Abstract
Developments in the genome organisation field has resulted in the recent methodology to infer spatial conformations of the genome directly from experimentally measured genome contacts (Hi-C data). This provides a detailed description of both intra- and inter-chromosomal arrangements. Chromosomal intermingling is an important driver for radiation-induced DNA mis-repair. Which is a key biological endpoint of relevance to the fields of cancer therapy (radiotherapy), public health (biodosimetry) and space travel. For the first time, we leverage these methods of inferring genome organisation and couple them to nano-dosimetric radiation track structure modelling to predict quantities and distribution of DNA damage within cell-type specific geometries. These nano-dosimetric simulations are highly dependent on geometry and are benefited from the inclusion of experimentally driven chromosome conformations. We show how the changes in Hi-C contract maps impact the inferred geometries resulting in significant differences in chromosomal intermingling. We demonstrate how these differences propagate through to significant changes in the distribution of DNA damage throughout the cell nucleus, suggesting implications for DNA repair fidelity and subsequent cell fate. We suggest that differences in the geometric clustering for the chromosomes between the cell-types are a plausible factor leading to changes in cellular radiosensitivity. Furthermore, we investigate changes in cell shape, such as flattening, and show that this greatly impacts the distribution of DNA damage. This should be considered when comparing in vitro results to in vivo systems. The effect may be especially important when attempting to translate radiosensitivity measurements at the experimental in vitro level to the patient or human level.
Highlights
The research fields of radiobiology and DNA structure have shared a symbiotic past
It is the radiation delivered to the healthy tissue which limits how much radiation we can safely give to the cancer without causing significant side effects in patients
To know how much radiation we can give, over time, we have learnt generally safe amounts of radiation that can be given to healthy tissue
Summary
The research fields of radiobiology and DNA structure have shared a symbiotic past. Radiation has been used to infer the presence of chromosome territories [1], structural cytotoxic responses [2, 3] and examinations of the chromatin dynamics [4]. As we gain a better description of the DNA and chromatin structure we observe an intrinsic relationship with the radiobiological properties of a cell [5, 6]. The formation of double-strand breaks (DSBs), which is where the sugar-phosphate backbone of the DNA is broken on both sides in close proximity (
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