DNA decompaction enhances the formation of radiation-induced DNA double strand breaks and chromosome aberrations

Chromosome aberrations, a biomarker of space radiation-induced carcinogenesis, are a direct consequence of DNA double-strand break (DSB) misrepair and play an important role in the fate of irradiated cells. Their formation is a function of different physical and biological factors including the 3D DNA architecture. At the nanometric scale, the DNA is wrapped around histone proteins to form nucleosomes, which fold together to form the chromatin fiber. Different levels of DNA density exist, namely the less compact euchromatin (EC) and the denser heterochromatin (HC). Recent studies showed that EC is more prone to DNA damage than HC at the same dose, suggesting that DNA compaction might influence chromosome aberration formation. In this work, we investigated how DNA compaction at the nucleosome level influences the formation of DSBs and total exchanges for exposure to high charge and energy ions (HZE) with linear energy transfer (LET) in the range 0.4 - 235 keV/μm. The radiation transport tool RITRACKS and DNA damage and chromosome aberration model RITCARD allow the transport of HZE ions in cell nuclei and evaluate the yield of DNA damage and chromosome aberrations but does not provide detailed geometries of the DNA with different compaction levels. In contrast, Geant4-DNA provide atomic scale models of HC or EC DNA and can be used to evaluate DNA damage. We combined Geant4-DNA and RITCARD to model radiation transport, DNA damage and DNA repair in fibroblast cell nuclei filled with EC or HC and compared the results to those obtained by RITRACKS/RITCARD. For all cell nuclei, the 3D distribution of the DNA was obtained with the tool G-NOME using experimental chromosome conformation capture (Hi-C) data. Large differences were obtained for the yield of DSB between RITRACKS/RITCARD and Geant4 DNA (-25% - 125% for HC nuclei), reflecting major differences in how the two models score DNA damage, which were responsible for large differences (-50% - 150% for HC nuclei) in the yield of total exchanges. For Geant4-DNA, we found that DNA decompaction increased the yield of DNA DSB by 4-8%, depending on the ion LET. The effect was more pronounced for total exchanges, with an increased yield of 50-75% for EC nuclei compared to HC nuclei. This larger total exchange yield was attributed mainly to differences in DNA distribution across the cell nucleus and, to a lesser extent, the increased DSB yield. Euchromatin nuclei presented chromosome domains that were more spread out, likely favoring inter-chromosomal proximity at the periphery of chromosome territories and, therefore, chromosome rearrangements. These findings provide further evidence that DNA compaction could be a factor of cell radiosensitivity.