2. Cross Cancer Institute, 11560 University Avenue, Edmonton AB T6G 1Z2, Canada.
Background: In this work we present, for the first time, a mechanistic mathematical model for single strand annealing (SSA) one of the three important double strand breaks (DSB) repair pathway. For this purpose, we predict the rate constants, which have not yet been measured experimentally, for the proteins involved in the repair. To maintain genome stability, DNA DSB are repaired by three main pathways, NHEJ (non-homologous end joining), HR (homologous recombination), and SSA. SSA is a compensating pathway for both HR and NHEJ. The three pathways are distinct in repair efficiency and fidelity. The SSA repair process is non-conservative which may cause genome translocation.
Methods: We employed a biochemical reaction rate model to investigate mechanistically the SSA repair pathway. The model resulted in a set of nonlinear differential equations which were solved numerically.
Results: The constant rates of the biochemical reactions were estimated by comparing the modelling results with chicken cell line (DT40), and mouse embryo fibroblast cell line (MEF) dose-equivalent unrepaired DSB (Deq) data after irradiation with 20 Gy X-rays. The model successfully predicted DSB repair of DT40 cell line irradiated with 80 Gy X-rays. The model was also employed to investigate dose rate effects on repair efficiency.
Conclusions: The model is capable of predicting repair efficiency of deficient cell lines (via mutation in specific enzyme). In the absence of quantitative data we present model predictions for protein reaction rate constants for Rad51 and Ku70 mutated DT40 and MEF cell lines. The present work is part of the development of a complete model of DNA DSB repair, including HR and NHEJ. A comprehensive model of DNA repair is needed in development of new ideas in radiation cancer therapy, and risk assessment in human from exposures to low doses of ionizing radiations.