Disparity of histone deacetylase inhibition on repair of radiation-induced DNA damage on euchromatin and constitutive heterochromatin compartments.
Epigenetic regulation of chromatin structure is central to the process of DNA repair. A well-characterized epigenetic feature is the dynamic phosphorylation of the histone H2AX (gammaH2AX) and mobilization of double strand break (DSB) recognition and repair factors to the site. How chromatin structure is altered in response to DNA damage and how such alterations influence DSB repair mechanisms are currently relevant issues. Despite the clear link between histone deacetylases (HDACs) and radiosensitivity, how histone hyperacetylation influence DSB repair remains poorly understood. We have determined the structure of chromatin is a major factor determining radiosensitivity and repair in human cells. Trichostatin A (TSA) enhances radiosensitivity with dose modification factors of 1.2 and 1.9 at 0.2 and 1 microM, respectively. Cells treated with TSA causing hyperacetylation and remodelling on euchromatic alleles coexist with gammaH2AX accumulation in radiosensitized cells. Formation of gammaH2AX on heterochromatin was significantly reduced even when cells were treated with TSA, suggesting that chromatin structure and histone hyperacetylation are pronounced features of radiation sensitivity and repair in euchromatic regions.
Karagiannis
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Trescowthick Research Laboratories, Department of Molecular Radiation Biology, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Harikrishnan
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El-Osta
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D000107:Acetylation / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022041:Euchromatin / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D006570:Heterochromatin / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020014:K562 Cells; D013997:Time Factors
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D022041:Euchromatin; D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D020169:Caspases; D006655:Histone Deacetylases