Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptional changes by RBN-2397 treatment and FRA1 knockdown in NCI-H1975 cells

ABSTRACT: PARP7 inhibitors reduce tumor growth in a cell-autonomous manner and by enhancing immune recognition through restoring nucleic acid (NA)-sensing-dependent innate immune signaling. However, the molecular targets of PARP7-mediated ADP-ribosylation, regulating cell survival and innate immune signaling, remained elusive. Here, we identified PARP7 as a nuclear and cysteine-specific mono-ART that ADP-ribosylates proteins critical for regulating gene expression, such as the AP-1 transcription factor FRA1. Upon PARP7 inhibition the loss of FRA1 ADP-ribosylation increased FRA1 degradation in a PSMC3 and proteasomal-dependent manner. To further investigate how FRA1 promotes cell survival, we investigated transcriptional changes after RBN-2397 treatment and FRA1 knockdown in the PARP7 inhibitor sensitive cell line NCI-H1975 by RNA sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229674 | GEO | 2023/12/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

PARP7-mediated ADP-ribosylation stabilizes FRA1 and restrains IRF3/IRF1-dependent apoptosis and immune signaling and in cancer cells

Project description:PARP7 inhibitors suppress tumor growth in a cell autonomous manner and by activating the immune system through restoring immune signaling. Nevertheless, the targets of PARP7-mediated ADP-ribosylation that regulate innate immune signaling and cancer cell survival remain elusive. Here, we identified PARP7 as a nuclear and cysteine-specific mono-ADP-ribosyltransferase that modified proteins critical for regulating transcription, such as the AP-1 transcription factor FRA1. Loss of FRA1 ADP-ribosylation via PARP7 inhibition by RBN-2397 or mutation of the ADP-ribosylation site C97 increased FRA1 degradation by PSMC3 and the proteasome. We found that the reduction in FRA1 protein levels promoted IRF3 and IRF1-dependent innate immune signaling and CASP8-mediated apoptosis. Furthermore, we demonstrated that high PARP7 expression are critical for inducing apoptosis in FRA1-positive cancer cells using the PARP7 inhibitor. Collectively, our findings highlight the connected roles of PARP7 and FRA1 and emphasize the clinical potential of PARP7 inhibitors for FRA1-driven cancers.

2024-01-26 | PXD041870 | Pride

Chemical genetics and proteome-wide site mapping reveal cysteine MARylation by PARP-7 on immune-relevant protein targets

Project description:Poly (ADP-ribose) polymerase 7 (PARP-7) has emerged as a critically important member of a large enzyme family that catalyze ADP-ribosylation in mammalian cells. PARP-7 is a critical regulator of the innate immune response. What remains unclear is the mechanism by which PARP-7 regulates this process, namely because the protein targets of PARP-7 mono-ADP-ribosylation (MARylation) are largely unknown. Here, we combine chemical genetics, proximity labeling, and proteome-wide amino acid ADP- ribosylation site profiling for identifying the direct targets and sites of PARP-7-mediated MARylation in a cellular context. We found that the inactive PARP family member, PARP13 (a critical regulator of the antiviral innate immune response) is a major target of PARP-7. PARP-13 is preferentially MARylated on cysteine residues in its RNA binding zinc finger domain. Proteome-wide ADP-ribosylation analysis reveals cysteine as a major MARylation acceptor of PARP-7. This study provides insight into PARP-7 targeting and MARylation site preference.

2021-07-21 | PXD020323 | Pride

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [iBMDM_Stat1_mutant_RNAseq]

Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.

2021-05-13 | GSE147959 | GEO

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [iBMDM_RNA-Seq_Parp1Ko]

2021-05-13 | GSE147958 | GEO

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [iBMDM_RNA-Seq_PJ34]

2021-05-13 | GSE147957 | GEO

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [BMDM_RNA-Seq_Parp1Ko]

2021-05-13 | GSE147956 | GEO

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [BMDM_RNA-Seq_PJ34]

2021-05-13 | GSE147955 | GEO

ADP-ribosylation of H3K27acα by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [H3K27ac_ChIP-Seq_mutants_iBMDM]

Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, H3K27acα. H3K27acα activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of H3K27acα and its IFNγ-dependent phosphorylation. We identified H3K27acα as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on H3K27acα transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of H3K27acα is a critical mediator of inflammation in macrophages.

2021-05-13 | GSE147954 | GEO

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [STAT1_ChIP-Seq_Mutants_iBMDM]

2021-05-13 | GSE147953 | GEO

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [H3K27ac_ChIP-Seq_BMDM]

2021-05-13 | GSE147952 | GEO