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Biochemical Kinetics Model of DSB Repair and Induction of γ-H2AX Foci by Non-homologous End Joining
Francis A. Cucinotta, Janice M. Pluth, Jennifer A. Anderson, Jane V. Harper and Peter O'Neill
Vol. 169, No. 2 (Feb., 2008), pp. 214-222
Published by: Radiation Research Society
Stable URL: http://www.jstor.org/stable/30130599
Page Count: 9
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We developed a biochemical kinetics approach to describe the repair of double-strand breaks (DSBs) produced by low-LET radiation by modeling molecular events associated with non-homologous end joining (NHEJ). A system of coupled nonlinear ordinary differential equations describes the induction of DSBs and activation pathways for major NHEJ components including Ku70/80, DNA-PKcs, and the ligase IV-XRCC4 heterodimer. The autophosphorylation of DNA-PKcs and subsequent induction of γ-H2AX foci observed after ion-izing radiation exposure were modeled. A two-step model of regulation of repair by DNA-PKcs was developed with an initial step allowing access of other NHEJ components to breaks and a second step limiting access to ligase IV-XRCC4. Our model assumes that the transition from the first to the second step depends on DSB complexity, with a much slower rate for complex DSBs. The model faithfully reproduced several experimental data sets, including DSB rejoining as measured by pulsed-field gel electrophoresis (PFGE) at 10 min postirradiation or longer and quantification of the induction of γ-H2AX foci. A process that is independent of DNA-PKcs is required for the model to reproduce experimental data for rejoining before 10 min postirradiation. Predictions are made for the behaviors of NHEJ components at low doses and dose rates, and a steady state is found at dose rates of 0.1 Gy/h or lower.
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