Modeling radiation-induced cell death: role of different levels of DNA damage clustering

Abstract

Some open questions on the mechanisms underlying radiation-induced cell death were addressed by a biophysical model, focusing on DNA damage clustering and its consequences. DNA "cluster lesions" (CLs) were assumed to produce independent chromosome fragments that, if created within a micrometer-scale threshold distance (d), can lead to chromosome aberrations following mis-rejoining; in turn, certain aberrations (dicentrics, rings and large deletions) were assumed to lead to clonogenic cell death. The CL yield and d were the only adjustable parameters. The model, implemented as a Monte Carlo code called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), provided simulated survival curves that were directly compared with experimental data on human and hamster cells exposed to photons, protons, α-particles and heavier ions including carbon and iron. d = 5 μm, independent of radiation quality, and CL yields in the range ~2-20 CLs Gy(-1) cell(-1), depending on particle type and energy, led to good agreement between simulations and data. This supports the hypothesis of a pivotal role of DNA cluster damage at sub-micrometric scale, modulated by chromosome fragment mis-rejoining at micrometric scale. To investigate the features of such critical damage, the CL yields were compared with experimental or theoretical yields of DNA fragments of different sizes, focusing on the base-pair scale (related to the so-called local clustering), the kbp scale ("regional clustering") and the Mbp scale, corresponding to chromatin loops. Interestingly, the CL yields showed better agreement with kbp fragments rather than bp fragments or Mbp fragments; this suggests that also regional clustering, in addition to other clustering levels, may play an important role, possibly due to its relationship with nucleosome organization in the chromatin fiber.

Carbon Ion Radiotherapy: A Review of Clinical Experiences and Preclinical Research, with an Emphasis on DNA Damage/Repair

“…Clustered DNA damage with dense IRIF along the particle track can dramatically increase the probability of chromosomal aberrations compared to X-rays in human lymphocytes [59] and their hematopoietic progenitors [60]. Extreme proximity of DSBs in clustered lesions may also give rise to increased chromosomal rearrangements [61] which was in agreement with computational modeling data [62]. Utilizing cytogenetic techniques like G2 premature chromosome condensation (G2 PCC) and multicolor banding fluorescence in situ hybridization (mFISH), it has been shown that charged particle radiation is more effective at inducing chromosomal aberrations when compared to low LET radiation [63,64,65,66].…”

Calculating Variations in Biological Effectiveness for a 62 MeV Proton Beam

“…In previous works [e.g., Ref. ( 13 )], where the threshold distance d was considered as an adjustable parameter, a d value of 5 μm led to good agreement with experimental survival curves for AG1522 human fibroblasts and V79 hamster fibroblasts exposed to different radiation qualities. However, this value seems to be larger than most estimations available in the literature.…”

“…Therefore, we chose not to provide a definition for the quantity “CL,” leaving the mean number of CLs per unit radiation dose and per unit DNA mass (that is, the mean number of CLs per Gy and per Dalton, which can be easily converted into CLs per Gy and per cell) as an adjustable parameter. In a previous work ( 13 ), CL yields for different radiation qualities showed good agreement with yields of kilo-base-pair (kbp) DNA fragments, suggesting that DSB clusters at the kbp scale, possibly in addition to other levels of clustering, may play a relevant role.…”

“…In this framework, a biophysical model of radiation-induced cell death and chromosome aberrations called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA) ( 10 – 13 ) was developed at the University of Pavia and INFN-Pavia, Italy. The model, which in the last few years has been tested against in vitro cell survival data and has been applied in the framework of Boron Neutron Capture Therapy ( 14 ), assumes that DNA cluster damage can lead to chromosome aberrations and that some aberration types lead to clonogenic cell death.…”

Ab Initio Molecular Dynamics Simulations to Interpret the Molecular Fragmentation Induced in Deoxyribose by Synchrotron Soft X-Rays

“…DNA complex damage is critical for the cell because it can lead to important biological consequences such as chromosome aberrations, cell death, and cell conversion to malignancy [5][6][7][8].…”