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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma

ABSTRACT: Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma

PROVIDER: PRJNA603300 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10969712.fastq.gz	Fastqsanger.gz
	SRR10969713.fastq.gz	Fastqsanger.gz
	SRR10969714.fastq.gz	Fastqsanger.gz
	SRR10969715.fastq.gz	Fastqsanger.gz
	SRR10969716.fastq.gz	Fastqsanger.gz

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIPseq_IMR5_RNAseqH1]

Project description:Targeting the function of MYC proteins for therapy is a major challenge in tumor biology. MYC proteins are transcription factors that can globally release RNA polymerase II (RNAPII) from core promoters. In neuroblastoma, the MYC paralogue, MYCN, and the Aurora-A kinase form a complex during S phase that stabilizes MYCN and enhances Aurora-A kinase activity. Here we show that Aurora-A phosphorylates histone H3 at serine 10 in S phase and suppresses transcription-dependent R-loop formation. Inhibition of Aurora-A causes global stalling of RNAPII at pause sites and exon/intron boundaries and induces transcription/replication conflicts, activating the Ataxia telangiectasia and Rad3 related (ATR) kinase. Activation of ATR is required to prevent the accumulation of double-strand breaks. In genetically-engineered mice with MYCN-driven neuroblastoma, combined inhibition of Aurora-A and ATR induces rampant tumor-specific apoptosis and tumor regression, leading to permanent eradication of tumors in a subset of mice. The therapeutic efficacy is not only due to tumor cell-intrinsic mechanisms, but also engages the host immune system for tumor eradication. Since stabilization of MYCN promotes promoter-proximal transcription termination, we propose that MYCN/Aurora-A complex formation enables tumor cells to prevent transcription-replication conflicts and that targeting this mechanism is an effective therapy for MYCN-driven neuroblastoma.

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIPseq_IMR5]

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [PDX]

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [4SU-seq]

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIP-seq_SHEP]

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIPseq_IMR5_RNAseqH1]

Project description:Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIPseq_IMR5_RNAseqH1]

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [PDX]

Project description:Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [PDX]

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIPseq_IMR5]

Project description:Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIPseq_IMR5]

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Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIP-seq GB]

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