Abstract
Mechanistic modeling of DNA double strand break (DSB) rejoining is important for quantifying and medically exploiting radiation-induced cytotoxicity (e.g. in cancer radiotherapy). Most radiation-induced DSBs are quickly-rejoinable and are rejoined within the first 1–2 hours after irradiation. Others are slowly-rejoinable (persist for several hours), and yet others are essentially unrejoinable (persist for >24 hours). The dependences of DSB rejoining kinetics on radiation dose and dose rate remain incompletely understood. We hypothesize that the fraction of slowly-rejoinable and/or unrejoinable DSBs increases with increasing dose/dose rate. This radiation-dependent (RD) model was implemented using differential equations for three DSB classes: quickly-rejoinable, slowly-rejoinable and unrejoinable. Radiation converts quickly-rejoinable to slowly-rejoinable, and slowly-rejoinable to unrejoinable DSBs. We used large published data sets on DSB rejoining in yeast exposed to sparsely-ionizing (electrons and γ-rays, single or split-doses, high or low dose rates) and densely-ionizing (α-particles) radiation to compare the performances of the proposed RD formalism and the established two-lesion kinetic (TLK) model. These yeast DSB rejoining data were measured within the radiation dose range relevant for clonogenic cell survival, whereas in mammalian cells DSB rejoining is usually measured only at supra-lethal doses for technical reasons. The RD model described both sparsely-ionizing and densely-ionizing radiation data much better than the TLK model: by 217 and 14 sample-size-adjusted Akaike information criterion units, respectively. This occurred because: the RD (but not the TLK) model reproduced the observed upwardly-curving dose responses for slowly-rejoinable/unrejoinable DSBs at long times after irradiation; the RD model adequately described DSB yields at both high and low dose rates using one parameter set, whereas the TLK model overestimated low dose rate data. These results support the hypothesis that DSB rejoining is progressively impeded at increasing radiation doses/dose rates.
Highlights
Mechanistic quantitative modeling of DNA double strand break (DSB) rejoining kinetics is important for predicting radiation-induced cytotoxicity and for exploiting it [1,2,3,4,5], as well as for assessment of radiation risks at low doses [6,7,8]
Dose-dependent accumulation of radiation damage to chromatin and/or to the enzymatic repair complexes themselves can occur [24, 27]. We mathematically implemented this radiation-dependent (RD) model, and compared its performance to that of the two-lesion kinetic (TLK) model using large published data sets on DSB rejoining in yeast (Saccharomyces cerevisiae) exposed to sparsely-ionizing (30 MeV electrons, single or split-doses, high dose rate; γ-rays, low dose rate) [38, 39] and densely-ionizing (α-particles) radiation [40, 41]
We analyzed large published data sets on DSB rejoining in yeast (Saccharomyces cerevisiae) exposed to sparsely-ionizing and densely-ionizing radiation [38,39,40,41] to enhance the understanding of dose/dose rate dependences of radiation-induced DSB rejoining kinetics
Summary
Mechanistic quantitative modeling of DNA double strand break (DSB) rejoining kinetics is important for predicting radiation-induced cytotoxicity and for exploiting it (e.g. in cancer radiotherapy) [1,2,3,4,5], as well as for assessment of radiation risks at low doses [6,7,8]. Mechanistic quantitative analysis of DSB rejoining (and clonogenic cell survival) is often performed using kinetic models which describe the rates of change of the average number of DSBs per cell during and/or after radiation exposure. Many such models have been proposed, some of which attempt very detailed descriptions of molecular machinery involved in DSB repair [5, 30,31,32,33]. Such models aim to capture the main rate-limiting steps in DSB rejoining in a sufficiently parsimonious manner to be applicable for quantitative analysis of experimental data sets, which are often quite limited in the range of radiation doses and/or dose rates
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