Modeling double-strand breaks from direct and indirect action in a complete human genome single cell Geant4 model

Abstract

The aim of this work is to develop and validate a computational model to investigate direct and indirect DNA damage by directly quantifying DNA strand breaks. A detailed geometrical target model was created in the Monte Carlo toolkit Geant4 to represent the nucleus of a single human cell with complete human genome. A calculation framework to simulate double-strand breaks (DSBs) was implemented using this single cell model in the Geant4-DNA extension. A detailed ellipsoidal single cell model was implemented using a compacted DNA structure representing the fibroblast cell in the G0/G1 phase of the cycle using a total of 6 Gbp within the nucleus to represent the complete human genome. This geometry was developed from the publicly available Geant4-DNA example (wholeNuclearDNA), and modified to record DNA damage for both the physical and chemical stages. A clustering algorithm was implemented in the analysis process in order to quantify direct, indirect, and mixed DSBs. The model was validated against published experimental and computational results for DSB Gy−1Gbp−1 and the relative biological effectiveness (RBE) values for 250 kVp and Co-60 photons, as well as 2–100 MeV mono-energetic protons. A general agreement was observed over the whole simulated proton energy range, Co-60 beam, and 250 kVp in terms of the yield of DSB Gy−1Gbp−1 and RBE. The DSB yield was 8.0 ± 0.3 DSB Gy−1Gbp−1 for Co-60, and 9.2 ± 0.2 DSB Gy−1Gbp−1 for 250 kVp, and between 11.1 ± 0.9 and 8.1 ± 0.5 DSB Gy−1Gbp−1 for 2–100 MeV protons. The results also show mixed DSBs composed of direct and indirect SSBs make up more than half of the total DSBs. The results presented indicate that the current model reliably predicts the DSB yield and RBE for proton and photon irradiations, and allows for the detailed computational investigation of direct and indirect effects in DNA damage.

Quantification of gold nanoparticle photon radiosensitization from direct and indirect effects using a complete human genome single cell model based on Geant4

“…23 This probability was empirically determined using the "dnadamage1" F I G U R E 1 Different organization levels in the model of DNA geometry in the single cell model, which was also used in our previous work. 23 Nucleosomes were formed by DNA double helix and histone protein core and organized into chromatin fibers composed of 90 nucleosomes each. Diamond shape loops and rosette-shaped loop were formed by chromatin fibers and organized to fill a total of 46 chromosome territories located within the ellipsoidal nucleus example in order to determine the differences of indirect damage yield in two DNA molecules: (1) with nucleic bases and (2) without nucleic bases (only 2-deoxyribose and histone molecules were considered).…”

“…For the SB indirect selection,a uniform probability of 20.4% was applied because of the structure of DNA chain and the absence of DNA base molecules in this model. 23 This probability was empirically determined using the "dnadamage1" F I G U R E 1 Different organization levels in the model of DNA geometry in the single cell model, which was also used in our previous work. 23 Nucleosomes were formed by DNA double helix and histone protein core and organized into chromatin fibers composed of 90 nucleosomes each.…”

Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair

“…Variations among different simulations can be attributed to different initial conditions fed into the algorithm, and especially the concentration of antioxidants, oxygen levels and nuclear DNA density. As a general conclusion, it can be deducted that an increase in LET leads to an increase of DSBs and to a reduction of SSB levels as well as of other non-DSB oxidative damage (Refs 98–101). This of course suggests a higher level of complexity for DSBs at least.…”

“…For example, using the Geant4DNA MC code and an improved DNA geometry model as well as clustering algorithms, DNA damage yields were calculated and compared to literature (Ref. 98). The model was tested against published experimental and computational results for DSB rates and RBE values.…”

“…The specific results suggest that DSBs consist of direct and indirectly-induced (through ROS) SSBs that account approximately for half of the total DSBs (Ref. 98).…”