Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ATR inhibition affects RNA Polymerase II transcription during S-phase

ABSTRACT: Transcription and replication are the key processes in cell growth and division that utilize DNA as their template. Concurrently, conflicts between the two processes increase genome instability levels. Evidence in the literature indicate that transcription and replication can however coexist, suggesting the requirement for cellular mechanisms to avoid reciprocal interference. To identify factors important in this regulatory process, we performed a screening of known DNA damage response proteins. Among the factors assessed, we found that specifically inhibition of ATR affected cells’ ability to replicate long transcribed genes, impacting also on cells’ ability to transcribe these genes. However, ATR activity was also required later during S-phase the control transcription activity on all genes. Dissecting which of ATR’s roles is important for this process, we uncovered that SMARCAL1 is likewise required to regulate genes transcription later during S-phase. Altogether, we have uncovered how DNA damage response factors are required to support the replication of transcribed regions, but also how their role extends to regulate also genes transcription levels during S-phase.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269242 | GEO | 2026/06/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ATR inhibition affects RNA Polymerase II transcription during S-phase

Project description:Transcription and replication are the key processes in cell growth and division that utilize DNA as their template. Concurrently, conflicts between the two processes increase genome instability levels. Evidence in the literature indicate that transcription and replication can however coexist, suggesting the requirement for cellular mechanisms to avoid reciprocal interference. To identify factors important in this regulatory process, we performed a screening of known DNA damage response proteins. Among the factors assessed, we found that specifically inhibition of ATR affected cells’ ability to replicate long transcribed genes, impacting also on cells’ ability to transcribe these genes. However, ATR activity was also required later during S-phase the control transcription activity on all genes. Dissecting which of ATR’s roles is important for this process, we uncovered that SMARCAL1 is likewise required to regulate genes transcription later during S-phase. Altogether, we have uncovered how DNA damage response factors are required to support the replication of transcribed regions, but also how their role extends to regulate also genes transcription levels during S-phase.

2026-06-08 | GSE269289 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [HTGTS]

Project description:The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that Atr is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.

2022-12-31 | GSE212195 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [CRISPR-Cas9 gRNA screen]

2022-12-31 | GSE214643 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [RNA-seq]

2022-12-31 | GSE212194 | GEO

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

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 | GSE152476 | 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 [ChIP-seq_SHEP]

2022-01-18 | GSE152478 | GEO

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

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