A kinetic model of single-strand annealing for the repair of DNA double-strand breaks

Abstract

Ionising radiation induces different types of DNA damage, including single-strand breaks, double-strand breaks (DSB) and base damages. DSB are considered to be the most critical lesion to be repaired. The three main competitive pathways in the repair of DSB are non-homologous end joining (NHEJ), homologous recombination (HR) and single-strand annealing (SSA). SSA is a non-conservative repair pathway requiring direct repeat sequences for the repair process. In this work, a biochemical kinetic model is presented to describe the SSA repair pathway. The model consists of a system of non-linear ordinary differential equations describing the steps in the repair pathway. The reaction rates were estimated by comparing the model results with the experimental data for chicken DT40 cells exposed to 20 Gy of X-rays. The model successfully predicts the repair of the DT40 cells with the reaction rates derived from the 20-Gy X-ray experiment. The experimental data and the kinetic model show fast and slow DSB repair components. The half time and fractions of the slow and the fast components of the repair were compared for the model and the experiments. Mathematical and computational modelling in biology has played an important role in predicting biological mechanisms and stimulating future experimentation. The present model of SSA adds to the modelling of NHEJ and HR to provide a more complete description of DSB repair pathways.

Genome-based, mechanism-driven computational modeling of risks of ionizing radiation: The next frontier in genetic risk estimation?

“…The solutions of the equations provide individual protein activity kinetics and overall repair kinetics, and these can be compared with experimental measurements (usually rate of repair of DSBs, post-irradiation, using PFGE in the dose range of 40-100 Gy). While most of the models dealt with the NHEJ pathway (e.g., [41,42,44,49,63,64,[111][112][113][114], some have also considered single-strand annealing (SSA) [115]; microhomology-mediated end-joining (MMEJ) [48]; application to high LET radiations [48]; and base-excision-repair (BER) [46].…”

“…Taleei et al [115] published a study on the biochemical kinetic modeling of single strand annealing (SSA) for the repair of radiation-induced DSBs. Although this work was done earlier than that on NHEJ, the basic principles and modeling procedures were similar.…”

Mechanistic modelling and Bayesian inference elucidates the variable dynamics of double-strand break repair

“…Inspection of the interquartile range of the hyperparameters confirms that a combination of fast, slow and intermediate repair is sufficient to describe the wild type and mutant data, furthermore a two sided Kolmogorov Smirnov test between the posterior distributions for the hyperparameters confirmed that the four distributions were significantly different to one another Table 3: Median posterior parameter values with 0.5 credible regions. Values can be compared to initial binding rate constants from two models in the literature; k = 0.5 hrs −1 for NHEJ [50] and k = 0.057 hrs −1 for SSA [51]. Half times of DSBs can be calculated using t 1/2 = log e /K .…”

“…Mean parameter values and repair half times after ABC SMC. Values can be compared to initial binding rate constants from two models in the literature[55] and[56].…”

Ionising radiation and genetic risks. XVI. A genome-based framework for risk estimation in the light of recent advances in genome research

“…While, at the time of the earlier paper (Sankaranarayanan and Wassom 2005), we did not have a genome-based model for specifically considering NHEJ, HRR and NAHR repair for predicting genetic risks associated with radiation exposure of males (spermatogonial irradiation), such a model is currently being developed (Taleei et al 2010a(Taleei et al , 2010b.…”