Abstract
Non-homologous end joining (NHEJ) is the dominant DNA double strand break (DSB) repair pathway and involves several repair proteins such as Ku, DNA-PKcs, and XRCC4. It has been experimentally shown that the choice of NHEJ proteins is determined by the complexity of DSB. In this paper, we built a mathematical model, based on published data, to study how NHEJ depends on the damage complexity. Under an appropriate set of parameters obtained by minimization technique, we can simulate the kinetics of foci track formation in fluorescently tagged mammalian cells, Ku80-EGFP and DNA-PKcs-YFP for simple and complex DSB repair, respectively, in good agreement with the published experimental data, supporting the notion that simple DSB undergo fast repair in a Ku-dependent, DNA-PKcs-independent manner, while complex DSB repair requires additional DNA-PKcs for end processing, resulting in its slow repair, additionally resulting in slower release rate of Ku and the joining rate of complex DNA ends. Based on the numerous experimental descriptions, we investigated several models to describe the kinetics for complex DSB repair. An important prediction of our model is that the rejoining of complex DSBs is through a process of synapsis formation, similar to a second order reaction between ends, rather than first order break filling/joining. The synapsis formation (SF) model allows for diffusion of ends before the synapsis formation, which is precluded in the first order model by the rapid coupling of ends. Therefore, the SF model also predicts the higher number of chromosomal aberrations observed with high linear energy transfer (LET) radiation due to the higher proportion of complex DSBs compared to low LET radiation, and an increased probability of misrejoin following diffusion before the synapsis is formed, while the first order model does not provide a mechanism for the increased effectiveness in chromosomal aberrations observed.
Highlights
The induction of DNA double strand break (DSB) by ionizing radiation and other agents can lead to cell death and mutation if not repaired efficiently, and are associated with genomic instability and cancer risk
We proposed that DSB repair can be modeled in different ways, through either break filling (BF) which leads to a first order model, or synapsis formation (SF) [40]
We found that a SF model provides an improved fit to experimental data compared to the BF model, suggesting that DSB repair is through synapsis formation more likely than break filling for complex DSB, whereas the repair of simple DSB has a higher BF rate than that for complex DSB
Summary
The induction of DNA double strand break (DSB) by ionizing radiation and other agents can lead to cell death and mutation if not repaired efficiently, and are associated with genomic instability and cancer risk. One of the most important DNA repair pathways is non-homologous end-joining (NHEJ) which is utilized by the majority of DSBs, whereas replication-induced DSBs, formed at stalled replication forks, are normally repaired by homologous recombination (HR). The classical sequential model of NHEJ assumes that once induced by ionizing radiation (IR), a DNA end will first recruit Ku, and DNAPKcs followed by other repair proteins [6]. The twophase model suggested that, except Ku, the recruitment ordering of DNA-PKcs and other proteins does not matter [7]
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