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Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin

ABSTRACT: The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a “cleavable complex”. To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment affected transcription initiation, elongation, termination, splicing and enhancer activity. Following removal of camptothecin, transcription spread as a wave from the 5’-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. In addition, a set of mitotic regulator genes and histone genes were inhibited in a size-independent manner. Cockayne syndrome group B fibroblasts showed a very similar RNA synthesis recovery profile to normal fibroblasts suggesting that transcription-coupled repair is not involved in the repair of transcription-blocking TOP1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48678 | GEO | 2013/10/29

SECONDARY ACCESSION(S): PRJNA211115

REPOSITORIES: GEO

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Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin

Project description:The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a M-bM-^@M-^\cleavable complexM-bM-^@M-^]. To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment affected transcription initiation, elongation, termination, splicing and enhancer activity. Following removal of camptothecin, transcription spread as a wave from the 5M-bM-^@M-^Y-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. In addition, a set of mitotic regulator genes and histone genes were inhibited in a size-independent manner. Cockayne syndrome group B fibroblasts showed a very similar RNA synthesis recovery profile to normal fibroblasts suggesting that transcription-coupled repair is not involved in the repair of transcription-blocking TOP1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons. Analysis of the effect of Camptothecin (CPT) on transcription. Normal fibroblasts and Cockayne syndrome group B fibroblasts were exposed to CPT for 60 minutes, after which a washout was performed. Nascent RNA was labeled using bromouridine for 15 minutes starting at time points: 1) 15 minutes before the washout; 2) Immediately after the washout; 3) 15 minutes after the washout. Test samples are compared to control cells that were not exposed to CPT.

2013-10-29 | E-GEOD-48678 | biostudies-arrayexpress

Expression data from camptothecin-treated rat primary motor neurons

Project description:Topoisomerase 1 (TOP1) poisons like camptothecin (CPT), which are used as chemotherapeutic agents in cancer, elicit DNA damage in quiescient neurons. In this study, we examined the effects of CPT and actinomycin D (ActD) on neuronal cells. Motor (MNs) and cortical (CNs) neurons were more susceptible to the toxic effects of CPT and ActD than fibroblasts. MNs and CNs exhibited a delayed DNA damage response—increase in nuclear γ-H2AX foci—relative to fibroblasts. Neuronal cells expressed higher levels of Top1 mRNA than fibroblasts which could explain their enhanced vulnerability to CPT and ActD toxicity. Microarray analysis was performed to identify differentially regulated transcripts in MNs treated with CPT for 2 hours. Many immediate-early genes including Fos and Egr-1 were upregulated in CPT-treated MNs. Fos mRNA levels were elevated in all cells types treated with CPT; Egr-1 transcript levels, however, were reduced in CPT-treated fibroblasts even though they were elevated in treated MNs and CNs. Pathway and network analysis of the differentially expressed transcripts revealed activation of ERK and JNK signaling cascades in CPT-treated MNs. In conclusion, MNs were more vulnerable than fibroblasts to the damaging effects of TOP1 poisons and they elicit a unique intracellular response to CPT treatment.

2016-09-20 | GSE67146 | GEO

Untreated vs. Camptothecin Treated HeLa cells

Project description:Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin. The response of tumor cells to the unusual form of DNA damage caused by topoisomerase poisons such as camptothecin (CPT) is poorly understood, and knowledge regarding which drugs can be effectively combined with CPT is lacking. To better understand the response of tumor cells to CPT and to identify potential targets for adjuvant therapy, we examined global changes in mRNA abundance in HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include all annotated human genes (22,283 probe sets). Statistical analysis of the data using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction for multiple hypotheses testing identified 188 probe sets that are induced and 495 that are repressed 8 h after CPT treatment at a False Discovery Rate of <0.05 and a minimum 3-fold change. This pharmacogenomic approach led us to identify two pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b) nuclear factor-kappaB-regulated antiapoptotic factors. Experiments using HeLa cells in our lab and prior animal model studies performed elsewhere confirm that inhibitors of these respective pathways super-additively enhance CPT's cytotoxicity, suggesting their potential as targets for adjuvant therapy with CPT. Cancer Res. 2004 Mar 15;64(6):2096-104 Keywords = HeLa Keywords = Camptothecin Keywords: ordered

2004-05-18 | GSE1417 | GEO

Topoisomerase I cleavage complexes preferentially down-regulate ubiquitin- and RNA degradation-related transcripts in relationship to gene length, exon-intron junctions and p53-dependent up-regulation of miR-142-3p [miRNA]

Project description:DNA topoisomerase I (Top1) is required for transcription as it relaxes positive and negative supercoils by forming transient Top1 cleavage complexes (Top1cc) up- and down-stream of transcription complexes. However, Top1cc can also be trapped by endogenous DNA lesions and by camptothecin (CPT) and its anticancer derivatives, which results in transcription blocks. Here, we undertook a genome-wide analysis of the effects of CPT on gene expression at exon resolution. We tested the impact of Top1 inhibition on miRNA expression at the genome-wide level in human colon carcinoma HCT116. The miRNA of cells treated with camptothecin (CPT) for were measured at several timepoints with Agilent Human miRNA Microarray V3 (8x15K).

2013-04-17 | E-GEOD-37357 | biostudies-arrayexpress

Transcription profiling of human Hela cells treated with the topoisomerase poison camptothecin

2007-07-29 | E-GEOD-1417 | biostudies-arrayexpress

Camptothecin-miRNA

Project description:DNA Topoisomerase I inhibition by Camptothecin (CPT) derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of CPT effects on HIF-1alpha activity in human cancer cells. In particular, we provide evidence that low concentrations of CPT, without interfering with HIF-1alpha mRNA levels, can reduce HIF-1alpha protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1alpha mRNA 3M-^RUTR in CPT-induced impairment of HIF-1alpha protein regulation, we performed microarray analysis to identify CPT-induced modification of miRNAs targeting HIF-1alpha mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed demonstrating a role for miR-17-5p and miR-155 in HIF-1alpha protein expression after CPT treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1alpha protein regulation and activity, widening the biological and molecular activity of CPT derivatives and the perspective for novel clinical interventions.

2013-12-02 | E-MTAB-2022 | biostudies-arrayexpress

Transcription poisoning by topoisomerase I is controlled by gene length, splice sites and miR-142-3p

Project description:DNA topoisomerase I (Top1) is required for transcription as it relaxes positive and negative supercoils by forming transient Top1 cleavage complexes (Top1cc) up- and down-stream of transcription complexes. However, Top1cc can also be trapped by endogenous DNA lesions and by camptothecin (CPT) and its anticancer derivatives, which results in transcription blocks. Here, we undertook a genome-wide analysis of the effects of CPT on gene expression at exon resolution. We tested the impact of Top1 inhibition on gene expression at the genome-wide level in human colon carcinoma HCT116 and human breast carcinoma MCF7 cells. The RNA of cells treated with camptothecin (CPT) for various times was analyzed with Affy Exon array (GeneChip Human Exon 1.0 ST array). Moreover, we tested the impact of Top1 down-regulation on gene expression at the genome-wide level in human colon carcinoma HCT116 cells. The RNA of cells treated transfected with a Top1 siRNA was analyzed with Affy Exon array (GeneChip Human Exon 1.0 ST array).

2013-04-17 | E-GEOD-37352 | biostudies-arrayexpress

miRNA Profiles of Camptothecin-Sensitive and Resistant Jurkat T-Cells

Project description:MicroRNAs which are non-coding RNAs 19-25 nt in length regulate gene expression at post-transcriptional and translational stages. Although it is known that they play a role in critical processes such as development and differentiation of T cells, a major component of the immune system, the function of miRNAs in T cell apoptosis is unknown. This study has aimed to identify miRNAs’ involvement in camptothecin-induced T cell apoptosis in the Jurkat T cell leukemia cell line model. Following the enrichment of the apoptotic population by magnetic seperation, the negative and apoptotic fractions were profilled and compared according to the expression levels of microRNAs.

2018-11-13 | GSE37763 | GEO

Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

Project description:Topoisomerase 1 (TOP1) inhibitors, including camptothecin and topotecan, covalently trap TOP1 on DNA, creating cleavage complexes (cc’s) that must be resolved before gene transcription and DNA replication can proceed. We previously found that topotecan reduces the expression of long (>100 kb) genes and unsilences the paternal allele of Ube3a in neurons. Here, we sought to evaluate overlap between TOP1cc-dependent and -independent gene regulation in neurons. To do this, we utilized Top1 conditional knockout mice, Top1 knockdown, the CRISPR-Cas9 system to delete Top1, TOP1 catalytic inhibitors that do not generate TOP1cc’s, and a TOP1 mutation (T718A) that stabilizes TOP1cc’s. We found that topotecan treatment significantly alters the expression of many more genes, including long neuronal genes, immediate early genes, and paternal Ube3a, when compared to Top1 deletion. Our data show that topotecan has a stronger effect on neuronal transcription than Top1 deletion, and identifies TOP1cc-dependent and -independent contributions to gene expression.

2016-05-27 | GSE79951 | GEO

Genome-wide analysis of novel splice variants induced by topoisomerase I poisoning shows preferential occurrence in genes encoding splicing factors

Project description:Topoisomerase I (Top1) relaxes both positive and negative supercoilings by producing transient Top1 cleavage complexes (Top1cc). Several studies have suggested the implication of Top1 in splicing. Here, we tested the implication of Top1cc in splicing at the global genome level in human carcinoma cells to determine whether Top1 inhibition selectively affects particular families of genes. We tested the impact of Top1 inhibition on splicing at the genome-wide level in human colon carcinoma HCT116 cells. The RNA of HCT116 cells treated with camptothecin (CPT) for various times was analyzed with ExonHit Human Splice Array.

2011-07-21 | E-GEOD-23677 | biostudies-arrayexpress

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