Session Item

It is widely acknowledged that DNA Double Strand Breaks (DSBs) are the key driver of the cellular lethality following ionising radiation. Improved understanding of how these breaks are generated, how the cell responds to them and their eventual fate are key to improving our understanding of radiotherapy and other radiation exposures. As a result, DSB induction and repair have been a major focus of radiobiological modelling, as investigators seek to understand both radiation responses in general, as well as specific effects such as the greater Relative Biological Effectiveness (RBE) of high Linear Energy Transfer (LET) radiation.

Models of DSB induction have evolved from early phenomenological approaches into modern Monte Carlo modelling based approaches which simulate in full detail how energy is deposited within the cell, and the subsequent radiochemistry. These interactions take place in simulations of realistic cellular geometries incorporating the full structure of DNA including individual bases, nucleosomes and higher-order chromosome territories. This allows for realistic predictions of DNA damage, in particular single- and double-strand breaks, with a minimum of free parameters.

These approaches have been shown to effectively reproduce trends in DSB quantity across a range of experimental systems and measurement approaches, indicating they effectively reproduce the underlying trends in total yields of DSBs. Moreover, modern DNA damage simulations enable a detailed classification of the quality of DSBs. These range from ‘simple’ DSBs which consist only of two individual strand breaks, to ‘complex’ DSBs which also involve additional nearby strand breaks or base modifications, and ‘clustered’ DSBs which involve DSBs in proximity.

However, how these features combine to give rise to lethality remains an outstanding question. The lethality of a given break depends on a number of factors, including both the cell’s genetic background and its current environment, indicating a complex interplay between the initial physical damage and eventual biological effect. How these breaks are processed and repaired by the cell is also the subject of a range of modelling approaches.

Many of these models give similar predictions, for example reproducing the observation that high LET radiation gives rise to an increase in RBE. However, their underlying assumptions differ dramatically. Some assume that only the quantity of DSBs matter, while some consider spatial interactions and density of identical DSBs, to others which consider DSB quality as a key factor. Distinguishing between these assumptions would offer a significant improvement in our understanding of the mechanisms of radiation induced cell death, and open the opportunity for refined therapeutic approaches.

A key requirement to better understand these effects is the development of new model systems, which enable the contributions of break quality and quantity to be evaluated independently. By separating these effects, more robust and accurate models could be developed, providing new insights into radiobiological mechanisms and the scope to optimise novel therapeutic approaches including drug-radiotherapy combinations, altered fractionation, and high-LET therapy.