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Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239328 | GEO | 2024/06/05

REPOSITORIES: GEO

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Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells [END-seq]

Project description:DNA topoisomerase I is an essential enzyme in higher eukaryotes that regulates DNA torsional tension during fundamental processes, such as replication and transcription. During its catalytic activity, a transient Topoisomerase I-DNA cleavage complex, called Top1cc, forms to allow strand rotation and duplex relaxation. However, the stabilization of Top1cc can lead to increased DNA:RNA hybrid duplexes, DNA double-strand cuts (DSBs) and genome instability as shown by formation of micronuclei, extranuclear chromatin enveloped by a nuclear membrane. To better comprehend the underlying mechanisms, we have established genomic maps of Top1cc-mediated R-loop changes and DSBs at short times upon Top1cc induction. Our findings show that Top1ccs dynamically changed the genomic distribution of R-loops, with regions of stable hybrid gains. DSBs were at specific gene loci, strongly associated with stable anterior R-loops at highly-transcribed genes and close to backtracked RNA polymerase II. Moreover, DSBs and stable anterior R-loops were highly enriched at early replication origins, thus revealing the location of replication conflicts with backtracked RNA polymerases.

2024-06-05 | GSE239327 | GEO

Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells [DRIP-seq]

2024-06-05 | GSE239326 | GEO

Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells.

Project description:Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells.

| PRJNA998805 | ENA

Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells [END-seq]

Project description:Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells [END-seq]

| PRJNA998812 | ENA

Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells [DRIP-seq]

Project description:Topoisomerase I poisoning induces R-loop changes and DNA damage in human cancer cells [DRIP-seq]

| PRJNA998813 | ENA

PREP1 down-regulation changes the DNA replication timing of Lamin-associated DNA and induces DNA damage

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-02-28 | GSE101776 | GEO

The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells.

Project description:Background and purposeThe catalytic topoisomerase II inhibitor dexrazoxane has been associated not only with improved cancer patient survival but also with secondary malignancies and reduced tumour response.Experimental approachWe investigated the DNA damage response and the role of the activating transcription factor 3 (ATF3) accumulation in tumour cells exposed to dexrazoxane.Key resultsDexrazoxane exposure induced topoisomerase IIα (TOP2A)-dependent cell death, γ-H2AX accumulation and increased tail moment in neutral comet assays. Dexrazoxane induced DNA damage responses, shown by enhanced levels of γ-H2AX/53BP1 foci, ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), Chk1 and Chk2 phosphorylation, and by p53 accumulation. Dexrazoxane-induced γ-H2AX accumulation was dependent on ATM. ATF3 protein was induced by dexrazoxane in a concentration- and time-dependent manner, which was abolished in TOP2A-depleted cells and in cells pre-incubated with ATM inhibitor. Knockdown of ATF3 gene expression by siRNA triggered apoptosis in control cells and diminished the p53 protein level in both control and dexrazoxane -treated cells. This was accompanied by increased γ-H2AX accumulation. ATF3 knockdown also delayed the repair of dexrazoxane -induced DNA double-strand breaks.Conclusions and implicationsAs with other TOP2A poisons, dexrazoxane induced DNA double-strand breaks followed by activation of the DNA damage response. The DNA damage-triggered ATF3 controlled p53 accumulation and generation of double-strand breaks and is proposed to serve as a switch between DNA damage and cell death following dexrazoxane treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with dexrazoxane.

| S-EPMC4403091 | biostudies-literature

Topoisomerase poisoning by the flavonoid nevadensin triggers DNA damage and apoptosis in human colon carcinoma HT29 cells.

Project description:Nevadensin, an abundant polyphenol of basil, is reported to reduce alkenylbenzene DNA adduct formation. Furthermore, it has a wide spectrum of further pharmacological properties. The presented study focuses the impact of nevadensin on topoisomerases (TOPO) in vitro. Considering the DNA-intercalating properties of flavonoids, first, minor groove binding properties (IC50 = 31.63 µM), as well as DNA intercalation (IC50 = 296.91 µM) of nevadensin, was found. To determine potential in vitro effects on TOPO I and TOPO IIα, the relaxation and decatenation assay was performed in a concentration range of 1-500 µM nevadensin. A partial inhibition was detected for TOPO I at concentrations ≥ 100 µM, whereas TOPO IIα activity is only inhibited at concentrations ≥ 250 µM. To clarify the mode of action, the isolating in vivo complex of enzyme assay was carried out using human colon carcinoma HT29 cells. After 1 h of incubation, the amount of TOPO I linked to DNA was significantly increased by nevadensin (500 µM), why nevadensin was characterized as TOPO I poison. However, no effects on TOPO IIα were detected in the cellular test system. As a subsequent cellular response to TOPO I poisoning, a highly significant increase of DNA damage after 2 h and a decrease of cell viability after 48 h at the same concentration range were found. Furthermore, after 24 h of incubation a G2/M arrest was observed at concentrations ≥ 100 µM by flow cytometry. The analysis of cell death revealed that nevadensin induces the intrinsic apoptotic pathway via activation of caspase-9 and caspase-3. The results suggest that cell cycle disruption and apoptotic events play key roles in the cellular response to TOPO I poisoning caused by nevadensin in HT29 cells.

| S-EPMC8536574 | biostudies-literature

DNA damage responsive microRNAs misexpressed in human cancer regulate chemotherapy sensitivity

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-05-31 | E-GEOD-47526 | biostudies-arrayexpress

Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells.

Project description:Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of ?-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition.

| S-EPMC4588569 | biostudies-literature

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