title: Modeling damage complexity-dependent non-homologous end-joining repair pathway.
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.
authors: Division of Space Life Sciences, Universities Space Research Association, Houston, Texas, United States of America.
authors: Yongfeng
authors: Y
authors: Li
authors: Department of Oncology, Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, United Kingdom.
authors: Pamela
authors: P
authors: Reynolds
authors: Department of Oncology, Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, United Kingdom.
authors: Peter
authors: P
authors: O'Neill
authors: University of Nevada, Las Vegas, Department of Health Physics and Diagnostics Sciences, Las Vegas, Nevada, United States of America ; NASA, Lyndon B. Johnson Space Center, Space Radiation Program, Houston, Texas, United States of America.
authors: Francis A
authors: FA
authors: Cucinotta
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D023902:Chromosome Pairing / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D008164:Luminescent Proteins / Q000378:metabolism; D008957:Models, Genetic
chemical_list: D034961:Antigens, Nuclear; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; C485184:enhanced green fluorescent protein; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D051747:DNA-Activated Protein Kinase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen