Similar Datasets
Project description:Copper inhibits ATR and synergizes with PARP inhibitors (RNA-seq)
| PRJNA1031244 | ENA
Project description:Copper inhibits ATR and synergizes with PARP inhibitors (DTP model RNA-seq and Ola-ATRi-EC cGAS-STING RNA-seq)
| PRJNA1035060 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-11-28 | GSE246893 | GEO
Project description:Inhibition of the deubiquitinating enzyme USP1 can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD) and represents a novel therapeutic strategy for the treatment of BRCA1/2 mutant cancers, potentially including patients whose tumors have primary or acquired resistance to PARP inhibitors (PARPi). Here, we present a comprehensive characterization of TNG348, an allosteric, selective, and reversible inhibitor of USP1 (USP1i). TNG348 induces dose-dependent accumulation of ubiquitinated protein substrates both in vitro and in vivo. CRISPR screens show that TNG348 exerts its anti-tumor effect by disrupting the translesion synthesis pathway of DNA damage tolerance through RAD18-dependent ub-PCNA induction. Though TNG348 and PARPi share the ability to selectively kill HRD tumor cells, CRISPR screens reveal that TNG348 and PARPi do so through discrete mechanisms. Particularly, knocking out PARP1 causes resistance to PARPi but sensitizes cells to TNG348 treatment. Consistent with these findings, combination of TNG348 with PARPi leads to synergistic anti-tumor effects in HRD tumors, resulting in tumor growth inhibition and regression in multiple mouse xenograft tumor models. Importantly, our data in human cancer models further show that the addition of TNG348 to PARPi treatment can overcome acquired PARPi resistance in vivo. While the clinical development of TNG348 has been discontinued due to unexpected liver toxicity in patients (NCT06065059), the present data provides preclinical and mechanistic support for the continued exploration of USP1 as a drug target for the treatment of patients with BRCA1/2 mutant or HRD cancers.
2024-12-29 | GSE284239 | GEO
Project description:The inhibition of poly(ADP-ribose) polymerases (PARPs) and ataxia telangiectasia and Rad3-related (ATR) would be an alternative approach for cancer treatments. The aim of this study is to investigate the synergy of the different combinations of PARP inhibitors (olaparib, talazoparib, or veliparib) and ATR inhibitor AZD6738. A drug combinational synergy screen that combines olaparib, talazoparib, or veliparib with AZD6738 was performed to identify the synergistic interaction, and the combination index was calculated to verify synergy. TK6 isogenic cell lines with defects in different DNA repair genes were used as a model. Cell cycle analysis, micronucleus induction, and focus formation assays of serine-139 phosphorylation of the histone variant H2AX demonstrated that AZD6738 diminished G2/M checkpoint activation induced by PARP inhibitors and allowed DNA damage-containing cells to continue dividing, leading to greater increases in micronuclei as well as double-strand DNA breaks in mitotic cells. We also found that AZD6738 was likely to potentiate cytotoxicity of PARP inhibitors in homologous recombination repair deficiency cell lines. AZD6738 sensitized more genotypes of DNA repair-deficient cell lines to talazoparib than to olaparib and veliparib, respectively. The combinational approach of PARP and ATR inhibition to enhance response to PARP inhibitors could expand the utility of PARP inhibitors to cancer patients without BRCA1/2 mutations.
| S-EPMC9925244 | biostudies-literature
Project description:Global gene expression patterns were compared among wild-type Col-0, teb, atr, teb atr of A. thaliana using shoot apices.
2008-04-01 | E-MEXP-1329 | biostudies-arrayexpress
Project description:Leukemic stem cells (LSC) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins are folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-Adenosylhomocysteine Hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.
2020-04-14 | GSE146252 | GEO
Project description:Mitochondria are the central metabolic hub of the cell and their function is vital for cellular activities. Mitochondrial autophagy, or mitophagy, is a quality control mechanism to surveille the fitness and functionality of mitochondria and is therefore essential for life. Both mitochondrial dysfunction and malfunctional DNA damage response (DDR) are a major etiology for tissue impairment and aging. ATR has been shown mainly as a nuclear factor to conduct DNA damage response under DNA replication stress. Paradoxically, the human Seckel syndrome caused by ATR mutations is characterized by premature aging and neuropathies, suggesting a role of ATR in non-replicating tissues. Here we report a previously unknown yet direct role of ATR at mitochondria. We find that HSP90 chaperones ATR and PINK1 to mitochondria, where ATR interacts with and thereby stabilizes PINK1 docking at the mitochondrial translocase TOM/TIM complex as well as with the electron transport chain (ETC). ATR mutant cells are refractory to mitophagy initiation, which can be reverted by an ectopic expression of full length, but not ATR-interaction mutant, PINK1. ATR deletion alters mitochondrial dynamics and OXPHOS functions producing aberrantly high reactive oxygen species (ROS) that attack cytosolic macromolecules prior to damaging nuclear DNA. Intriguingly, pharmacological intervention of mitochondrial metabolism to prevent ROS overproduction can mute ATR-mediated nuclear DDR. This study demonstrates that ATR is an integrated component of the mitochondrial membrane to ensure mitochondrial fitness as a primary physiological function, which, together with its essential DDR function, safeguards the cell fate under physiological and genotoxic conditions.
2025-02-26 | GSE244464 | GEO
Project description:Because a single treatment with CCC-002 downregulated the expression of DDR-related genes in CHP-134 cells, the expression profile of SK-N-BE(2) cells after co-treatment with CCC-002 and an ATR inhibitor was evaluated using a microarray assay
2025-01-31 | GSE285823 | GEO
Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information. Various shRNAs that target genes involved in homologous recombination (HR) were transfected in MCF-10A non-transformed breast cells lines. Stable HR gene knockdown MCF-10A cells were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling. The shRNAs that target ATM, ATR, CHK1, CHK2, and 53BP1 genes were transfected in MCF-10A non-transformed breast cell line by lentiviral particles and selected stable ATM, ATR, CHK1, CHK2, and 53BP1 knockdown MCF-10A cells. Scrambled control shRNA-transfected and wild type MCF-10A cells were applying as control. All knockdown and control MCF-10A cells were seeded with 2 x 10^5 cells at 10 cm culture plate. Cells were cultured in MCF-10A medium and harvested after 48 hours culturing. mRNA was extracted from collected cells and performing gene expression profiling. Three biological replicates were applied.
2014-01-24 | E-GEOD-54268 | biostudies-arrayexpress