A Stochastic Model of DNA Double-Strand Breaks Repair Throughout the Cell Cycle.

ABSTRACT

Cell cycle phase is a decisive factor in determining the repair pathway of DNA double-strand breaks (DSBs) by non-homologous end joining (NHEJ) or homologous recombination (HR). Recent experimental studies revealed that 53BP1 and BRCA1 are the key mediators of the DNA damage response (DDR) with antagonizing roles in choosing the appropriate DSB repair pathway in G1, S, and G2 phases. Here, we present a stochastic model of biochemical kinetics involved in detecting and repairing DNA DSBs induced by ionizing radiation during the cell cycle progression. A three-dimensional stochastic process is defined to monitor the cell cycle phase and DSBs repair at times after irradiation. To estimate the model parameters, a Metropolis Monte Carlo method is applied to perform maximum likelihood estimation utilizing the kinetics of γ-H2AX and RAD51 foci formation in G1, S, and G2 phases. The recruitment of DSB repair proteins is verified by comparing our model predictions with the corresponding experimental data on human cells after exposure to X and γ-radiation. Furthermore, the interaction between 53BP1 and BRCA1 is simulated for G1 and S/G2 phases determining the competition between NHEJ and HR pathways in repairing induced DSBs throughout the cell cycle. In accordance with recent biological data, the numerical results demonstrate that the maximum proportion of HR occurs in S phase cells and the high level of NHEJ takes place in G1 and G2 phases. Moreover, the stochastic realizations of the total yield of simple and complex DSBs ligation are compared for G1 and S/G2 damaged cells. Finally, the proposed stochastic model is validated when DSBs induced by different particle radiation such as iron, silicon, oxygen, proton, and carbon.