CX DHPG TRAP-seq
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA827184 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18774408_1.fastq.gz | Fastqsanger.gz | |||
| SRR18774408_2.fastq.gz | Fastqsanger.gz | |||
| SRR18774409_1.fastq.gz | Fastqsanger.gz | |||
| SRR18774409_2.fastq.gz | Fastqsanger.gz | |||
| SRR18774410_1.fastq.gz | Fastqsanger.gz |
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Project description:Sequencing files from TRAP-seq samples isolated from DHPG-stimulated WT and Fmr1-/y hippocampal slices incubated with vehicle or 200 nM CX-5461
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Project description:We discovered two small molecule drugs - CX-5461 and CX-3543 - with specific toxicity against BRCA deficiencies in cancer cells and xenograft models. Both CX-5461 and CX-3543 have been previously recognized as RNA pol I inhibitors. CX-5461 is in advanced phase 1 trials for treatment of lymphoma and leukemia through rDNA transcription inhibition in a p53-dependent mechanism. We have discovered a novel activity of CX-5461, as a stabilizer of G-quadruplex DNA sequences inside cells the same as CX-3543. We found that BRCA1 and BRCA2 deficiency markedly increases (one log order) sensitivity to CX-5461 and a related drug CX-3543 in human cancer cell lines and polyclonal patient derived xenograft models, providing a direct therapeutic hypothesis, including PDX tumours resistant to PARP inhibition. We show that in epithelial cells, exposure to CX-5461 and CX-3543 blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543 induced DNA damage and failure to do so leads to lethality. RNA pol I inhibition is not a required component of the cell killing mechanism in these tumours, because BRCA2 deficient cells are not more sensitive to BMH-21, a more potent rDNA transcription inhibitor. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumors deficient for DNA damage repair. Since CX-5461 is already in advanced phase 1 trials for other indications, this has resulted in immediately testable translational implications (Canadian trial, NCT02719977, opened May 2016) as no phase-1 eligible G4 stabilizers have been described to date.
2016-12-06 | GSE90967 | GEO
Project description:Rhodococcus sp. CX strain:CX Genome sequencing and assembly
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Project description:Culex pipiens pallens and Cx. p. quinquefasciatus are important vectors of many diseases, such as West Nile fever and lymphatic filariasis. The widespread use of insecticides to control these disease vectors and other insect pests has led to insecticide resistance becoming common in these species. High throughput screening using SSH and specific microarray platforms was thought to have identified some resistance-related genes. However, limitations of these methods meant that only a few hundred of the many thousand genes could be screened. It wasn’t until the sequencing of the Cx. quinquefasciatus genome in 2010 that it became possible to screen all 18.9 thousand genes in the mosquito genome for anti-insecticidal activity. We used high throughout Illumina sequencing to identify hundreds of Cx. p. pallens and Cx. p. quinquefasciatus genes that were differentially expressed in response to pesticide exposure. The identification of these genes is a vital first step for more detailed investigation of the molecular mechanisms involved in insecticide resistance in mosquitoes. In this study, larvae of Cx. pipiens pallens and Cx. pipiens quinquefasciatus were collected from field and transported to the laboratory and reared to adulthood to get F1 generation. Then, half of the F1 generation was conducted to pesticide bioassay. RNA extraction and Illumina sequencing were undertaken in another half of the F1 generation. Therefore, Samples used in Illumina sequencing did not contact any insecticides. Twelve Cx. pipiens pallens and Cx. pipiens quinquefasciatus lavae were undertaken Illumina RNA sequencing.
2014-05-07 | E-GEOD-57307 | biostudies-arrayexpress
Project description:In recent years, several small molecule cytotoxic drugs have been identified as potential inhibitors of ribosome biogenesis (Drygin et al., 2011; Peltonen et al., 2014a; Peltonen et al., 2014b). CX-5461 is one such drug that has also demonstrated anticancer potential for a wide range of malignancies (Bywater et al., 2012; Cornelison et al., 2017; Devlin et al., 2015; Drygin et al., 2011; Hald et al., 2019; Hein et al., 2017; Ismael et al., 2019; Lawrence et al., 2018; Lee et al., 2017; Negi and Brown, 2015; Taylor et al., 2019; Xu et al., 2017; Yan et al., 2017) (Haddach et al., 2012), and is presently under phase I trials for the treatment of both hematological cancers and solid tumours (Group, 2016; Khot et al., 2019). CX-5461 was initially characterized as an inhibitor of RNA Polymerase I (RPI/PolR1/PolI) that is responsible for the synthesis of the major ribosomal RNAs and the initial step in ribosome biogenesis (Drygin et al., 2011). Since RPI and its corresponding core transcription factors are dedicated to this task alone, they present ideal molecular targets by which to modulate ribosome biogenesis. However, the specificity of CX-5461 has been questioned and it has been suggested that this drug may also act by stabilizing DNA G-quadruplexes or by “poisoning” topoisomerase II (Topo II). Thus, the primary target of this drug and its mode of action are still in doubt. Here we used Deconvolution-ChIP-Seq in NIH3T3 and HEK293T cells treated for different times with CX-5461. The data show that the primary target of CX5461 is the initiation of ribosomal RNA gene (rDNA) transcription. CX-5461 blocks transcription initiation in vitro and in vivo by arresting RNA polymerase I (RPI/Pol1) within the preinitiation complex. In contrast to previous suggestions, CX-5461 does not effect recruitment of the TBP-TAF complex SL1 to the rDNA promoter, the recruitment of the initiation competent RPI-Rrn3 complex or ongoing transcription elongation, arguing against a role for G-quadruplex stabilization or topoisomerase II poisoning. Inhibition of transcription by CX-5461 is not reversible, the RPI-Rrn3 complex remains arrested in the preinitiation complex even after drug removal. This leads to nucleolar stress, extensive DNA damage and cell senescence. Our data show that the cytotoxicity of CX-5461 is the downstream result of the highly specific inhibition of rDNA transcription. The observation that this inhibition is irreversible will be important for the future design of chemotherapeutic strategies and the avoidance of drug resistance.
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