Development and implementation of a metaphase DNA model for ionizing radiation induced DNA damage calculation

Abstract

Objective: To develop a metaphase chromosome model representing the complete genome of a human lymphocyte cell to support microscopic Monte Carlo (MMC) simulation-based radiation-induced DNA damage studies. Approach: We employed coarse-grained polymer physics simulation to obtain a rod-shaped chromatid segment to match Hi-C data. We voxelized the segment and connected the chromatid with pre-constructed nucleosomes and linker DNAs in base-pair (bp) resolutions. We then piled different numbers of voxelized chromatid segments to create the chromosomes. Finally, we arranged the chromosomes at the cell metaphase plate to create the complete set of metaphase chromosomes. We implemented the model in gMicroMC simulation by denoting the DNA structure in a four-level hierarchical tree: nucleotide pairs, nucleosomes and linker DNAs, chromatid segments, and chromosomes. We applied the model to compute DNA damage under different radiation conditions and compared the results to those obtained with G0/G1 model and experimental measurements. We also performed uncertainty analysis for relevant simulation parameters. Main Results: The chromatid segment was successfully voxelized and connected in base-pair (bps) resolution. With 466 segments, we obtained the metaphase chromosome containing 12.5 Gbps of DNA. Applying it to compute radiation-induced DNA damage, the obtained results were self-consistent and agreed with experimental measurements. Through parameter uncertainty study, we found the DNA damage ratio between metaphase and G0/G1 phase was not sensitive to the chemical simulation time. The damage was also not sensitive to the specific parameter settings in the polymer physics simulation, as long as the produced metaphase model followed a similar contact probability. Significance: Experimental data reveal that ionizing radiation induced DNA damage is cell-cycle dependent. Yet, DNA chromosome models, except for G0/G1 phase, are not available in the state-of-the-art MMC simulation. For the first time, we successfully built a metaphase chromosome model and implemented it into MMC simulation for radiation-induced DNA damage computation.

A fast Monte Carlo cell-by-cell simulation for radiobiological effects in targeted radionuclide therapy using pre-calculated single-particle track standard DNA damage data

“…More generally, beyond TRT for a reference cell nucleus, the approach can be adapted to develop libraries for other forms of ionizing radiation (e.g., x-ray/gamma photons, protons, alpha particles) and for different cell types (as represented by different chromatin structures and radiochemistry). In regards to the latter generalization, it is especially worth mentioning the emerging recognition of the important role that dynamic chromatin architecture throughout the cell cycle plays in regulating radiosensitivity, alongside DNA repair pathway dynamics (24). This dynamic architecture is determined by the complex interplay of many different factors, particularly the histone electric charge and its influence on electron transport in the nucleosome (25) as well as the Hi-C data of different cell types (26).…”