BARD1 is an exploitable therapeutic target for homologous repair proficient pancreatic ductal adenocarcinomas [MiaPaCa-2]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1161637 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30675679_1.fastq.gz | Fastqsanger.gz | |||
| SRR30675679_2.fastq.gz | Fastqsanger.gz | |||
| SRR30675680_1.fastq.gz | Fastqsanger.gz | |||
| SRR30675680_2.fastq.gz | Fastqsanger.gz | |||
| SRR30675681_1.fastq.gz | Fastqsanger.gz |
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Project description:The overall 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is only 13% and there is an unmet need for better therapies. For the minority (5-10%) of patients with homologous recombination repair (HRR) deficient PDAC tumors (BRCA1/2, PALB2 mutations), poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) and platinum-based therapies offer the best-personalized treatment approach. However, the efficacy of these treatments is often limited due to inherent (HRR proficient tumors) or acquired drug resistance. We have previously shown that expression of BARD1 or BRCA1- Associated- Ring- Domain- 1, a DNA repair protein and an obligate binding partner of BRCA1, is post-transcriptionally upregulated by the pro-survival RNA binding protein HuR (ELAVL-1), in PDAC. Here, we evaluated BARD1’s functional role in PDAC cell biology and evaluated its potential as a therapeutic target in HRR-proficient PDAC. BARD1 expression was silenced in HRR- proficient PDAC cells using both small interfering RNAs and CRISPR/Cas9 deletion. Silencing BARD1 decreased cell proliferation and 3D matrigel invasion in vitro. Tumor growth of BARD1KO mouse xenografts was markedly impaired. Mechanistically, using RNA sequencing of BARD1 silenced cells, we found a de-enrichment of the epithelial-mesenchymal-transition (EMT) pathway and global downregulation of c-Myc-target genes, which control diverse cell signaling events in PDAC. BARD1 stabilized the c-Myc protein through inhibition of the ubiquitin–proteasome system. Further, to evaluate if BARD1 loss is synergistic with DNA damage agents, we employed a focused DNA damage drug library in BARD1 silenced cells and found that cells were uniquely sensitized to the PARP inhibitors class of drugs. Our proof-of-concept study implicates BARD1 as an attractive, exploitable therapeutic target for HRR proficient PDAC patients and presents a unique opportunity to expand the PDAC patient population that could benefit from PARP inhibitors in the clinical setting.
2025-04-09 | GSE277278 | GEO
Project description:The overall 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is only 13% and there is an unmet need for better therapies. For the minority (5-10%) of patients with homologous recombination repair (HRR) deficient PDAC tumors (BRCA1/2, PALB2 mutations), poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) and platinum-based therapies offer the best-personalized treatment approach. However, the efficacy of these treatments is often limited due to inherent (HRR proficient tumors) or acquired drug resistance. We have previously shown that expression of BARD1 or BRCA1- Associated- Ring- Domain- 1, a DNA repair protein and an obligate binding partner of BRCA1, is post-transcriptionally upregulated by the pro-survival RNA binding protein HuR (ELAVL-1), in PDAC. Here, we evaluated BARD1’s functional role in PDAC cell biology and evaluated its potential as a therapeutic target in HRR-proficient PDAC. BARD1 expression was silenced in HRR- proficient PDAC cells using both small interfering RNAs and CRISPR/Cas9 deletion. Silencing BARD1 decreased cell proliferation and 3D matrigel invasion in vitro. Tumor growth of BARD1KO mouse xenografts was markedly impaired. Mechanistically, using RNA sequencing of BARD1 silenced cells, we found a de-enrichment of the epithelial-mesenchymal-transition (EMT) pathway and global downregulation of c-Myc-target genes, which control diverse cell signaling events in PDAC. BARD1 stabilized the c-Myc protein through inhibition of the ubiquitin–proteasome system. Further, to evaluate if BARD1 loss is synergistic with DNA damage agents, we employed a focused DNA damage drug library in BARD1 silenced cells and found that cells were uniquely sensitized to the PARP inhibitors class of drugs. Our proof-of-concept study implicates BARD1 as an attractive, exploitable therapeutic target for HRR proficient PDAC patients and presents a unique opportunity to expand the PDAC patient population that could benefit from PARP inhibitors in the clinical setting.
2025-04-09 | GSE277280 | GEO
Project description:BARD1 is an exploitable therapeutic target for homologous repair proficient pancreatic ductal adenocarcinomas [PANC-1]
| PRJNA1161640 | ENA
Project description:We report the BRCA1/BARD1 complex associated RNA in HEK293T cells using RNA-seq following PAR-Clip.
2022-07-04 | GSE207338 | GEO
Project description:NDRG1 functions as a metastasis suppressor in pancreatic and other cancers. To determine the molecular function of NDRG1 in MIAPaCa-2 pancreatic cancer cells, we performed a whole genome gene array analysis on these cells stably transfected with NDRG1 when compared to empty vector-transfected controls. The differentially expressed genes indetified in this microarray may represent potential molecular targets of NDRG1 in pancreatic cancer. Two separate RNA extracts of MIAPaCa-2 vector control and NDRG1 transfected cells were collected and hybridised to Affymetrix Human Genome U133 Plus 2.0 chips.
2011-07-22 | E-GEOD-25086 | biostudies-arrayexpress
Project description:MiaPaCa-2 xenografts SHP2i + ERKi
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Project description:BRCA1/BARD1 is a tumor suppressor E3 ubiquitin (Ub) ligase with roles in DNA damage repair and in transcriptional regulation. BRCA1/BARD1 RING domains interact with nucleosomes to facilitate mono-ubiquitylation of distinct residues on the C-terminal tail of histone H2A. These enzymatic domains constitute a small fraction of the heterodimer, raising the possibility of functional chromatin interactions involving other regions such as the BARD1 C-terminal domains that bind nucleosomes containing the DNA damage signal H2A K15-Ub and H4 K20me0, or portions of the expansive intrinsically disordered regions found in both subunits. Herein, we reveal novel interactions that support robust H2A ubiquitylation activity mediated through a high-affinity, intrinsically disordered DNA-binding region of BARD1. These interactions support BRCA1/BARD1 recruitment to chromatin and sites of DNA damage in cells and contribute to their survival. We also reveal distinct BRCA1/BARD1 complexes that depend on the presence of H2A K15-Ub, including a complex where a single BARD1 subunit spans adjacent nucleosome units. Our findings identify an extensive network of multivalent BARD1-nucleosome interactions that serve as a platform for BRCA1/BARD1-associated functions on chromatin.
2023-06-21 | PXD035345 | Pride
Project description:Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway, and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial and most efforts aimed to identify BRCA1/BARD1 ubiquitination substrates rely on indirect evidence. Here, we observed that the BRCA1/BARD1 ubiquitin E3 activity was not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identified substrates for BRCA1/BARD1. We found that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results address the controversy about the function of BRCA1/BARD1 E3 activity in Homologous Recombination.
2024-05-07 | PXD050319 | Pride
Project description:Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway, and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial and most efforts aimed to identify BRCA1/BARD1 ubiquitination substrates rely on indirect evidence. Here, we observed that the BRCA1/BARD1 ubiquitin E3 activity was not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identified substrates for BRCA1/BARD1. PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18, avoiding the formation of ssDNA gaps during DNA replication and promoting replication fork stability upon replication stress, solving the controversy about the function of BRCA1/BARD1 E3 activity in Homologous Recombination.
2024-05-07 | PXD039167 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) relies on hyper-activated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome-profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in Miapaca-2 cells. This was performed by isolating cytoplasmic and efficiently translated (heavy polysome-associated) mRNAs from MiaPaca-2 cells upon PP242-mediated mTOR inhibition
2019-09-18 | GSE137553 | GEO