generate NMD substrates, however, the extent of coupled AS and NMD remained unclear. To investigate NMD targeting of AS variants, we performed transcriptome-wide splicing studies using Arabidopsis thaliana single and double mutants in the NMD factor homologues UPF1 and UPF3, as well as samples treated with the translation inhibitor cycloheximide (CHX). Our analyses revealed that at least 17.5% of all multi-exon, protein-coding genes produce splicing variants of all major types that are targeted by NMD, with a significant fraction originating from the splicing of cryptic introns. Furthermore, accumulation of many intron-retained mRNAs in the mutants, but not in response to CHX suggests the action of distinct routes of NMD with variable impact of translation. Importantly, 92.3% of the NMD-responsive mRNAs exhibit classical NMD-eliciting features, supporting their authenticity as direct targets. NMD-dependent AS variants are linked to diverse biological functions, including the poison exon-mediated regulation of signaling and posttranslational protein modification components. In addition to mRNAs, numerous non-coding RNAs as well as newly identified transcripts derived from intergenic regions were shown to be NMD responsive. In summary, our comprehensive analysis of AS-coupled NMD provides strong evidence for a major function of this pathway in shaping the transcriptome, having fundamental implications in gene regulation and quality control of transcript processing steps in higher eukaryotes. Comparison of gene expression and alternative splicing patterns in control and nonsense-mediated decay (NMD)-impaired Arabidopsis seedlings
2013-10-01 | E-GEOD-41432 | biostudies-arrayexpress