Chromatin structure influences the sensitivity of DNA to gamma-radiation.
For the first time, DNA double-strand breaks (DSBs) were directly visualized in functionally and structurally different chromatin domains of human cells. The results show that genetically inactive condensed chromatin is much less susceptible to DSB induction by gamma-rays than expressed, decondensed domains. Higher sensitivity of open chromatin for DNA damage was accompanied by more efficient DSB repair. These findings follow from comparing DSB induction and repair in two 11 Mbp-long chromatin regions, one with clusters of highly expressed genes and the other, gene-poor, containing mainly genes having only low transcriptional activity. The same conclusions result from experiments with whole chromosome territories, differing in gene density and consequently in chromatin condensation. It follows from our further results that this lower sensitivity of DNA to the damage by ionizing radiation in heterochromatin is not caused by the simple chromatin condensation but very probably by the presence of a higher amount of proteins compared to genetically active and decondensed chromatin. In addition, our results show that some agents potentially used for cell killing in cancer therapy (TSA, hypotonic and hypertonic) influence cell survival of irradiated cells via changes in chromatin structure and efficiency of DSB repair in different ways.
Falk
Martin
M
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 61265 Brno, Czech Republic.
Lukásová
Emilie
E
Kozubek
Stanislav
S
D017209:Apoptosis / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000528:radiation effects*; D047369:Chromatin Immunoprecipitation; D003037:Cobalt Radioisotopes; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017404:In Situ Hybridization, Fluorescence; D016196:S Phase / Q000502:physiology / Q000528:radiation effects; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects
D002843:Chromatin; D003037:Cobalt Radioisotopes; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D004247:DNA; D006655:Histone Deacetylases