title: A quantitative model of the major pathways for radiation-induced DNA double-strand break repair.
abstract: We have developed a model approach to simulate the major pathways of DNA double-strand break (DSB) repair in mammalian and human cells. The proposed model shows a possible mechanistic explanation of the basic regularities of DSB processing through the non-homologous end-joining (NHEJ), homologous recombination (HR), single-strand annealing (SSA) and two alternative end-joining pathways. It reconstructs the time-courses of radiation-induced foci specific to particular repair processes including the major intermediate stages. The model is validated for ionizing radiations of a wide range of linear energy transfer (0.2-236 keV/µm) including a relatively broad spectrum of heavy ions. The appropriate set of reaction rate constants was suggested to satisfy the kinetics of DSB rejoining for the considered types of exposure. The simultaneous assessment of several repair pathways allows to describe their possible biological relations in response to irradiation. With the help of the proposed approach, we reproduce several experimental data sets on γ-H2AX foci remaining in different types of cells including those defective in NHEJ, HR, or SSA functions. The results produced confirm the hypothesis suggesting existence of at least two alternative Ku-independent end-joining pathways.
authors.affiliation: Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 6 Joliot-Curie St., 141980 Dubna, Moscow Region, Russia. Electronic address: dem@jinr.ru.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Belov
authors.affiliation: Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 6 Joliot-Curie St., 141980 Dubna, Moscow Region, Russia.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Krasavin
authors.affiliation: Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 6 Joliot-Curie St., 141980 Dubna, Moscow Region, Russia.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Lyashko
authors.affiliation: Laboratory of Radiation Biology, Joint Institute for Nuclear Research, 6 Joliot-Curie St., 141980 Dubna, Moscow Region, Russia; School of Physics and Electronics, National University of Mongolia, 1 University St., Sukhbaatar District, 210646 Ulaanbaatar, Mongolia.
authors.forename: Munkhbaatar
authors.initials: M
authors.lastname: Batmunkh
authors.affiliation: Mathematics Department, Faculty of Science, Cairo University, Giza 12613, Egypt.
authors.forename: Nasser H
authors.initials: NH
authors.lastname: Sweilam
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D059766:DNA End-Joining Repair; D004260:DNA Repair / Q000528:radiation effects*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D007700:Kinetics; D000072200:Ku Autoantigen; D008322:Mammals / Q000378:metabolism; D008954:Models, Biological; D051135:Rad51 Recombinase / Q000378:metabolism; D051716:Replication Protein A / Q000378:metabolism; D013997:Time Factors
chemical_list: D034961:Antigens, Nuclear; D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D006657:Histones; D051716:Replication Protein A; D051747:DNA-Activated Protein Kinase; D051135:Rad51 Recombinase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen
keywords: DNA double-strand break repair; Ionizing radiation; Mathematical modeling