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

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

PROVIDER: PRJNA998812 | ENA |

REPOSITORIES: ENA

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

| PRJNA998813 | ENA

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 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

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

Topoisomerase 1 dependent R-loop deficiency drives accelerated replication and genomic instability

Project description:DNA replication is a complex process tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Replication stress is commonly associated with slow and stalled replication forks. Recently, accelerated replication has emerged as a non-canonical form of replication stress. However, the molecular basis underlying fork acceleration is largely unknown. Here we show that mutated HRAS activation leads to increased topoisomerase 1 (TOP1) expression leading to aberrant replication fork acceleration and DNA damage by decreasing RNA-DNA hybrids or R-loops. In these cells, restoration of TOP1 expression or mild replication inhibition rescues the perturbed replication and reduces DNA damage. Furthermore, TOP1 or RNaseH1 overexpression induces accelerated replication and DNA damage, highlighting the importance of TOP1 equilibrium in regulating R-loop homeostasis to ensure faithful DNA replication and genome integrity. Altogether, our results reveal a novel mechanism of oncogene-induced DNA damage induced by aberrant replication fork acceleration.

2022-09-08 | GSE168738 | GEO

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 Neural Damage and Cognitive Dysfunction After CO Poisoning.

Project description:Severe carbon monoxide (CO) poisoning can cause structural damage to the nervous system, leading to long-term cognitive dysfunction in patients. Correctly terminating the inflammatory response caused by neuronal damage is a prerequisite for tissue repair. Macrophages can clear the cell corpses/fragments caused by brain injury through efferocytosis, and produce cytokines to coordinate the immune response, promoting neuronal repair and regeneration. However, in the microenvironment of the nervous system affected by CO poisoning, the function of macrophages is inhibited. Our research 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 neural cell repair and regeneration. Simultaneously, CLCF1 can regulate the efferocytosis function of macrophages, thus controlling the degree of inflammation and assisting in the repair of the damaged nervous system. In experiments, it was observed that targeting the regulation of macrophage CLCF1 expression led to improvements in memory, learning, and motor abilities in rats poisoned with CO.

2024-04-07 | GSE262987 | GEO

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

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

2024-06-05 | GSE239328 | GEO