Point mutations in topoisomerase I alter the mutation spectrum in E. coli
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB35213 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3641390.fastq.gz | Fastqsanger.gz | |||
| ERR3641400.fastq.gz | Fastqsanger.gz | |||
| ERR3641410.fastq.gz | Fastqsanger.gz | |||
| ERR3641420.fastq.gz | Fastqsanger.gz | |||
| ERR3641430.fastq.gz | Fastqsanger.gz |
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Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology. [Mouse] 5 biological replicates of transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated controls; Pol2 ChIPseq of topotecan and vehicle treated neurons [Human] Transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated control.
2013-08-30 | E-GEOD-43526 | biostudies-arrayexpress
Project description:Identifying the molecular mechanisms that give rise to genetic variation is essential for the understanding of evolutionary processes. Previously, we have used adaptive laboratory evolution to enable biomass synthesis from CO2 in Escherichia coli. Genetic analysis of adapted clones from two independently evolving populations revealed distinct enrichment for insertion and deletion mutational events. Here, we follow these observations to show that mutations in the gene encoding for DNA topoisomerase I (topA) give rise to mutator phenotypes with characteristic mutational spectra. Using genetic assays and mutation accumulation lines, we find that point mutations in topA increase the rate of sequence deletion and duplication events. Interestingly, we observe that a single residue substitution (R168C) results in a high rate of head-to-tail (tandem) short sequence duplications, which are independent of existing sequence repeats. Finally, we show that the unique mutation spectrum of topA mutants enhances the emergence of antibiotic resistance in comparison to mismatch-repair (mutS) mutators, and leads to new resistance genotypes. Our findings highlight a potential link between the catalytic activity of topoisomerases and the fundamental question regarding the emergence of de novo tandem repeats, which are known modulators of bacterial evolution.
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Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology.
2013-08-30 | GSE43899 | GEO
Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology.
2013-08-30 | GSE43526 | GEO
Project description:Trovafloxacin is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. Specific members of this drug family display high activity against eukaryotic type II topoisomerase, as well as cultured mammalian cells and in vivo tumor models. Trovafloxacin seems to have a higher affinity for eukaryotic polymerase II system than the other quinolone agents tested. This effect coupled with other factors, such as an inflammatory response, might result in a hepatotoxic reaction seen with drug. In this study we found genes regulated by trovafloxacin - induced and repressed - to be located much closer to each other than genes distributed randomly all over the genome (< 100 kbp). Keywords: Trovafloxacin-treated human hepatocytes versus non-treated human hepatocytes
2008-10-01 | GSE11941 | GEO
Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology. 9 experiments, gene expression measured by Affymetrix microarray. 1) cultured mouse cortical neurons treated with 300nM topotecan vs vehicle-treated controls 2) cultured mouse neurons treated with 1uM topotecan vs vehicle-treated controls 3) cultured mouse cortical neurons treated with 3uM ICRF-193 vs vehicle-treated controls. 4) cultured mouse cortical neurons treated with 10 uM irinotecan vs vehicle-treated controls. 5) cultured mouse cortical neurons treated with 3-1000 nM topotecan vs vehicle treated controls 6) cultured mouse cortical neurons treated with lentivirus expressing shRNA against Top1 and Top2b vs scrambled shRNA controls 7) cultured mouse cortical neurons treated with DRB vs vehicle-treated controls 8) cultured mouse cortical neurons treated with hydrogen peroxide or paraquat vs vehicle-treated controls 9) cultured mouse cortical neurons treated with topotecan with or without subsequent drug washout, vs vehicle-treated controls.
2013-08-30 | E-GEOD-43899 | biostudies-arrayexpress
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
Project description:Topoisomerase 3β (TOP3B) and TDRD3 form a dual-activity topoisomerase complex that interacts with FMRP and can change the topology of both DNA and RNA. Here, we investigated the post-transcriptional influence of TOP3B and associated proteins on mRNA translation and turnover. First, we discovered that in human HCT116 colon cancer cells, knock-out (KO) of TOP3B had similar effects on mRNA turnover and translation as did TDRD3-KO, while FMRP-KO resulted in rather distinct effects, indicating that TOP3B had stronger coordination with TDRD3 than FMRP in mRNA regulation. Second, we identified TOP3B-bound mRNAs in HCT116 cells; we found that while TOP3B did not directly influence the stability or translation of most TOP3B target mRNAs, it stabilized a subset of target mRNAs but had a more complex effect on translation--enhancing for some mRNAs whereas reducing for others. Interestingly, a point mutation that specifically disrupted TOP3B catalytic activity only partially recapitulated the effects of TOP3B-KO on mRNA stability and translation, suggesting that the impact of TOP3B on target mRNAs is only in part linked to its ability to change topology of mRNAs. Collectively, our data suggest that TOP3B-TDRD3 can regulate mRNA translation and turnover by mechanisms that are dependent and independent of topoisomerase activity.
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