Academic Commons

Articles

Mechanistic Modeling of Dose and Dose Rate Dependences of Radiation-Induced DNA Double Strand Break Rejoining Kinetics in Saccharomyces cerevisiae

Shuryak, Igor

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.

Files

Also Published In

More About This Work

Academic Units
Center for Radiological Research
Publisher
Public Library of Science
Published Here
March 15, 2016
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.