The Impact of the Geometrical Structure of the DNA on Parameters of the Track-Event Theory for Radiation Induced Cell Kill

Schneider, Uwe; Vasi, Fabiano; Besserer, Jürgen

doi:10.1371/journal.pone.0164929

Cited by 6 publications

(14 citation statements)

References 25 publications

(36 reference statements)

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“…Furthermore, another limitation of the model is that a realistic spatial arrangement of DNA in the cell nucleus is not considered (Kellerer and Rossi 1978;Schneider et al 2016). In fact it is assumed that in case a radiation track intersects a BIV and produces a DSB somewhere in the cell nucleus, this DSB is embedded in a volume with a diameter of 7.5 nm that is homogeneously filled by DNA.…”

Section: Discussionmentioning

confidence: 99%

A model of radiation action based on nanodosimetry and the application to ultra-soft X-rays

Schneider

Vasi

Schmidli

et al. 2020

Radiat Environ Biophys

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A radiation action model based on nanodosimetry is presented. It is motivated by the finding that the biological effects of various types of ionizing radiation lack a consistent relation with absorbed dose. It is postulated that the common fundamental cause of these effects is the production of elementary sublesions (DSB), which are created at a rate that is proportional to the probability to produce more than two ionisations within a volume of 10 base pairs of the DNA. The concepts of nanodosimetry allow for a quantitative characterization of this process in terms of the cumulative probability F2. The induced sublesions can interact in two ways to produce lethal damage. First, if two or more sublesions accumulate in a locally limited spherical volume of 3-10 nm in diameter, clustered DNA damage is produced. Second, consequent interactions or rearrangements of some of the initial damage over larger distances ( µm) can produce additional lethal damage. From the comparison of theoretical predictions deduced from this concept with experimental data on relative biological effectiveness, a cluster volume with a diameter of 7.5 nm could be determined. It is shown that, for electrons, the predictions agree well with experimental data over a wide energy range. The only free parameter needed to model cell survival is the intersection cross-section which includes all relevant cell-specific factors. Using ultra-soft X-rays it could be shown that the energy dependence of cell survival is directly governed by the nanodosimetric characteristics of the radiation track structure. The cell survival model derived in this work exhibits exponential cell survival at a high dose and a finite gradient of cell survival at vanishing dose, as well as the dependence on dose-rate.

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Section: Discussionmentioning

confidence: 99%

A model of radiation action based on nanodosimetry and the application to ultra-soft X-rays

Schneider

Vasi

Schmidli

et al. 2020

Radiat Environ Biophys

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“…Radiation has been used to infer the presence of chromosome territories [ 1 ], structural cytotoxic responses [ 2 , 3 ] and examinations of the chromatin dynamics [ 4 ]. In turn, 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 ]. This is due to the radiobiological response being majorly driven by damage to the DNA structure.…”

Section: Introductionmentioning

confidence: 99%

Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage

et al. 2020

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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.

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“…In this Section, the fundamental model equations of the TET and RAMN are derived from an abstract perspective, with a clear distinction between the initial radiation effects at the cellular and subcellular levels and between single-event and multi-event distributions. It should be noted that this derivation is not completely aligned with the formulation of the TET by Schneider et al (2016Schneider et al ( , 2017Schneider et al ( , 2019Schneider et al ( , 2020, but believed by the authors to be more consistent.…”

Section: Theoretical Foundations Of Tet and Ramnmentioning

confidence: 73%

“…A low-dose approximation of the fundamental model equation was shown to be equivalent to the commonly used linear-quadratic model and to have a dose dependence that matches the experimentally observed exponential dose dependence at higher doses (Besserer and Schneider 2015a). In later work, the parameters of the model have been related to nanodosimetry (Schneider et al 2016(Schneider et al , 2017(Schneider et al , 2019, and recently the TET has been developed into a radiation action model based on nanodosimetry (RAMN) that tried to resolve the shortcomings of the original TET model (Schneider et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Investigation into the foundations of the track-event theory of cell survival and the radiation action model based on nanodosimetry

Ngcezu

Rabus

2021

Radiat Environ Biophys

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This work aims at elaborating the basic assumptions behind the “track-event theory” (TET) and its derivate “radiation action model based on nanodosimetry” (RAMN) by clearly distinguishing between effects of tracks at the cellular level and the induction of lesions in subcellular targets. It is demonstrated that the model assumptions of Poisson distribution and statistical independence of the frequency of single and clustered DNA lesions are dispensable for multi-event distributions because they follow from the Poisson distribution of the number of tracks affecting the considered target volume. It is also shown that making these assumptions for the single-event distributions of the number of lethal and sublethal lesions within a cell would lead to an essentially exponential dose dependence of survival for practically relevant values of the absorbed dose. Furthermore, it is elucidated that the model equation used for consideration of repair within the TET is based on the assumption that DNA lesions induced by different tracks are repaired independently. Consequently, the model equation is presumably inconsistent with the model assumptions and requires an additional model parameter. Furthermore, the methodology for deriving model parameters from nanodosimetric properties of particle track structure is critically assessed. Based on data from proton track simulations it is shown that the assumption of statistically independent targets leads to the prediction of negligible frequency of clustered DNA damage. An approach is outlined how track structure could be considered in determining the model parameters, and the implications for TET and RAMN are discussed.

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The Impact of the Geometrical Structure of the DNA on Parameters of the Track-Event Theory for Radiation Induced Cell Kill

Cited by 6 publications

References 25 publications

A model of radiation action based on nanodosimetry and the application to ultra-soft X-rays

A model of radiation action based on nanodosimetry and the application to ultra-soft X-rays

Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage

Investigation into the foundations of the track-event theory of cell survival and the radiation action model based on nanodosimetry

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