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Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

ABSTRACT: Whole genome sequencing of ATRX / TP53 knockdown clones of the neuroblastoma cell line SK-N-SH

PROVIDER: EGAS00001004550 | EGA |

REPOSITORIES: EGA

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Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma.

Project description: Not available

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Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma

Project description:To elucidate ATRX-dependent transcriptional alterations and their functional consequences, we performed a microarray analysis of Ctrl and ATRX KO NGP cells.

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ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation

Project description:We report on the characterization of ATRX in-frame fusion neuroblastoma and identify that ATRX IFF proteins re-locate from H3K9me3 enriched regions to active chromatin, such as the promoter of neural repressor REST. We further identify that REST is upregulated in ATRX IFF NB and that several neurogenesis and REST target genes are transcriptionally downregulated. Through ChIP-seq analysis, we observe that REST is bound to ATRX IFF Down genes, which have higher levels of H3K27me3. We further show that ATRX in-frame fusion neuroblastoma cells are sensitive to EZH2 inhibitors through de-repression of H3K27me3 bound neuronal function genes, includiing a subset of REST targets.

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DAC Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

Project description:Data Access Committee EGAC00001001675

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Two opposing gene expression patterns within ATRX aberrant neuroblastoma

Project description:To study the role of distinct ATRX aberrations in neuroblastoma we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid. We created ATRX knock-out models, ATRX in-frame exon 2-10 deletions and ATRX in-frame exon 2-13 deletions. Additionally, we included patient-derived models data (i.e. cell line data and one tumoroid).

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Impaired gene expression in ATRX-depleted cells following interferon signaling

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Alterations in chromatin accessibility in ATRX-depleted cells following interferon signaling

Project description:We investigated the role of the chromatin remodeling protein ATRX on chromatin accessibility specifically upon IFN-β stimulation utilizing stable ATRX knockdown cells.

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DAXX-ATRX-H3.3 Regulation of p53 Chromatin Binding and DNA Damage Response [ChIP-Seq]

Project description:DAXX and ATRX are tumor suppressor proteins that form a complex with histone H3.3 chaperone and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that a key feature of ALT selected DAXX and ATRX null glioblastoma cells is the attenuation of p53 function. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with wt DAXX rescued p53 binding and transcription, while the tumor associated mutation L130R, that disrupts ATRX binding, was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.

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DAXX-ATRX-H3.3 Regulation of p53 Chromatin Binding and DNA Damage Response [ATAC-Seq]

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