XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1041442 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26856902_1.fastq.gz | Fastqsanger.gz | |||
| SRR26856902_2.fastq.gz | Fastqsanger.gz | |||
| SRR26856903_1.fastq.gz | Fastqsanger.gz | |||
| SRR26856903_2.fastq.gz | Fastqsanger.gz | |||
| SRR26856904_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 84 |
Similar Datasets
Project description:Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene (ISG) expression. XRN1 deletion causes PKR pathway activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-b stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR, and how this interaction creates a vulnerability in cancer cells with an activated interferon cell state.
2024-04-17 | GSE248036 | GEO
Project description:Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene (ISG) expression. XRN1 deletion causes PKR activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and nominate XRN1 as a potential therapeutic target in cancer cells with an activated interferon cell state.
| S-EPMC10418227 | biostudies-literature
Project description:Despite the remarkable achievement of immune checkpoint blockade (ICB) therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. We hypothesize that targeting RNA decay machinery may lead to accumulation of aberrantRNA, triggering interferon (IFN) signaling and sensitizing tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1 as a potential target. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy, while silencing of XRN1 alone did not affect tumor growth in immune deficient mice. Mechanistically, XRN1 depletion activated interferon signaling and viral defense pathway; both pathways play determinant roles in regulating immune evasion. We identified aberrant-RNA sensing signaling proteins (RIG-I/MAVS and PKR) in mediating the expression of IFN genes, as depletion of each of them blunted the elevation of anti-viral/IFN signaling in Xrn1 silenced cells. Analysis of pan-cancer CRISPR screening data indicated that IFN signaling triggered by Xrn1 silencing is a common phenomenon, suggesting that the effect of Xrn1 silencing may be extend to multiple types of cancers.
2023-02-21 | GSE199744 | GEO
Project description:Despite the remarkable achievement of immune checkpoint blockade (ICB) therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. We hypothesize that targeting RNA decay machinery may lead to accumulation of aberrantRNA, triggering interferon (IFN) signaling and sensitizing tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1 as a potential target. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy, while silencing of XRN1 alone did not affect tumor growth in immune deficient mice. Mechanistically, XRN1 depletion activated interferon signaling and viral defense pathway; both pathways play determinant roles in regulating immune evasion. In murine tumors engrafted on immmunocompetent mice, XRN1 depletion significantly enhanced immune cell infiltration in solid tumors especially in combinatory with PD-1 blockade. We identified aberrant-RNA sensing signaling proteins (RIG-I/MAVS and PKR) in mediating the expression of IFN genes, as depletion of each of them blunted the elevation of anti-viral/IFN signaling in Xrn1 silenced cells. Analysis of pan-cancer CRISPR screening data indicated that IFN signaling triggered by Xrn1 silencing is a common phenomenon, suggesting that the effect of Xrn1 silencing may be extend to multiple types of cancers.
2023-02-21 | GSE202587 | GEO
Project description:PKR is an interferon induced serine/threonine protein kinase, that is activated by double stranded RNA. PKR plays an important role in the antiviral defense by interferon. In addition to its role in translation, PKR participates in several signaling pathways to transcription. The goal of this experiment is to study the role of PKR in regulating gene expression in our NIH 3T3 inducible cell line, which could overexpress PKR wt protein after the removal of tetracycline (Donze O, Dostie J, Sonenberg N. (1999) Virology 256: 322-9).
2004-01-30 | E-MEXP-50 | biostudies-arrayexpress
Project description:To determine the effects of inactivation of both the nosense-mediated mRNA decay pathway and the general 5' to 3' decay pathway on yeast mRNA decay, we compared the expression profiles of the wild-type, xrn1, xrn1 upf1, xrn1 nmd2, and xrn1 upf3 strains.
2011-11-08 | E-MEXP-27 | biostudies-arrayexpress
Project description:Protein kinase R (PKR) is a key antiviral kinase activated by binding double-stranded RNA (dsRNA) produced during viral replication. Upon activation, PKR phosphorylates eIF2α, leading to the inhibition of translation and viral replication. However, many viruses have evolved mechanisms to counteract PKR activity. In Cardioviruses, the Leader protein (L), a short peptide cleaved from the N-terminus of the viral polyprotein, not only inhibits PKR but also blocks interferon production and disrupts nucleocytoplasmic trafficking (NCT). L disrupts NCT by recruiting host RSK kinases to the nuclear pore complex (NPC), where RSK phosphorylates FG-nucleoporins, thereby impairing NCT. L mutations that affect NCT disruption also impact its ability to inhibit PKR, suggesting a mechanistic link. Recombinant TMEV and EMCV viruses designed to disrupt NCT through different mechanisms exhibited some extent of PKR inhibition, supporting the link between NCT disruption and PKR inhibition. Immunostaining and live-cell imaging revealed that L-induced NCT disruption redistributes a fraction of PKR to the nucleoli, where PKR remains inactive. This suggests that nucleolar sequestration contributes to PKR inhibition. Additionally, L-mediated NCT disruption leads to the release of nuclear RNA-binding proteins (nRBPs) into the cytosol, which may bind or modify viral dsRNA, further preventing PKR activation. Collectively, these results highlight nucleocytoplasmic trafficking as a critical regulatory mechanism governing PKR activation. Thus, beyond the specific action of the Cardiovirus L protein, our study reveals a broader principle in which interference with host nucleocytoplasmic transport can significantly impact the subcellular localization and functional regulation of immune effectors, such as PKR
2025-11-17 | PXD066206 | Pride
Project description:To study the role of the exonuclease Xrn1 in translational control, we performed ribosome profiling and RNA-seq in Xrn1-depleted cells. By using an auxin-inducible degron, we were able to study immediate effects of Xrn1 depletion in translational control. Therefore, we could overcome experimental limitations associated to stable deletion mutants.
2019-02-08 | GSE109734 | GEO
Project description:Xrn1 is a cytoplasmic 5’-3’ exoribonuclease responsible for degradation of multiple types of RNA. Data obtained on yeast model described Xrn1 function in degradation of messenger (m)RNA, Rapid transfer (t)RNA Decay (RTD) of hypomodified and unstable tRNA transcripts as well as maturation of 25S ribosomal (r)RNA and small nucleolar (sno)RNAs. Our group discovered previously that deletion of Xrn1 gene results in stabilization of a group of long non-coding RNAs which are often transcribed antisense to protein-coding genes and may regulate their expression on transcriptional level. However much less is known about human (h)Xrn1 function. Data available from human cell lines confirm involvement of hXrn1 in degradation of mRNA, initiator tRNA methionine and some miRNA. The high sequence similarity of Xrn1 between yeast and man suggests that also its function should be well conserved for hXrn1. Therefore, in this experiment using inducible shRNA we want to define hXrn1 targets by analyzing RNAs that are stabilized after Xrn1 silencing with focus on both coding and non-coding transcripts.
2020-01-14 | GSE114605 | GEO
Project description:To study the role of the exonuclease Xrn1 in gene expression dynamics under osmotic stress conditions, we performed RNA-seq in Xrn1-depleted cells. By using an auxin-inducible degron, we were able to study immediate effects of Xrn1 depletion in gene expression dynamics. Therefore, we could overcome experimental limitations associated to stable deletion mutants.
2023-01-28 | GSE144440 | GEO