ArticlePloS one2010
Topoisomerase II-mediated DNA damage is differently repaired during the cell cycle by non-homologous end joining and homologous recombination.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 48 citations in OpenAlex.
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- HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.Inflammopharmacology · 2024Review
- DNA-PK inhibition extends the therapeutic effects of Top2 poisoning to non-proliferating cells, increasing activity at a cost.Scientific reports · 2023Article
- Exploring the Molecular Players behind the Potentiation of Chemotherapy Effects by Durvalumab in Lung Adenocarcinoma Cell Lines.Pharmaceutics · 2023Article
- Anti-cancer potency by induced apoptosis by molecular docking P53, caspase, cyclin D1, cytotoxicity analysis and phagocytosis activity of trisindoline 1,3 and 4.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2022Article
- Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells.Journal of experimental & clinical cancer research : CR · 2022Article
- Utility of a next-generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide.Environmental and molecular mutagenesis · 2021Review
- Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play.Translational oncology · 2021Review
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- Fatherhood and Sperm DNA Damage in Testicular Cancer Patients.Frontiers in endocrinology · 2018Review
- Macrophages and Galectin 3 Control Bacterial Burden in Acute and Subacute Murine Leptospirosis That Determines Chronic Kidney Fibrosis.Frontiers in cellular and infection microbiology · 2018Article
- Review
- DNA double-strand breaks with 5' adducts are efficiently channeled to the DNA2-mediated resection pathway.Nucleic acids research · 2016Article
- Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs-deficient context.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2015Article
- Article
- Article
- TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo.PLoS genetics · 2013Article
- Prognostic values of filamin-A status for topoisomerase II poison chemotherapy.International journal of biological sciences · 2012Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2alpha was largely responsible for the induction of gammaH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. As DSB resulting from Top2 poisons-mediated damage may be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR), we aimed to analyze both DNA repair pathways. We found that DNA-PKcs was rapidly activated in human cells, as evidenced by autophosphorylation at serine 2056, following Top2-mediated DNA damage. The chemical inhibition of DNA-PKcs by wortmannin and vanillin resulted in an increased accumulation of DNA DSB, as evaluated by the comet assay. This was supported by a hypersensitive phenotype to Top2 poisons of Ku80- and DNA-PKcs- defective Chinese hamster cell lines. We also showed that Rad51 protein levels, Rad51 foci formation and sister chromatid exchanges were increased in human cells following Top2-mediated DNA damage. In support, BRCA2- and Rad51C- defective Chinese hamster cells displayed hypersensitivity to Top2 poisons. The analysis by immunofluorescence of the DNA DSB repair response in synchronized human cell cultures revealed activation of DNA-PKcs throughout the cell cycle and Rad51 foci formation in S and late S/G2 cells. Additionally, we found an increase of DNA-PKcs-mediated residual repair events, but not Rad51 residual foci, into micronucleated and apoptotic cells. Therefore, we conclude that in human cells both NHEJ and HR are required, with cell cycle stage specificity, for the repair of Top2-mediated reversible DNA damage. Moreover, NHEJ-mediated residual repair events are more frequently associated to irreversibly damaged cells.
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