Chromatin structure influences the sensitivity of DNA to γ-radiation

Abstract

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.

Imaging of the DNA damage‐induced dynamics of nuclear proteins via nonlinear photoperturbation

“…Since we cannot exclude the presence of less dense patches of DNA at the periphery of the nucleolus, this result highlights the sensitivity of our method with respect to chromatin structure. The observation is also consistent with the reduced susceptibility to damage and slower decondensation of highly compacted chromatin regions supporting the validity of our approach [25][26][27]. Our data are also in accordance with the slower kinetics and less efficient DNA repair in heterochromatin as compared to euchromatin [28].…”

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

“…The loss of accessibility is accompanied by a gain of H3, indicating that the progressively occurring chromatin compaction is achieved either by active chromatin remodeling or incorporation of new nucleosomes. Although previous studies have suggested that heterochromatic regions are less prone to DNA damage in response to ionizing irradiation, γ-rays or chemical agents (Falk et al, 2008;Seo et al, 2012;Takata et al, 2013; Wei Yu, Genome-wide analysis of DNA damage and repair, Technische Universität Darmstadt, PhD thesis, 2014), our and other published data indicate that UV-induced DNA damage might occur both in eu-and hetero-chromatic regions (Wei Yu, Genome-wide analysis of DNA damage and repair, Technische Universität Darmstadt, PhD thesis, 2014; Zavala et al, 2014).…”

Nucleosomes Suppress the Formation of Double-strand DNA Breaks during Attempted Base Excision Repair of Clustered Oxidative Damages

“…Indeed, chromatin condensation has been reported to protect DNA from damaging radiation, and decondensation (not necessarily transcription-related) is sufficient to sensitize DNA to radiation (59,60). A proposed mechanism for this phenomenon is that condensation of chromatin helps to exclude water, and thus fewer reactive oxygen species are generated near DNA as a result of irradiation.…”