Assessing DNA Damage in Reduced-Scale Fractal Geometries with Geant4-DNA
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Accurate modeling of radiation-induced DNA damage is critical for understanding radiobiologicaleffects at the nanometer scale. This study evaluates the feasibility of using reduced-scale fractal chromatin geometriesto simulate complex DNA damage in Geant4-DNA, with a focus on non-double-strand-break (non-DSB) clusteredlesions. Two ellipsoidal models, minihumanA and minihumanB, were developed to preserve the DNA base-pairdensity (0.015 bp nm−3) of a whole human fibroblast nucleus while minimizing geometric volume. Monte Carlosimulations were performed using γ-rays, protons, and carbon ions to span a wide LET range. The complexity ofclustered lesions increased with both LET and particle type, with heavier ions producing more complex breaks. Across all radiation types, non-DSB lesions accounted for 92-98% of total damage, with increasing LET associatedwith rising DSB yields and declining SSB frequencies, consistent with both prior simulation studies and experimentalobservations. Notably, despite differing in size and genomic content (13.2 Mbp for minihumanA and 7.2 Mbp forminihumanB), the predicted damage yields aligned closely with experimental findings, indicating that absolutenuclear dimensions and base pair number have minimal influence when chromatin density is preserved. This suggeststhat density-preserving geometries capture the essential features of radiation-induced damage formation and providepredictions that more closely reflect experimental observations than models based on randomly distributed DNAsegments in prior simulation studies. Non-DSB clustered lesions, predominantly complex single-strand breaks withbase damage, were the most abundant clustered damage type, with non-DSB-to-DSB ratios ranging from 4.5 to 14. These findings validate the use of downsized, density-preserving models for efficient and biologically realistic DNAdamage simulations and underscore the importance of systematically quantifying non-DSB clusters as potentiallymutagenic, yet often underappreciated, radiation-induced lesions.
Abstract
Accurate modeling of radiation-induced DNA damage is critical for understanding radiobiologicaleffects at the nanometer scale. This study evaluates the feasibility of using reduced-scale fractal chromatin geometriesto simulate complex DNA damage in Geant4-DNA, with a focus on non-double-strand-break (non-DSB) clusteredlesions. Two ellipsoidal models, minihumanA and minihumanB, were developed to preserve the DNA base-pairdensity (0.015 bp nm−3) of a whole human fibroblast nucleus while minimizing geometric volume. Monte Carlosimulations were performed using γ-rays, protons, and carbon ions to span a wide LET range. The complexity ofclustered lesions increased with both LET and particle type, with heavier ions producing more complex breaks. Across all radiation types, non-DSB lesions accounted for 92-98% of total damage, with increasing LET associatedwith rising DSB yields and declining SSB frequencies, consistent with both prior simulation studies and experimentalobservations. Notably, despite differing in size and genomic content (13.2 Mbp for minihumanA and 7.2 Mbp forminihumanB), the predicted damage yields aligned closely with experimental findings, indicating that absolutenuclear dimensions and base pair number have minimal influence when chromatin density is preserved. This suggeststhat density-preserving geometries capture the essential features of radiation-induced damage formation and providepredictions that more closely reflect experimental observations than models based on randomly distributed DNAsegments in prior simulation studies. Non-DSB clustered lesions, predominantly complex single-strand breaks withbase damage, were the most abundant clustered damage type, with non-DSB-to-DSB ratios ranging from 4.5 to 14. These findings validate the use of downsized, density-preserving models for efficient and biologically realistic DNAdamage simulations and underscore the importance of systematically quantifying non-DSB clusters as potentiallymutagenic, yet often underappreciated, radiation-induced lesions.