Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Chemotherapeutic drugs inhibiting Topoisomerase 1 activity inhibit TNF-induced inflammatory gene expression

ABSTRACT: Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian cancer, small cell lung cancer and cervical cancer. As torsional stress is generated by replication and transcription we tested the effects of clinically used TOP1 inhibitors Topotecan and SN-38 on TNF-induced gene expression. RNA-seq experiments showed that inhibition of TOP1 activity interfered with the vast majority of TNF-triggered genes, while interference with TOP2 activity had only a minor impact. TOP1 inhibition affected the expression of early and late induced genes and the relative strength of gene induction played no role in the sensitivity to TOP1 interfering drugs. These data raise the possibility that the inhibition of inflammatory gene expression contributes to the increased risk of infection seen in some patients treated with TOP1 inhibtors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128798 | GEO | 2019/06/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors [Seq]

2013-08-30 | E-GEOD-43526 | biostudies-arrayexpress

Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

Project description:Topoisomerase 1 (TOP1) inhibitors, including camptothecin and topotecan, covalently trap TOP1 on DNA, creating cleavage complexes (cc’s) that must be resolved before gene transcription and DNA replication can proceed. We previously found that topotecan reduces the expression of long (>100 kb) genes and unsilences the paternal allele of Ube3a in neurons. Here, we sought to evaluate overlap between TOP1cc-dependent and -independent gene regulation in neurons. To do this, we utilized Top1 conditional knockout mice, Top1 knockdown, the CRISPR-Cas9 system to delete Top1, TOP1 catalytic inhibitors that do not generate TOP1cc’s, and a TOP1 mutation (T718A) that stabilizes TOP1cc’s. We found that topotecan treatment significantly alters the expression of many more genes, including long neuronal genes, immediate early genes, and paternal Ube3a, when compared to Top1 deletion. Our data show that topotecan has a stronger effect on neuronal transcription than Top1 deletion, and identifies TOP1cc-dependent and -independent contributions to gene expression.

2016-05-27 | GSE79951 | GEO

Co-ordinate inhibiton of autism candidate genes by topoisomerase inhibitors [array]

Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology. 9 experiments, gene expression measured by Affymetrix microarray. 1) cultured mouse cortical neurons treated with 300nM topotecan vs vehicle-treated controls 2) cultured mouse neurons treated with 1uM topotecan vs vehicle-treated controls 3) cultured mouse cortical neurons treated with 3uM ICRF-193 vs vehicle-treated controls. 4) cultured mouse cortical neurons treated with 10 uM irinotecan vs vehicle-treated controls. 5) cultured mouse cortical neurons treated with 3-1000 nM topotecan vs vehicle treated controls 6) cultured mouse cortical neurons treated with lentivirus expressing shRNA against Top1 and Top2b vs scrambled shRNA controls 7) cultured mouse cortical neurons treated with DRB vs vehicle-treated controls 8) cultured mouse cortical neurons treated with hydrogen peroxide or paraquat vs vehicle-treated controls 9) cultured mouse cortical neurons treated with topotecan with or without subsequent drug washout, vs vehicle-treated controls.

2013-08-30 | E-GEOD-43899 | biostudies-arrayexpress

Co-ordinate inhibiton of autism candidate genes by topoisomerase inhibitors [array]

2013-08-30 | GSE43899 | GEO

Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors [Seq]

2013-08-30 | GSE43526 | GEO

G-quadruplex on Chromosomal DNA Negatively Regulates Topoisomerase 1 Activity [CUT&Tag]

Project description:Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.

2024-01-01 | GSE239690 | GEO

G-quadruplex on Chromosomal DNA Negatively Regulates Topoisomerase 1 Activity [ChIP-seq]

2024-01-01 | GSE239692 | GEO

NEDDylated-Cullin 3 mediates the adaptive response to topoisomerase 1 inhibitors (RNA-Seq)

Project description:DNA topoisomerase 1 (Top1) inhibitors are mainstays of anticancer therapy. These drugs trap Top1 on DNA, stabilizing the Top1-cleavage complex (Top1-cc). The accumulation of Top1-ccs perturbs DNA replication fork progression, leading to DNA breaks and cell death. By analyzing the genomic occupancy and activity of Top1, we show that cells adapt to treatment with multiple doses of Top1 inhibitor by promoting the degradation of Top1-ccs, allowing cells to better tolerate subsequent doses of Top1 inhibitor. The E3-RING Cullin 3 Ligase in complex with the BTBD1 and BTBD2 adaptor proteins promote Top1-cc ubiquitination and subsequent proteasomal degradation. NEDDylation of Cullin 3 activates this pathway and inhibition of protein NEDDylation or depletion of Cullin 3 sensitizes cancer cells to Top1 inhibitors. Collectively, our data identify a novel NEDD8-Cullin 3 pathway involved in the adaptive response to Top1 inhibitors, which can be targeted to improve the efficacy of Top1 drugs in cancer therapy.

2022-11-04 | GSE212469 | GEO

NEDDylated-Cullin 3 mediates the adaptive response to topoisomerase 1 inhibitors (ChIP-Seq)

2022-11-04 | GSE212468 | GEO

Novel ABCG2 antagonists to reverse topotecan-mediated chemotherapeutic resistance in ovarian carcinoma xenografts.

Project description:In order to address the treatment difficulties associated with chemotherapetic resistance in ovarian cancer, we combined our compounds with topotecan and admininstered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice.

2017-02-10 | GSE85582 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data