Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The MYCN oncoprotein resolves conflicts of stalling RNA Polymerase with the replication fork [DP_EXOSC10_Screen]

ABSTRACT: During the S-phase, conflicts of replication forks with RNA Polymerase II (RNAPII) threaten genomic stability. While the PAF complex can resolve such conflicts during elongation, the particularly deleterious conflicts with stalling RNAPII are resolved by an as of yet unknown mechanism. Here we show that the MYCN oncoprotein forms a ternary complex with RNAPII and the nuclear RNA exosome, a 3’‑5’ exoribonuclease complex. Together with TFIIS, this complex restarts promoter‑proximal RNAPII, allows escape from co-directional transcription-replication conflicts and prevents double‑strand break accumulation. In cells lacking RNA exosome function, MYCN globally terminates transcription. MYCN-mediated termination is triggered by ATM‑dependent recruitment of BRCA1, which then stabilizes nuclear mRNA decapping complexes. Disruption of mRNA decapping activates ATR, indicative of head-on transcription-replication conflicts, and inhibits DNA replication. We propose that MYCN resolves transcription-replication conflicts via this two-step mechanism to sustain the rapid proliferation of neuroendocrine tumor cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164568 | GEO | 2021/12/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The MYCN oncoprotein resolves conflicts of stalling RNA Polymerase with the replication fork [DP_EXOSC10_ChIP_4sUseq]

Project description:During the S-phase, conflicts of replication forks with RNA Polymerase II (RNAPII) threaten genomic stability. While the PAF complex can resolve such conflicts during elongation, the particularly deleterious conflicts with stalling RNAPII are resolved by an as of yet unknown mechanism. Here we show that the MYCN oncoprotein forms a ternary complex with RNAPII and the nuclear RNA exosome, a 3’‑5’ exoribonuclease complex. Together with TFIIS, this complex restarts promoter‑proximal RNAPII, allows escape from co-directional transcription-replication conflicts and prevents double‑strand break accumulation. In cells lacking RNA exosome function, MYCN globally terminates transcription. MYCN-mediated termination is triggered by ATM‑dependent recruitment of BRCA1, which then stabilizes nuclear mRNA decapping complexes. Disruption of mRNA decapping activates ATR, indicative of head-on transcription-replication conflicts, and inhibits DNA replication. We propose that MYCN resolves transcription-replication conflicts via this two-step mechanism to sustain the rapid proliferation of neuroendocrine tumor cells.

2021-12-10 | GSE164555 | GEO

The MYCN oncoprotein resolves conflicts of stalling RNA Polymerase with the replication fork [DP_EXOSC10_BLISS]

2021-12-10 | GSE164567 | GEO

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

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.

2020-11-27 | GSE144287 | GEO

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

2020-11-27 | GSE144286 | GEO

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

2020-11-27 | GSE144285 | GEO

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

2022-01-18 | GSE152478 | GEO

Targeting transcription-replication conflicts is an effective therapeutic principle for MYCN-driven neuroblastoma [ChIP-seq IMR-5]

2020-11-27 | GSE144284 | GEO

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

2020-11-27 | GSE144283 | GEO

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