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

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

PROVIDER: PRJNA998813 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25430863_1.fastq.gz	Fastqsanger.gz
	SRR25430863_2.fastq.gz	Fastqsanger.gz
	SRR25430864_1.fastq.gz	Fastqsanger.gz
	SRR25430864_2.fastq.gz	Fastqsanger.gz
	SRR25430865_1.fastq.gz	Fastqsanger.gz

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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 [DRIP-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 | GSE239326 | GEO

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 [END-seq]

2024-06-05 | GSE239327 | GEO

Topoisomerase I Poisoning by Electrophiles Derived from Oxidative Stress

Project description:The cancer target enyzme topoisomerase 1 transiently cleaves one strand of chromosomal DNA to relax accumulated strain that can prevent transcription, replication or chromatin assembly. The topoisomerase 1 poison camptothecin and its synthetic analogs are widely used chemotherapeutics that act by trapping the enzyme on DNA in a ‘covalent complex’, resulting in persistent DNA damage and cell death. The prevailing model, interfacial inhibition, contends that the covalent complex is trapped by drug binding alone. In contrast, here we show that camptothecins produce extensive oxidative stress and that topoisomerase 1 is reactive with electrophilic second messengers of oxidative damage. We show that blocking oxidative stress in cells inhibits covalent complex formation by camptothecin, while electrophiles such as 4-hydroxynonenal are able to induce covalent complex formation in cells on their own. Towards mechanism of action, we show that 4-hydroxynonenal electrophilically modifies a cysteine within the DNA-binding active site of human topoisomerase 1. Taken together, our results suggest a mechanism in which oxidative stress mediates the effects of many topoisomerase 1 poisons, and suggest that this critical DNA-regulating enzyme may have a dual role as a sensor of cellular redox stress, linking oxidative stress to DNA damage response in cancer cells.

2021-03-24 | PXD018549 | Pride

Interferon-dependent R-loop Induction by Zika Virus Contributes to Growth Attenuation [U251 DRIP-Seq]

Project description:Zika virus (ZIKV) infection in human neural progenitors triggers DNA damage and activates DNA damage response, leading to cell cycle arrest that can retard brain development. Here we link the ZIKV- induced S phase arrest to replication fork stalling and R-loop induction. DRIP-seq reveals that ZIKV infection induces R-loops at specific loci strongly enriched in the interferon-stimulated genes (ISGs). Bru-seq results further indicate that nascent ISGs transcripts are prone to R-loop induction upon infection. Knockout of interferon receptor eliminated the R-loops on ISGs and partially rescued S phase arrest in infected cells. And overexpression of RNaseH1 reduced ZIKV-mediated DNA damage and cell cycle arrest. We conclude that unscheduled expression of ISGs induced by ZIKV alters R-loop homeostasis and perturbs replication fork progression, leading to fork stalling and eventually DNA damage. IFN- dependent R-loop induction represents a previously unknown, nucleic acid-based mechanism for cell cycle arrest.

2025-05-29 | GSE274207 | GEO

R-loop landscapes in Rice (Oryza sativa) [DRIP-seq]

Project description:R-loop landscapes in Rice (Oryza sativa) [DRIP-seq]

| PRJNA495027 | ENA

Identification of biomarkers of central nervous system damage in mice of benzene poisoning based on TMT proteomics

Project description:Benzene is known to be a common toxic industrial chemical, and prolonged benzene exposure may cause nervous system damage. At present, there were few studies on benzene-induced neurological damage. This research aimed to identify protein biomarkers to predict central nervous system damage of benzene poisoning. We established a benzene poisoning model of C57 mice by gavage of benzene-peanut oil suspension and identified differentially expressed proteins (DEPs) in brain tissue using TMT proteomics. The results showed a significant weight loss and decrease in leukocyte and neutrophil counts in benzene poisoning mice compared to the control group. We also observed significant cerebral oedema and enhanced basophilic of neurons in the hippocampus in benzene poisoning group of mice. TMT proteomic results showed that a total 6985 proteins were quantified, with a Fold Change (FC) > 1.2 (or <1/1.2) and P value <0.05 were considered as DEPs. Compared with the control group, we identified 43 DEPs, comprising 14 upregulated and 29 downregulated proteins. KEGG pathway analysis showed that the candidate proteins were mainly involved in cholesterol metabolism, complement and coagulation cascades, african trypanosomiasis, PPAR signaling pathway and vitamin digestion and absorption. Three proteins, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (UGT8), Apolipoprotein A-I (APOA1) and Complement C3 (C3) were validated using immunoblotting and immunohistochemical. In conclusion, our results may provide some molecular biomarkers for identifying the nervous system damage of benzene poisoning.

2025-05-06 | PXD046028 | Pride

Drivers of topoisomerase II poisoning mimic and complement cytotoxicity in AML cells

Project description:Drivers of topoisomerase II poisoning mimic and complement cytotoxicity in AML cells

| PRJNA523616 | ENA

CLCF1/NF-κB signaling pathway regulates macrophage efferocytosis to ameliorate neurological damage and cognitive dysfunction following CO poisoning

Project description:Severe carbon monoxide (CO) poisoning can induce structural damage to the nervous system, leading to long-term cognitive dysfunction in patients. The proper termination of the inflammatory response caused by neuronal cell damage is a prerequisite for tissue repair. Macrophages can clear cell corpses/fragments caused by brain injury through efferocytosis and produce cytokines to coordinate immune responses, thereby promoting neuronal repair and regeneration. However, in the microenvironment of the nervous system affected by CO poisoning, the function of macrophages is inhibited. Our study found that CLCF1 can regulate the secretion of cytokines such as TNF-α, IL-1β, and IL-10 through the NF-κB signaling pathway, thereby affecting neuronal cell repair and regeneration.

2024-01-01 | GSE250190 | GEO

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