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The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163517 | GEO | 2020/12/19

REPOSITORIES: GEO

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The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

Project description:The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

| PRJNA686417 | ENA

Single-cell transcriptomics of normal pancreas, intraductal papillary mucinous neoplasm, and pancreatic adenosquamous carcinoma reveals the heterogeneous progression of pancreatic ductal and stromal cells

Project description:Background: Single-cell RNA sequencing (scRNA-seq) contributes to discovering intrinsic heterogeneity of pancreatic adenosquamous carcinoma (PASC), a lethal human malignancy. However, the gene-pattern variations within ductal and stromal cells remain unclear. Methods: We fulfilled scRNA-seq profiling with one healthy donor pancreas, one intraductal papillary mucinous neoplasm (IPMN), and one PASC sample tissue. Multiple bioinformatics analyses were used to investigate the transcriptomics abnormalities from normal stage to tumor formation. Results: We identified ten subpopulations from 10,346 single cells, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and malignant cells. Within our analysis, pancreatic cancer cells were further divided into five clusters; notably, cluster 1 exhibited stem-like phenotypes, such as UBE2C, ASPM, and TOP2A. We also found that S100A2 could be a specific biomarker for tumor cells, relating to PASC progression. LGALS1, NPM1, RACK1, and PERP were upregulated gradually from ductal to malignant cells. Furthermore, the level of copy number variation in ductal and cancer cells was significantly greater than reference cells. The expression of EREG, FCGR2A, FCGR2A, and CCL4L2 increased in myeloid cells along with tumor development, while cancer-associated fibroblast could induce the immunosuppressive tumor microenvironment, promoting pancreatic cancerogenesis. Finally, we demonstrated that EGFR-associated ligand-receptor pairs were activated in stromal to malignant cell communication. Conclusion: This study revealed the variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered cellular interactions following PASC progression. Thus, we provided valuable information to further understand the crucial regulatory mechanisms that embrace the potential therapeutic targets for PASC.

2021-08-03 | GSE165399 | GEO

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.

2014-08-15 | GSE60045 | GEO

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

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

Target discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity (CLIP-Seq)

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

Target discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity (RIP-Seq)

2015-07-06 | E-GEOD-69585 | biostudies-arrayexpress

Target discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity (RIP-Seq)

2015-07-06 | GSE69585 | GEO

Target discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity (CLIP-Seq)

2015-07-06 | GSE69584 | GEO

Arabidopsis thaliana strain:Col-0 Transcriptome or Gene expression

Project description:Arabidopsis thaliana infiltrated with different strains of DC3000 were used to elicit PTI, ETI, or a disease response compared to a mock control. This experiment was carried out in both Col-0 wild-type plants as well as mutants deficient in non-sense mediated decay via disruption of the promoter of upf1 (genotype background upf1-5). To identify differentially expressed and alternatively spliced transcripts elicited by bacterial infection, the NMD-impaired and wild-type host transcriptomes were profiled using RNA-seq. Wild-type and upf1-5 mutant plants were independently challenged with pathogenic (DC3000 COR-) or non-pathogenic P. syringae strains (DC3000 COR- ÎhrpS and DC3000 COR- avrPphB).

2014-10-06 | E-MTAB-4416 | biostudies-arrayexpress

Nonsense-mediated decay of alternative precursor mRNA splicing variants is a major determinant of the eukaryotic steady state transcriptome

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

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