Low physiological pH drives P300-mediated acetylation of PARP1 and promotes PARP inhibitor resistance [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE314447 | GEO | 2026/07/13
REPOSITORIES: GEO
Similar Datasets
Project description:Resistance to PARP inhibitors (PARPi) remains a major clinical obstacle in epithelial ovarian carcinoma (EOC), ultimately limiting therapeutic efficacy and contributing to patient mortality. Here, we demonstrate that the acidic tumor microenvironment drives a novel mechanism of PARPi resistance. Decreasing the pH is sufficient to reduce PARPi anti-tumor efficacy in multiple in vitro and in vivo EOC models. Through three independent, epigenetically focused CRISPR/Cas9 screens conducted under low pH conditions, we identified p300 as a druggable target for overcoming pH-induced PARPi resistance. Mechanistically, in an unbiased functional proteomic evaluation we uncovered an ERK1/2–p300–PARP1 signaling axis activated under low pH, which alleviates PARPi-induced PARP1 trapping by promoting PARP1 K505 acetylation and thereby reducing replication fork collapse and associated DNA damage and driving PARPi resistance. Notably, in multiple in vivo patient-derived and syngeneic EOC models, two novel p300 bromodomain inhibitors, IACS-16559 and TT125-802, restore sensitivity to PARPi. Together, our findings establish p300 as a promising therapeutic target for overcoming pH-driven PARPi resistance in EOC.
2026-07-13 | GSE314448 | GEO
Project description:Poly (ADP-ribose) polymerase inhibitors (PARPi) induce cytotoxicity in homologous recombination deficient cancers by causing PARP1 to become trapped on chromatin, resulting in irreparable replication-associated DNA damage. Cancer cells commonly develop resistance to PARPi, with a recently proposed mechanism being the clearance of trapped PARP1 from chromatin, yet details surrounding this process remain unclear. PARPi treatment causes increased autophagy flux, whilst autophagy inhibition can hypersensitise cells to PARPi. With selective autophagy of nuclear substrates (nucleophagy) shown, we wanted to explore if this occurs during DNA damage repair by clearance of trapped PARP1. We used various biochemical, cell biological and live imaging-based assays, demonstrating that trapped PARP1 is processed by selective nucleophagy. We identified that nucleophagy of trapped PARP1 is orchestrated by selective autophagy receptor TEX264 and its partner protein p97/VCP. TEX264 directly interacts with trapped PARP1, then bridges PARP1 to autophagosomal resident protein LC3 for processing via autophagy. Impeding this process, either chemically or genetically, heightened PARP1 trapping, leading to replication-associated DNA damage and cell lethality, re-sensitising PARPi-resistant cells to various PARPi. In conclusion, we show that selective nucleophagy acts in a cytoprotective manner to directly target PARPi-induced trapped PARP1 for degradation.
2026-03-23 | GSE277366 | GEO
Project description:The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.
2022-07-07 | GSE202437 | GEO
Project description:The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.
2022-07-07 | GSE202435 | GEO
Project description:The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.
2022-07-07 | GSE202434 | GEO
Project description:Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of messenger RNA (mRNA). The m6A modification affects RNA fate and functions such as RNA stability. Despite the high initial response rates to PARP inhibitors in BRCA1/2-mutated epithelial ovarian cancers (EOC), PARP inhibitor (PARPi) resistance remains a major challenge. The role of m6A modification in PARPi resistance has not previously been explored. Here we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/-catenin pathway in BRCA-mutated EOC cells. Global m6A profile reveals a significant increase in m6A modification in FZD10 mRNA. This correlates with an increase in FZD10 mRNA stability and an upregulation of the Wnt/-catenin pathway in PARPi resistant cells. FZD10 knockdown or inhibition of the Wnt/-catenin sensitizes the resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 is sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlates with an increase in homologous recombination activity. Moreover, PAPRi and Wnt/-catenin inhibitor showed synergistic suppression of growth of PAPRi resistant cells both in vitro and in vivo in a xenograft ovarian cancer mouse model. Our results show that m6A contributes to PAPRi resistance in BRCA-deficient EOC cells by upregulating the Wnt/-catenin pathway through stabilizing FZD10. They also suggest that inhibition of Wnt/-catenin pathway represents a potential strategy to overcome PARPi resistance.
2019-09-14 | GSE119963 | GEO
Project description:The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.
2022-07-08 | PXD033530 | Pride
Project description:Poly (ADP-ribose) polymerase inhibitors (PARPi) are widely used as targeted therapies against breast cancers with BRCA mutations. However, the development of resistance to PARPi poses a significant challenge for long-term efficacy of these therapies, warranting further understanding of mechanisms of PARPi resistance. Here, we generated and characterized Olaparib resistance (OR) in BRCA1/2 mutant breast cancer cell lines MDAMB436 and HCC1428 using a systems-level multi-omics approach, including transcriptome, proteome, phosphoproteome, and ADP-ribosylation analysis. Our analyses revealed that resistance development strongly correlated with protein expression changes, while modest effects on phosphorylation- and ADP-ribosylation-dependent signaling pathways were observed. We found that BRCA1 expression was reestablished in OR MDAMB436 cell lines, while PARP1 expression was decreased. In OR HCC1428 cell lines, the BRCA2 mutation was not reverted. However, we observed increased expression of Fanconi anemia group D2 (FANCD2), histone parylation factor 1 (HPF1, and Nicotinamide phosphoribosyltransferase (NAMPT) in various cell lines, suggesting increased replication fork protection, and changes in the ADPr pathway and adaptation of metabolic pathways as resistance mechanisms. Our findings provide valuable insights into the complex landscape of PARPi resistance, offering potential targets for further investigation and therapeutic intervention.
2026-05-11 | MTBLS12109 | MetaboLights
Project description:Poly (ADP-ribose) polymerase inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HRR)-deficient cancers by causing PARP1 to become trapped on chromatin, resulting in irreparable replication-associated DNA damage. Cancer cells commonly develop resistance to PARPi, with a recently proposed mechanism being the clearance of trapped PARP1 from chromatin, yet details surrounding this process remain unclear. PARPi treatment causes increased autophagy flux, whilst autophagy inhibition can hypersensitise cells to PARPi. With selective autophagy of nuclear substrates (nucleophagy) shown, we wanted to explore if this occurs during DNA damage repair by the clearance of trapped PARP1. We used various biochemical, cell biological and live imaging-based assays, demonstrating that trapped PARP1 is processed by nucleophagy. We identified that nucleophagy of trapped PARP1 is orchestrated by selective autophagy receptor TEX264 and its partner protein p97/VCP. TEX264 directly interacts with trapped PARP1, then bridges PARP1 to autophagosomal resident protein LC3 for processing via autophagy. Impeding this process, either chemically or genetically, heightened PARP1 trapping, leading to accumulation of protein aggregates, replication-associated DNA damage and cell lethality, re-sensitising PARPi-resistant cells to various PARPi. In conclusion, we show that nucleophagy acts in a cytoprotective manner to directly target PARPi-induced trapped PARP1 for degradation.
2026-04-15 | PXD071389 | Pride
Project description:Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair particularly in homologous recombination (HR)-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce DNA Damage Chemical Inducers of Proximity (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemical induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1 which induces the DNA damage response (DDR) and apoptosis to a range of cancer lines at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis in vitro, leading to anti-tumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical induced proximity as a strategy for modulating the DDR in cancer.
Exp ID # 1050 contains FLAG-BRD4 IP-MS for DD-CIP1 (TWQ-03-052) & TWQ-03-184 (DD-CIP2). 1086 contains FLAG-PARP1 for DD-CIP2 (TQ-03-184). 1103 contains FLAG-PARP1 IP-MS for Olaparib. 1131 contains FLAG-PARP1 IP-MS for DD-CIP1 (TWQ-03-052).
2025-12-06 | MSV000100135 | MassIVE