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The kinase inhibitor GNF-7 is synthetically lethal in topoisomerase 1 deficient Ewing Sarcoma

ABSTRACT: Relapsed Ewing sarcoma is treated with TOP1 inhibitors. Our study confirmed prior studies showing that downregulation of TOP1 is a mechanism of resistance to camptothecin. We then screened a large library of clinically relevant compounds and found that TOP1-deficient Ewing sarcoma cells are more sensitive to the kinase inhibitor GNF-7. RNA-seq results reveal that GNF-7 modulates EWS/FLI1 gene signatures in both TOP1 wild type and TOP1-deficient cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298880 | GEO | 2025/08/20

REPOSITORIES: GEO

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The kinase inhibitor GNF-7 is synthetically lethal in topoisomerase 1 deficient Ewing Sarcoma

Project description:The kinase inhibitor GNF-7 is synthetically lethal in topoisomerase 1 deficient Ewing Sarcoma

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

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

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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).

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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.

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

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Non-Classical Functions of Human Topoisomerase I: Genome-wide and Pharmacological Analyses

Project description:The biological functions of nuclear topoisomerase I (Top1) have been difficult to study because knocking out TOP1 is lethal in metazoans. To reveal the functions of human Top1, we have generated stable Top1siRNA cell lines from colon and breast carcinomas (HCT116-siTop1 and MCF-7-siTop1, respectively). In those cells, Top2 compensates for Top1 deficiency. A prominent feature of the siTop1 cells is genomic instability, with chromosomal aberrations and histone gamma-H2AX foci associated with replication. siTop1 cells also show rDNA and nucleolar alterations, and increased nuclear volume. Genome-wide transcription profiling revealed 55 genes with consistent changes in siTop1 cells. Among them, asparagine synthetase (ASNS) was reduced in siTop1 cells, as it also was in cells with transient Top1 downregulation. Conversely, Top1 complementation increased ASNS, indicating a causal link between Top1 and ASNS expression. Correspondingly, pharmacological profiling showed l-asparaginase hypersensitivity in the siTop1 cells. Resistance to camptothecin, aphidicolin, hydroxyurea and staurosporine, and hypersensitivity to etoposide and actinomycin D demonstrated that Top1, in addition to being the target of camptothecins, also regulates DNA replication, rDNA stability and apoptosis. Overall, our studies demonstrate the pleiotropic nature of human Top1 activities. In addition to its classical DNA nicking-closing functions, Top1 plays critical non-classical roles in genomic stability, gene-specific transcription, and response to various anticancer agents. Keywords: genetic modification design

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siRNA profiling of stable HCT116-siTop1 and MCF-7-siTop1 cell lines reveal non-classical functions of human Topoisomerase I:

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