Abstract
DNA double strand breaks (DSB) play a pivotal role for cellular damage, which is a hazard encountered in toxicology and radiation protection, but also exploited e.g. in eradicating tumors in radiation therapy. It is still debated whether and in how far clustering of such DNA lesions leads to an enhanced severity of induced damage. Here we investigate - using focused spots of ionizing radiation as damaging agent - the spatial extension of DNA lesion patterns causing cell inactivation. We find that clustering of DNA damage on both the nm and µm scale leads to enhanced inactivation compared to more homogeneous lesion distributions. A biophysical model interprets these observations in terms of enhanced DSB production and DSB interaction, respectively. We decompose the overall effects quantitatively into contributions from these lesion formation processes, concluding that both processes coexist and need to be considered for determining the resulting damage on the cellular level.
Highlights
DNA double strand breaks (DSB) play a pivotal role for cellular damage, which is a hazard encountered in toxicology and radiation protection, and exploited e.g. in eradicating tumors in radiation therapy
We analyzed the impact of DNA damage induction on CHO cells using cellular survival level measured by colony formation as endpoint, which is regarded as a ‘gold standard’ in radiation biology
To quantify the radiation effect, three spatial scales of DNA damage formation are implemented in Local effect model (LEM) and the corresponding processes are hypothesized to be relevant for the cellular survival after irradiation: (i) On the nm level the interaction of single strand breaks (SSB) to DSB gives rise to an enhanced production of DSB per Gy for high local energy concentrations; (ii) on the μm scale the interaction of DSB within chromatin loops of the DNA 30 nm fiber leads to even more complex lesions which are harder to repair for the cell; (iii) on the 10 μm scale the hit statistics of a cell population may decrease the overall effect to correct for unhit cells
Summary
DNA double strand breaks (DSB) play a pivotal role for cellular damage, which is a hazard encountered in toxicology and radiation protection, and exploited e.g. in eradicating tumors in radiation therapy. The hit statistics even results in a restoration in cell survival for carbon and lithium beams when accumulating more particles per spot and widening the irradiation grid.
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