Effects of acetylation and deacetylation inhibitors on DNA double strand breaks repair and cell survival

Sammanfattning: During treatment with ionizing radiation (IR), cells are killed mainly due to ionizing radiation caused acute damage to DNA, such as double-strand breaks, where opposite DNA strands in close proximity are cut. To counteract toxicity of double-strand breaks, cells have evolved DNA damage repair systems such as homologous recombination and non-homologous end joining. An important factor regulating DNA repair after exposure to ionizing radiation is chromatin structure. Interfering with normal functions of chromatin remodelling results in reduced cell survival as seen with histone deacetylase (HDAC) inhibitors such as trichostatin A (TSA) which exhibits antitumoral effects in various cancers. Furthermore, TSA interferes with functions of DNA repair proteins similarly as histone acetyltransferase inhibitors, such as C646, however, the effect of these inhibitors on DNA repair is not fully characterized. In this study, DNA damage repair after exposure to TSA and C646 in combination with ionizing radiation was assessed and the results indicated that both TSA and C646 suppressed the survival and proliferation of cancer cells in a dose-dependent manner. When combined with radiation, clonogenic assay shows that C646 radiosensitized HCT116 cells. As measured with flow cytometry, the drugs had no significant effect on the H3K9ac and H3K9me3 histone modifications over the time course of 24 hours. Futhermore, TSA and C646 inhibited ionizing radiation induced foci (IRIF) formation of 53BP1but had no effects on the ability to repair radiation-induced DSBs.