PloS one, 2014-01, Vol.9 (1), p.e87203
2014
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- Autor(en) / Beteiligte
- Titel
- Histone deacetylase inhibitors selectively target homology dependent DNA repair defective cells and elevate non-homologous endjoining activity
- Ist Teil von
- PloS one, 2014-01, Vol.9 (1), p.e87203
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- We have previously used the ATAD5-luciferase high-throughput screening assay to identify genotoxic compounds with potential chemotherapeutic capabilities. The successful identification of known genotoxic agents, including the histone deacetylase inhibitor (HDACi) trichostatin A (TSA), confirmed the specificity of the screen since TSA has been widely studied for its ability to cause apoptosis in cancer cells. Because many cancers have acquired mutations in DNA damage checkpoints or repair pathways, we hypothesized that these cancers may be susceptible to treatments that target compensatory pathways. Here, we used a panel of isogenic chicken DT40 B lymphocyte mutant and human cell lines to investigate the ability of TSA to define selective pathways that promote HDACi toxicity. HDACi induced a DNA damage response and reduced viability in all repair deficient DT40 mutants although ATM-nulls were least affected. The most dramatic sensitivity was observed in mutants lacking the homology dependent repair (HDR) factor BLM or the non-homologous end-joining (NHEJ) and HDR factors, KU/RAD54, suggesting an involvement of either HDR or NHEJ in HDACi-induced cell death. To extend these findings, we measured the frequencies of HDR and NHEJ after HDACi treatment and monitored viability in human cell lines comparably deficient in HDR or NHEJ. Although no difference in HDR frequency was observed between HDACi treated and untreated cells, HDR-defective human cell lines were clearly more sensitive than wild type. Unexpectedly, cells treated with HDACis showed a significantly elevated NHEJ frequency. HDACi targeting drugs induced significant increases in NHEJ activity in human cell lines but did not alter HDR frequency. Moreover, HDR is required for cellular resistance to HDACi therapy; therefore, NHEJ does not appear to be a critical axis for HDACi resistance. Rather, HDACi compounds induced DNA damage, most likely double strand breaks (DSBs), and HDR proficiency is correlated with cell survival.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0087203Titel-ID: cdi_plos_journals_1491323984
- Format
- –
- Schlagworte
- Animals, Antigens, Nuclear - genetics, Antigens, Nuclear - metabolism, Apoptosis, B-Lymphocytes - cytology, B-Lymphocytes - drug effects, B-Lymphocytes - metabolism, Biochemistry, Biology, Biophysics, Biotechnology, Blotting, Western, Cancer, Cell cycle, Cell death, Cell survival, Cell Survival - drug effects, Cells (Biology), Cells, Cultured, Chemotherapy, Chickens, Damage, Defects, Deoxyribonucleic acid, DNA, DNA damage, DNA Damage - drug effects, DNA Damage - genetics, DNA End-Joining Repair - drug effects, DNA End-Joining Repair - genetics, DNA repair, DNA Repair - drug effects, DNA Repair - genetics, DNA-Binding Proteins - antagonists & inhibitors, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Drug delivery, Drugs, Electrophoresis, Gel, Pulsed-Field, Environmental health, Fluorescent Antibody Technique, Genetic aspects, Genomes, Genotoxicity, Health aspects, High-throughput screening, Histone deacetylase, Histone Deacetylase Inhibitors - pharmacology, Homology, Humans, Hydroxamic Acids - pharmacology, Kinases, Ku Autoantigen, Luciferases - metabolism, Lymphocytes, Lymphocytes B, Medical schools, Medicine, Molecular biology, Mutants, Mutation, Mutation - genetics, Neoplasms - drug therapy, Neoplasms - genetics, Neoplasms - pathology, Non-homologous end joining, Phosphorylation, Proteins, Rad51 Recombinase - antagonists & inhibitors, Rad51 Recombinase - genetics, Rad51 Recombinase - metabolism, RecQ Helicases - genetics, RecQ Helicases - metabolism, Repair, RNA, Small Interfering - genetics, Toxicity, Trichostatin A, Viability, Vorinostat