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ATR-mediated Proteome Remodeling is a Major Determinant of Homologous Recombination Capacity in Cancer Cells

ABSTRACT: DMSO or 5uM ATR inhibitor(VE-821) were treated for 8 days on U2OS cells prior to anlaysis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Osteoblast

DISEASE(S): Bone Osteosarcoma

SUBMITTER: Dongsung Kim

LAB HEAD: Marcus Smolka

PROVIDER: PXD010223 | Pride | 2018-07-17

REPOSITORIES: Pride

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			Action	DRS
	DS_U2OS_ATRi_Exp6_hilic_10.raw	Raw
	DS_U2OS_ATRi_Exp6_hilic_11.raw	Raw
	DS_U2OS_ATRi_Exp6_hilic_12.raw	Raw
	DS_U2OS_ATRi_Exp6_hilic_13.raw	Raw
	DS_U2OS_ATRi_Exp6_hilic_14.raw	Raw

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ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells.

Kim Dongsung D Liu Yi Y Oberly Susannah S Freire Raimundo R Smolka Marcus B MB

Nucleic acids research 20180901 16

The ATR kinase is crucial for genome maintenance, but the mechanisms by which ATR controls the DNA repair machinery are not fully understood. Here, we find that long-term chronic inhibition of ATR signaling severely impairs the ability of cells to utilize homologous recombination (HR)-mediated DNA repair. Proteomic analysis shows that chronic ATR inhibition depletes the abundance of key HR factors, suggesting that spontaneous ATR signaling enhances the capacity of cells to use HR-mediated repair ...[more]

PMID: 30010936

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BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc- induced lymphoma cells

Project description:The aim of the project was to determine the expression profiles of murine Myc-driven lymphpma cells (Lambda-820) treated with vehicle (DMSO, 1:1000), a BET inhibitor (RVX2135), an ATR inhibitor (VE-821) or a combination of RVX2135 and VE-821. All experimnets were performed in presence of 10uM Q-VD-OPH to block apoptosis. Cells were harvested 24 h after treatment start. 4 samples (DMSO, RVX2135, VE-821 or RVX2135/VE-821) in duplicates

2015-12-18 | E-GEOD-74873 | biostudies-arrayexpress

BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc- induced lymphoma cells

2015-12-18 | GSE74873 | GEO

ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells.

Project description:The ATR kinase is crucial for genome maintenance, but the mechanisms by which ATR controls the DNA repair machinery are not fully understood. Here, we find that long-term chronic inhibition of ATR signaling severely impairs the ability of cells to utilize homologous recombination (HR)-mediated DNA repair. Proteomic analysis shows that chronic ATR inhibition depletes the abundance of key HR factors, suggesting that spontaneous ATR signaling enhances the capacity of cells to use HR-mediated repair by controlling the abundance of the HR machinery. Notably, ATR controls the abundance of HR factors largely via CHK1-dependent transcription, and can also promote stabilization of specific HR proteins. Cancer cells exhibit a strong dependency on ATR signaling for maintaining elevated levels of HR factors, and we propose that increased constitutive ATR signaling caused by augmented replication stress in cancer cells drives the enhanced HR capacity observed in certain tumor types. Overall, these findings define a major pro-HR function for ATR and have important implications for therapy by providing rationale for sensitizing HR-proficient cancer cells to PARP inhibitors.

| S-EPMC6144784 | biostudies-literature

KLF5 loss sensitizes to ATR inhibition and is synthetic lethal with ARID1A deficiency

Project description:DRIP-seq experiments conducted in WT U2OS and KLF5 KO U2OS with and without ATR inhibitor treatment

2024-12-09 | E-MTAB-14062 | biostudies-arrayexpress

The effect of ATR inhibition on the replication timing program

Project description:As a part of the project looking into the role of ATR in regulating replication initiation, we report the replication timing analysis of the U2OS cells treated with ATR kinase inhibitor AZD6738

2019-07-26 | GSE131018 | GEO

Atr maintains chromosomal integrity during postnatal cerebellar neurogenesis [Affymetrix]

Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.

2016-09-01 | GSE85393 | GEO

Atr maintains chromosomal integrity during postnatal cerebellar neurogenesis [RNA-Seq]

2016-09-01 | GSE83720 | GEO

LC-MS/MS of human T-ALL following 12h of ATR inhibition

Project description:Quantitative proteomic and phosphoproteomic analysis of the human T-ALL cell line, CCRF CEM, following 12 hours of ATR inhibiton using the Vertex drug, VE-822.

2017-07-31 | PXD006702 | Pride

Coupling of Homologous Recombination and the Checkpoint by ATR.

Project description:ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site. The PALB2-S59A/S64E mutant is defective for localization to DNA damage sites and HR, whereas the PALB2-S59E/S64A mutant partially bypasses ATR for its localization. Thus, HR is a biphasic process requiring both high-CDK and low-CDK periods. As exemplified by the regulation of PALB2 by ATR, ATR promotes HR by orchestrating a "CDK-to-ATR switch" post-resection, directly coupling the checkpoint to HR.

| S-EPMC5496772 | biostudies-literature

MOLT-4 radiosensitization by VE-821

Project description:DNA damage induction by either radio- or chemo-therapy has been the most widely used approach in cancer therapy, exploiting the genomic instability of cancer cells. A promising strategy takes advantage of tumour specific abnormalities in DNA damage response. Inhibition of the ATR/Chk1 pathway has been shown to be synthetically lethal in cells with high levels of oncogene-induced replication stress and in p53- or ATM- deficient cells. In the presented study, we aimed to elucidate molecular mechanisms underlying radiosensitization of MOLT-4 cells by VE-821, a higly potent and specific inhibitor of ATR. We combined multiple approaches: cell biology techniques to reveal the inhibitor-induced phenotypes, and quantitative proteomics, phosphoproteomics, and metabolomics to comprehensively describe drug-induced changes in irradiated cells.

2018-07-16 | PXD008925 | Pride

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