Nanodosimetric Calculations of Radiation-Induced DNA Damage in a New Nucleus Geometrical Model Based on the Isochore Theory

Abstract

Double-strand breaks (DSBs) in nuclear DNA represents radiation-induced damage that has been identified as particularly deleterious. Calculating this damage using Monte Carlo track structure modeling could be a suitable indicator to better assess and anticipate the side-effects of radiation therapy. However, as already demonstrated in previous work, the geometrical description of the nucleus and the DNA content used in the simulation significantly influence damage calculations. Therefore, in order to obtain accurate results, this geometry must be as realistic as possible. In this study, a new geometrical model of an endothelial cell nucleus and DNA distribution according to the isochore theory are presented and used in a Monte Carlo simulation chain based on the Geant4-DNA toolkit. In this theory, heterochromatin and euchromatin compaction are distributed along the genome according to five different families (L1, L2, H1, H2, and H3). Each of these families is associated with a different hetero/euchromatin rate related to its compaction level. In order to compare the results with those obtained using a previous nuclear geometry, simulations were performed for protons with linear energy transfers (LETs) of 4.29 keV/µm, 19.51 keV/µm, and 43.25 keV/µm. The organization of the chromatin fibers at different compaction levels linked to isochore families increased the DSB yield by 6–10%, and it allowed the most affected part of the genome to be identified. These new results indicate that the genome core is more radiosensitive than the genome desert, with a 3–8% increase in damage depending on the LET. This work highlights the importance of using realistic distributions of chromatin compaction levels to calculate radio-induced damage using Monte Carlo simulation methods.

ICRU Report 98, Stochastic Nature of Radiation Interactions: Microdosimetry

“…The Geant4-DNA platform has since been applied in many studies of damage to the DNA molecule and its higher-order structures in mammalian cells (Figs. 9.17 and 9.18) and other organisms exposed to many radiation types, including those of interest in radiotherapy, space travel, and radiobiology (Chatzipapas et al , 2020; 2021; 2023; Dominguez-Kondo et al , 2021; Dos Santos et al , 2020; Henthorn et al , 2017; Hilgers et al , 2022; Incerti et al , 2016; 2020; Kyriakou et al , 2021; 2022; Lee and Wang, 2019; Margis et al , 2020; Moeini et al , 2020; Mokari et al , 2020; Sakata et al , 2019; Tang et al , 2020; Thibault et al , 2022; Thompson et al , 2022). Development of the Geant4-DNA platform for radiobiological applications included incorporation of a feature allowing for prediction of DNA rejoining kinetics and corresponding cell surviving fraction as a function of time.…”

“…DSB = double-strand break; LET = linear energy transfer. Journal of the ICRU 23(1)1-165 2020; Sakata et al, 2019;Tang et al, 2020;Thibault et al, 2022;Thompson et al, 2022). Development of the Geant4-DNA platform for radiobiological applications included incorporation of a feature allowing for prediction of DNA rejoining kinetics and corresponding cell surviving fraction as a function of time.…”

Experimental validation in a neutron exposure frame of the MINAS TIRITH for cell damage simulation

“…In this context, the MINAS TIRITH tool has been proposed in order to model the distribution of radiation-induced DNA damage at the scale of a cell population (Thibaut et al 2023). This tool is based on databases generated by Monte Carlo simulation with the Geant4-DNA tool (Incerti et al 2010a, 2010b, Bernal et al 2015, Incerti et al 2018 coupled to realistic nucleus geometries (Meylan et al 2016, Tang et al 2019a, Thibaut et al 2022. The new damage distribution method enabled by MINAS TIRITH allows access to a higher spatial scale in the description of radiation-induced damage compared to the track structure codes typically used.…”

Simulation of DNA damage using Geant4‐DNA: an overview of the “molecularDNA” example application

“…It is extensively recognized in the scientific community that the quantification of DNA damage induction and complexity in the cell, produced by charged particles, including heavy ions, is paramount. [1][2][3][4][5][6][7][8] Ionizing radiation influences several aspects of everyday life due to natural radiation background (cosmic and terrestrial sources), medical intervention (imaging and therapy), and space exploration (astronauts' missions and space tourism). 9 Thus, it is important to achieve a better understanding of the fundamental mechanisms that are initiated by the interaction of radiation with living organisms.…”