Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1136979 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29869118_1.fastq.gz | Fastqsanger.gz | |||
| SRR29869118_2.fastq.gz | Fastqsanger.gz | |||
| SRR29869119_1.fastq.gz | Fastqsanger.gz | |||
| SRR29869119_2.fastq.gz | Fastqsanger.gz | |||
| SRR29869120_1.fastq.gz | Fastqsanger.gz |
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Project description:The androgen receptor (AR) transduces the effects of circulating and tumor-derived androgens to the nucleus through ligand-induced changes in protein conformation, localization, and chromatin engagement. Defining how these events are integrated with signal transduction is critical to understand how AR drives prostate cancer and unveil pathway features that are potentially amenable to therapeutic intervention. We describe a novel post-transcriptional mechanism that controls AR levels on chromatin and gene output based on highly selective, inducible degradation. We find that the mono-ADP-ribosyltransferase PARP7 generates an ADP-ribosyl degron in the DNA binding domain of AR, which is recognized by the ADP-ribose reader domain in the ubiquitin E3 ligase DTX2 and degraded by the proteasome. Mathematical modeling of the pathway suggested that PARP7 ADP-ribosylates chromatin-bound AR, a prediction that was validated in cells using an AR DNA-binding mutant. Non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and degradation by the proteasome forms the basis of a negative feedback loop that regulates modules of AR target genes. Our data expand the repertoire of mono-ADP-ribosyltransferases to include gene regulation via highly selective protein degradation.
2025-06-11 | GSE272500 | GEO
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
Project description:PARP7 is an enzyme that uses donor substrate NAD+ to attach a single ADP-ribose moiety onto proteins related to immunity, transcription, and cell growth and motility. Despite the importance of PARP7 in these processes, PARP7 signalling networks remain under-researched. Here, we used genome-wide CRISPR screens and multiplex quantitative proteomics in distinct lung cancer cell lines treated with a PARP7 inhibitor to better understand PARP7 molecular functions. We discover that manipulating the aryl hydrocarbon receptor (AHR) transcriptional activity mediates PARP7 inhibitor sensitivity and triggers robust changes to the AHR-controlled proteome (AHR-ome). One of the striking features of such AHR-ome remodelling was the downregulation of Filamins A and B concurrent with the induction of the corresponding E3 ubiquitin ligase ASB2. We also show that suppressor of cytokine signalling 3 (SOCS3) reciprocally crosstalks to AHR. Inhibition of PARP7 in SOCS3 knockout cells leads to reduced viability compared to wild type cells treated with a PARP7 inhibitor. Our results reveal new signalling interplay among PARP7, AHR and SOCS3, and establish a useful resource to study the role of PARP7 in the regulation of AHR signalling and innate immunity through its ADP-ribosyl transferase activity.
2025-05-11 | PXD062520 | Pride
Project description:PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. PARP7 expression is increased by aromatic hydrocarbons and cellular stress, and the PARP7 gene is amplified in cancers, especially in those of the upper aerodigestive tract. PARP7 is a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores Type I IFN signaling responses to nucleic acids in tumor models. Restored signaling can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. RBN-2397 is a potent and selective inhibitor of PARP7. To further investigate the mechanism of action of RBN-2397 and identify potential biomarkers we investigated transcriptional changes after RBN-2397 treatment in two PARP7 inhibitor sensitive cell lines, NCI-H1373 and NCI-H647, by RNA sequencing.
2021-06-13 | GSE177494 | GEO
Project description:PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. PARP7 expression is increased by aromatic hydrocarbons and cellular stress, and the PARP7 gene is amplified in cancers, especially in those of the upper aerodigestive tract. PARP7 is a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores Type I IFN signaling responses to nucleic acids in tumor models. Restored signaling can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. RBN-2397 is a potent and selective inhibitor of PARP7. To further explore how RBN-2397 inhibits NCI-H1373 cell proliferation, we performed unbiased genetic screens using whole-genome CRISPRi and CRISPRa libraries (le Sage et al., 2017; Jost and Weissman, 2018). Comparison of CRISPRi and CRISPRa phenotype scores highlights genes with opposing functionality upon RBN-2397 treatment.
2021-06-18 | GSE178386 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and despite low incidence rates, it remains the sixth leading cause of cancer related deaths worldwide. Immunotherapy, which aims to enhance the immune system’s ability to recognize and eliminate cancer cells, has emerged as a promising approach in the battle against PDAC. PARP7, a mono-ADP-ribosyltransferase, is a negative regulator of the type I interferon (IFN-I) pathway, thereby reducing antitumour immunity. By characterizing murine pancreatic cancer cells, we found that loss of PARP7 elevated the levels of interferon stimulated gene factor 3 (ISGF3) and its downstream target genes, even in the absence of STING. We also observed that cancer cells deficient in PARP7 resulted in smaller tumours when injected into wildtype mice. Transcriptomic analyses revealed that tumours knocked out for Parp7 (Parp7KO) had increased expression of genes involved in immunoregulatory interactions and interferon signalling pathways. Characterization of tumour infiltrating leukocyte (TIL) populations showed that Parp7KO tumours had higher proportions of natural killer cells, CD8+ T cells and a lower proportion of anti-inflammatory macrophages (M2). The overall TIL profile of Parp7KO tumours was suggestive of a better response to anti-PD-1 immune checkpoint therapy. Our data show that loss of PARP7 reduces PDAC tumour growth by increasing the infiltration of immune cells and enhancing antitumor immunity. These findings provide support to pursue PARP7 as a therapeutic target for PDAC
2025-01-03 | GSE276293 | GEO
Project description:ADP-ribosylation is a post-translational modification that, until recently, has remained elusive to study at the cellular level. Previously dependent on radioactive tracers to identify ADP-ribosylation targets, several advances in mass spectrometric workflows now permit global identification of ADP-ribosylated substrates. In this study, we capitalized on two ADP-ribosylation enrichment strategies, and multiple activation methods performed on the Orbitrap Fusion Lumos, to identify IFN--induced ADP-ribosylation substrates in macrophages. The ADP-ribosyl binding protein, Af1521, was used to enrich ADP-ribosylated peptides, and the anti-poly-ADP-ribosyl antibody, 10H, was used to enrich ADP-ribosylated proteins. ADP-ribosyl-specific mass spectra were further enriched by an ADP-ribose product ion triggered EThcD and HCD activation strategy, in combination with multiple acquisitions that segmented the survey scan into smaller ranges. HCD and EThcD resulted in overlapping and unique ADP-ribosyl peptide identifications, with HCD providing more peptide identifications but EThcD providing more reliable ADP-ribosyl acceptor sites. Our acquisition strategies also resulted in the first ever characterization of ADP-ribosyl on three poly-ADP-ribose polymerases, ARTD9/PARP9, ARTD10/PARP10, and ARTD8/PARP14. IFN- increased the ADP-ribosylation status of ARTD9/PARP9, ARTD8/PARP14, and proteins involved in RNA processes. This study therefore summarizes specific molecular pathways at the intersection of IFN- and ADP-ribosylation signaling pathways.
2020-01-27 | PXD011690 | Pride
Project description:PARP7 (TiPARP), a mono (ADP-ribosyl) transferase (MART) was found to target α-tubulin proteins in ovarian cancer cells, enhancing their growth and migration. RBN-2397 is a potent inhibitor that selectively acts on PARP7. Here, we show that RBN-2397 treatment leads to the stabilization of microtubules in ovarian cancer cells, namely α-tubulin, mimicking what was previously observed with PARP7 knockdown. When treated with RBN-2397, we observe a decrease in growth and migration of ovarian cancer cells and, interestingly, the effect is intensified upon adding the microtubule stabilizing chemotherapeutic agent, paclitaxel. Mutating the site of α-tubulin MARylation by PARP7 similarly results in α-tubulin stabilization and decreased cell migration in the presence of paclitaxel when the tubulin network is further stabilized. In sum, we demonstrate that PARP7 inhibition decreases α-tubulin MARylation resulting in its stabilization, and ultimately leading to decreased ovarian cancer cell proliferation and migration. Finally, we show that combining PARP7 inhibitor and paclitaxel results in a more robust inhibition of aggressive ovarian cancer phenotypes. Collectively, this study highlights the potential of targeting PARP7 in combination with established chemotherapeutic agents to enhance treatment efficacy for ovarian cancer.
2024-10-01 | GSE268985 | GEO
Project description:PARP14 is a mono-ADP-ribosyl transferase involved in the control of immunity, transcription and DNA replication stress management. However, little is known about the ADP-ribosylation activity of PARP14, including its substrate specificity or how PARP14-dependent ADP-ribosylation is reversed. Here we show that PARP14 is dual function enzyme with both ADP-ribosyl transferase and hydrolase activity acting on both protein and nucleic acid substrates. In particular, we show that the PARP14 macrodomain 1 is an active ADP-ribosyl hydrolase. We also demonstrate hydrolytic activity for the first macrodomain of PARP9. We reveal that expression of a PARP14 mutant with the inactivated macrodomain 1 results in a dramatic increase in mono(ADP-ribosyl)ation of proteins in human cells, including PARP14 itself and antiviral PARP13. Moreover, we demonstrate that the closely related hydrolytically active macrodomain of SARS2 Nsp3, Mac1, efficiently reverses PARP14 ADP-ribosylation in vitro and in cells, supporting the evolution of viral macrodomains to counteract PARP14-mediated antiviral response.
2023-08-14 | PXD043452 | Pride
Project description:Poly(ADP-ribosyl)ating enzymes cooperate to coordinate development
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