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

Area of Science:

• Computational Biology
• Radiation Biology
• Genetics

Background:

• Understanding DNA damage mechanisms is crucial for radiation therapy and safety.
• Quantifying direct and indirect DNA damage, particularly double-strand breaks (DSBs), remains a challenge.
• Accurate computational models are needed to simulate and analyze radiation-induced DNA damage.

Purpose of the Study:

• To develop and validate a computational model for investigating direct and indirect DNA damage.
• To quantify DNA strand breaks, specifically double-strand breaks (DSBs), using a detailed cell nucleus model.
• To assess the model's reliability in predicting DSB yield and relative biological effectiveness (RBE) for various radiation types.

Main Methods:

• A detailed human cell nucleus model with compacted DNA (6 Gbp) was created in Geant4.
• A framework simulating DSBs was implemented using the Geant4-DNA extension.
• A clustering algorithm was used to quantify direct, indirect, and mixed DSBs; model validated against experimental data.

Main Results:

• The model achieved general agreement with experimental and computational results for DSB yield and RBE.
• Simulated DSB yields for Co-60 photons, 250 kVp photons, and 2-100 MeV protons were within validated ranges.
• Mixed DSBs, resulting from direct and indirect damage, constituted over half of the total DSBs.

Conclusions:

• The developed computational model reliably predicts DSB yield and RBE for proton and photon irradiations.
• The model enables detailed investigation into the direct and indirect effects contributing to DNA damage.
• This tool can advance our understanding of radiation-induced DNA damage and its biological consequences.