AI Article Synopsis

  • Researchers created a biochemical kinetics model to explain the repair process of double-strand breaks (DSBs) caused by low-LET radiation, focusing on non-homologous end joining (NHEJ).
  • The model uses a system of nonlinear differential equations to describe the roles of key proteins involved in DSB repair, such as Ku70/80 and DNA-PKcs, and factors in the autophosphorylation of DNA-PKcs and formation of gamma-H2AX foci.
  • The model successfully replicated experimental observations regarding DSB rejoining and predicted behaviors of NHEJ components under varying radiation doses, showing a steady state at low dose rates.

Article Abstract

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 gamma-H2AX foci observed after ionizing 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 gamma-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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http://dx.doi.org/10.1667/RR1035.1DOI Listing

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