A Stochastic Model of DNA Fragments Rejoining

• Type of Material: Article
• Authors: Yongfeng Li, Universities Space Research Association; Hong Qian, University of Washington; Ya Wang, Emory University; Francis A. Cucinotta, NASA
• Language: English
• Date: 2012-09-13
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © Li et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0044293
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 7
• Issue: 9
• Start Page: e44293
• End Page: e44293
• Grant/Funding Information: This work was supported by the NASA Space Radiation Program.
• Keywords: MULTIDISCIPLINARY SCIENCES; IONIZING-RADIATION; Science & Technology; DOUBLE-STRAND BREAKS; END; Multidisciplinary Sciences; ENERGY-TRANSFER RADIATION; Science & Technology - Other Topics; HUMAN-CELLS; DSB-REPAIR; KU; GAMMA-H2AX FOCI; SPACE EXPLORATION; INDUCE CHROMOSOME BREAKAGE
• Research Categories: Health Sciences, Oncology; Biology, Radiation

Abstract

When cells are exposed to ionizing radiation, DNA damages in the form of single strand breaks (SSBs), double strand breaks (DSBs), base damage or their combinations are frequent events. It is known that the complexity and severity of DNA damage depends on the quality of radiation, and the microscopic dose deposited in small segments of DNA, which is often related to the linear transfer energy (LET) of the radiation. Experimental studies have suggested that under the same dose, high LET radiation induces more small DNA fragments than low-LET radiation, which affects Ku efficiently binding with DNA end and might be a main reason for high-LET radiation induced RBE [1] since DNA DSB is a major cause for radiation-induced cell death. In this work, we proposed a mathematical model of DNA fragments rejoining according to non-homologous end joining (NHEJ) mechanism. By conducting Gillespie's stochastic simulation, we found several factors that impact the efficiency of DNA fragments rejoining. Our results demonstrated that aberrant DNA damage repair can result predominantly from the occurrence of a spatial distribution of DSBs leading to short DNA fragments. Because of the low efficiency that short DNA fragments recruit repair protein and release the protein residue after fragments rejoining, Ku-dependent NHEJ is significantly interfered with short fragments. Overall, our work suggests that inhibiting the Ku-dependent NHEJ may significantly contribute to the increased efficiency for cell death and mutation observed for high LET radiation. © 2012 Li et al.