A Model of Photon Cell Killing Based on the Spatio-Temporal Clustering of DNA Damage in Higher Order Chromatin Structures

Abstract

We present a new approach to model dose rate effects on cell killing after photon radiation based on the spatio-temporal clustering of DNA double strand breaks (DSBs) within higher order chromatin structures of approximately 1–2 Mbp size, so called giant loops. The main concept of this approach consists of a distinction of two classes of lesions, isolated and clustered DSBs, characterized by the number of double strand breaks induced in a giant loop. We assume a low lethality and fast component of repair for isolated DSBs and a high lethality and slow component of repair for clustered DSBs. With appropriate rates, the temporal transition between the different lesion classes is expressed in terms of five differential equations. These allow formulating the dynamics involved in the competition of damage induction and repair for arbitrary dose rates and fractionation schemes. Final cell survival probabilities are computable with a cell line specific set of three parameters: The lethality for isolated DSBs, the lethality for clustered DSBs and the half-life time of isolated DSBs.By comparison with larger sets of published experimental data it is demonstrated that the model describes the cell line dependent response to treatments using either continuous irradiation at a constant dose rate or to split dose irradiation well. Furthermore, an analytic investigation of the formulation concerning single fraction treatments with constant dose rates in the limiting cases of extremely high or low dose rates is presented. The approach is consistent with the Linear-Quadratic model extended by the Lea-Catcheside factor up to the second moment in dose. Finally, it is shown that the model correctly predicts empirical findings about the dose rate dependence of incidence probabilities for deterministic radiation effects like pneumonitis and the bone marrow syndrome. These findings further support the general concepts on which the approach is based.

Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage

“…We have developed a general framework of cellular radiation response characterised using cellular phenotypic characteristics that can produce predictions of a range of endpoints including DNA repair, genetic aberration, and cellular survival. While other models have sought to make use of similar mechanistic approaches to radiation response 16 17 18 35 58 59 , we believe this is the first such model to explicitly incorporate this range of underlying mechanistic processes and endpoints together with cell survival in a single model.…”

The link between cell-cycle dependent radiosensitivity and repair pathways: A model based on the local, sister-chromatid conformation dependent switch between NHEJ and HR

“…It has thus to be understood as an effective model which allows to study some basic aspects of radiation action, as e.g. the general shape of dose-response curves [15], the impact of dose-rate effects [26] and the kinetics of DSB rejoining [25]. However, this strategy is in line with other modeling approaches as reported e.g.…”

“…However, these alternative mechanisms would fail to simultaneously explain other effects for which the concept of differential lethality between iDSB and cDSB has been demonstrated to have a high predictive power. For example dose-rate effects in the case of protracted photon irradiation can be explained by the temporal pattern of DSB induction [26], and the increased effectiveness of high-LET radiation can be explained by the microscopic, spatial DSB distribution pattern [14,27]. In both cases, even though the same total number of DSB might be induced, the variation of effectiveness can be traced back to the modification of the number of iDSB and cDSB, respectively, as a consequence of the variation in the temporal or spatial distribution pattern.…”

Recent progress and open challenges in modeling p53 dynamics in single cells

“…Indeed, measurements of DSBs by time-resolved microscopy showed that their number and repair kinetics vary in genetically identical cells, depending, for example, on cell cycle phase and repair pathways used [7,36]. Moreover, models of DSB induction by ionizing radiation suggest the existence of both simple and complex breaks that are repaired with differential kinetics [37,38]. Complex breaks are generated when DSBs cluster in chromatin loops.…”