Mapping of TOP1cc and R-loops im MCF-7 after TOP1 KD and/or RNase H OE [CHiP_DRIP_Seq]
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PROVIDER: PRJNA1007673 | ENA |
REPOSITORIES: ENA
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Project description:DNA double-stranded breaks (DSBs) pose a significant threat to genomic integrity, and their generation during essential cellular processes like transcription remains poorly understood. In this study, we employed DRIP-seq and ChIP-seq to map the change in TOP1cc and R-loops after the depletion of TOP1 and R-loops, to comprehensively investigate the interplay between transcription, DSBs, Topoisomerase 1 (TOP1), and R-loops. Our findings revealed the presence of DSBs at highly expressed genes enriched with TOP1 and R-loops, indicating their crucial involvement in transcription-associated genomic instability. Depletion of R-loops and TOP1 specifically reduced DSBs at highly expressed genes, uncovering their pivotal roles in transcriptional DSB formation. By elucidating the intricate interplay between TOP1cc trapping, R-loops, and DSBs, our study provides novel insights into the mechanisms underlying transcription-associated genomic instability. Moreover, we establish a link between transcriptional DSBs and early molecular changes driving cancer development. Notably, our study highlights the distinct etiology and molecular characteristics of driver mutations compared to passenger mutations, shedding light on the potential for targeted therapeutic strategies. Overall, these findings deepen our understanding of the regulatory mechanisms governing DSBs in hypertranscribed genes associated with carcinogenesis, opening avenues for future research and therapeutic interventions.
2024-05-22 | GSE241307 | GEO
Project description:DNA double-stranded breaks (DSBs) pose a significant threat to genomic integrity, and their generation during essential cellular processes like transcription remains poorly understood. In this study, we employed CEL-seq technique to investigate the effect of TOP1 KD and RNase H OE on transcriptional profile, with the different genetic manipulations. Our findings revealed the presence of DSBs at highly expressed genes enriched with TOP1 and R-loops, indicating their crucial involvement in transcription-associated genomic instability. Depletion of R-loops and TOP1 specifically reduced DSBs at highly expressed genes, uncovering their pivotal roles in transcriptional DSB formation. By elucidating the intricate interplay between TOP1cc trapping, R-loops, and DSBs, our study provides novel insights into the mechanisms underlying transcription-associated genomic instability. Moreover, we establish a link between transcriptional DSBs and early molecular changes driving cancer development. Notably, our study highlights the distinct etiology and molecular characteristics of driver mutations compared to passenger mutations, shedding light on the potential for targeted therapeutic strategies. Overall, these findings deepen our understanding of the regulatory mechanisms governing DSBs in hypertranscribed genes associated with carcinogenesis, opening avenues for future research and therapeutic interventions.
2024-05-22 | GSE241306 | GEO
Project description:Effect of TOP1 knockdown and/or RNase H OE on the transcriptional profile of MCF-7 cells [CEL_Seq]
| PRJNA1007671 | ENA
Project description:DNA topoisomerases solve topological problems during chromosome metabolism. We investigated where and when Top1 and Top2 are recruited on replicating chromosomes and how their inactivation affects fork integrity and DNA damage checkpoint activation. We show that, in the context of replicating chromatin, Top1 and Top2 act within a 600 bp region spanning the moving forks. Top2 exhibits additional S-phase clusters at specific intergenic loci, mostly containing promoters. TOP1 ablation does not affect fork progression and stability and does not cause activation of the Rad53 checkpoint kinase. top2 mutants accumulate sister chromatid junctions in S phase without affecting fork progression and activate Rad53 at the M/G1 transition. top1 top2 double mutants exhibit fork block and processing, and phosphorylation of Rad53 and γH2A in S phase. The exonuclease Exo1 influences fork processing and DNA damage checkpoint activation in top1 top2 mutants. Our data are consistent with a coordinated action of Top1 and Top2 in counteracting the accumulation of torsional stress and sister chromatid entanglement at replication forks, thus preventing the diffusion of topological changes along large chromosomal regions. A failure in resolving fork-related topological constrains during S phase may therefore result in abnormal chromosome transitions, DNA damage checkpoint activation and chromosome breakage during segregation. Keywords: ChIP-chip analysis
2007-08-01 | GSE8305 | GEO
Project description:Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. We found that Top1 cKO neurons developed properly but then showed biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degenerated. We used single-cell RNA-seq to verify cell-type decreases in long-gene expression as well as investigate how TOP1 loss may lead to premature neuronal death.
2020-03-10 | GSE146672 | GEO
Project description:Physiological and pathogen-induced oscillations in the plant cells' redox environment trigger response mechanisms that involve redox-sensitive cysteines and consequent changes in proteins' biochemical and functional characteristics. Arabidopsis thimet oligopeptidases (TOPs) TOP1 and TOP2 are components of the immune signaling and oxidative stress response. Here, TOP1 and TOP2 were evaluated comparatively to understand their role as redox sensors. We show that TOPs catalytic activity is augmented in plants undergoing an immune response and in mutant lines with altered expression of the chloroplastic NTRC impaired in the chloroplast thiol-disulfide regulatory system; ntrc was unable to mount a systemic immune response. Oxidation promoted TOP1 self-interaction to dimers and oligomers; Cys-to-Ala mutagenesis of multiple Cys residues inhibited TOP1 oxidative self-interaction. In contrast, TOP1 lacking the signal peptide (ΔSPTOP1) and TOP2 were detected solely as monomers. Treatment with oxidized glutathione increased the catalytic activities of TOPs; Ala substitution of the unique Cys405 of TOP2 abolished its oxidative activation. The immune regulator ROC1 was identified as a candidate TOPs substrate. TOPs cleaved a ROC1 peptide (ROC1p) at similar and unique cleavage sites; ROC1p concentration helped determine TOPs cleavage specificity. We propose that TOP1 and TOP2 form a proteolysis couple with divergent redox-sensing mechanisms and specificity.
2021-04-19 | PXD024059 | Pride
Project description:IM CD34+ vs BM CD34+ cells Keywords: parallel sample
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Project description:MeGRX232 and MeGRX360 are drought-inducible CC-type glutaredoxins in cassava. Overexpression of them in Arabidopsis caused different effects on plant growth. We used microarray to identified the different expression genes in MeGRX232-OE and MeGRX360-OE Arabidopsis
2016-05-06 | GSE81136 | GEO
Project description:RNAseq transcriptome of IRON MAN1 OE line. IMA1 OE plants accumulate Fe in their tissue and exhibit a constitutive induction of their root Fe uptake system.
2016-10-08 | GSE87745 | GEO