Simulation of cell cycle effects on DNA strand break induction due to α-particles

Purpose: Understanding cell cycle variations in radiosensitivity is important for α-particle therapies. Differences are due to both repair response mechanisms and the quantity of initial radiation-induced DNA strand breaks. Genome compaction within the nucleus has been shown to impact the yield of strand breaks. Compaction changes during the cell cycle are therefore likely to contribute to radiosensitivity differences. Simulation allows the strand break yield to be calculated independently of repair mechanisms which would be challenging experimentally.

Methods: Using Geant4 the impact of genome compaction changes on strand break induction due to α-particles was simulated. Genome compaction is considered to be described by three metrics: global base pair density, chromatin fibre packing fraction and chromosome condensation. Nuclei in the G1, S, G2 and M phases from two cancer cell lines and one normal cell line are simulated. Repair mechanisms are not considered to study only the impact of genome compaction changes.

Results: The three compaction metrics have differing effects on the strand break yield. For all cell lines the strand break yield is greatest in G2 cells and least in G1 cells. More strand breaks are induced in the two cancer cell lines than in the normal cell line.

Conclusions: Compaction of the genome affects the initial yield of strand breaks. Some radiosensitivity differences between cell lines can be attributed to genome compaction changes between the phases of the cell cycle. This study provides a basis for further analysis of how repair deficiencies impact radiation-induced lethality in normal and malignant cells.