Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage.
Characterising and predicting the effects of ionising radiation on cells remains challenging, with the lack of robust models of the underlying mechanism of radiation responses providing a significant limitation to the development of personalised radiotherapy. In this paper we present a mechanistic model of cellular response to radiation that incorporates the kinetics of different DNA repair processes, the spatial distribution of double strand breaks and the resulting probability and severity of misrepair. This model enables predictions to be made of a range of key biological endpoints (DNA repair kinetics, chromosome aberration and mutation formation, survival) across a range of cell types based on a set of 11 mechanistic fitting parameters that are common across all cells. Applying this model to cellular survival showed its capacity to stratify the radiosensitivity of cells based on aspects of their phenotype and experimental conditions such as cell cycle phase and plating delay (correlation between modelled and observed Mean Inactivation Doses R(2) > 0.9). By explicitly incorporating underlying mechanistic factors, this model can integrate knowledge from a wide range of biological studies to provide robust predictions and may act as a foundation for future calculations of individualised radiosensitivity.
Department of Radiation Oncology, Massachusetts General Hospital, 30 Fruit St, Boston, MA 02114, USA.|Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, N. Ireland.
Stephen J
SJ
McMahon
Department of Radiation Oncology, Massachusetts General Hospital, 30 Fruit St, Boston, MA 02114, USA.
Jan
J
Schuemann
Department of Radiation Oncology, Massachusetts General Hospital, 30 Fruit St, Boston, MA 02114, USA.
Harald
H
Paganetti
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, N. Ireland.
Kevin M
KM
Prise
D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000528:radiation effects*; D006801:Humans; D008962:Models, Theoretical; D009154:Mutation; D011836:Radiation Tolerance / Q000502:physiology*; D011839:Radiation, Ionizing