The Effects of Particle LET and Fluence on the Complexity and Frequency of Clustered DNA Damage

Abstract

Motivation: Clustered DNA-lesions are predominantly induced by ionizing radiation, particularly by high-LET particles, and considered as lethal damage. Quantification of this specific type of damage as a function of radiation parameters such as LET, dose rate, dose, and particle type can be informative for the prediction of biological outcome in radiobiological studies. This study investigated the induction and complexity of clustered DNA damage for three different types of particles at an LET range of 0.5–250 keV/µm. Methods: Nanometric volumes (36.0 nm3) of 15 base-pair DNA with its hydration shell was modeled. Electron, proton, and alpha particles at various energies were simulated to irradiate the nanometric volumes. The number of ionization events, low-energy electron spectra, and chemical yields for the formation of °OH, H°, eaq−, and H2O2 were calculated for each particle as a function of LET. Single- and double-strand breaks (SSB and DSB), base release, and clustered DNA-lesions were computed from the Monte-Carlo based quantification of the reactive species and measured yields of the species responsible for the DNA lesion formation. Results: The total amount of DNA damage depends on particle type and LET. The number of ionization events underestimates the quantity of DNA damage at LETs higher than 10 keV/µm. Minimum LETs of 9.4 and 11.5 keV/µm are required to induce clustered damage by a single track of proton and alpha particles, respectively. For a given radiation dose, an increase in LET reduces the number of particle tracks, leading to more complex clustered DNA damage, but a smaller number of separated clustered damage sites. Conclusions: The dependency of the number and the complexity of clustered DNA damage on LET and fluence suggests that the quantification of this damage can be a useful method for the estimation of the biological effectiveness of radiation. These results also suggest that medium-LET particles are more appropriate for the treatment of bulk targets, whereas high-LET particles can be more effective for small targets.

Health Effects of Ionizing Radiation on the Human Body

“…Photon radiation with low LET (X-rays, beta, or γ-rays, <10 keV/µm) means a homogeneous energy deposition in the entire tissue volume. In contrast, high LET radiation (protons, alpha particles, and neutrons, >10 keV/µm) decelerates faster than photons, resulting in the formation of a fast Bragg peak, which produces a low entrance dose with a greater depth of tissue penetration that increases with radiation energy [29]. A wide range of DNA lesions can occur during radiation treatment.…”

“…Approximately two-thirds of radiation-induced DNA damage is caused by the indirect effects of reactive oxygen species (ROS) [40]. High-LET radiation is more lethal than comparable doses of low-LET radiation due to a condensed energy deposition pattern and a very dense ionization pattern that causes potentially lethal DNA damage [29].…”

The DNA damage response relies on the characteristics of ionizing particles in myogenic cells

“…There are multiple studies pointing out that irradiations with different types of particles (i.e., species, energy and linear energy transfer (LET) of particles) induce different kinds of DNA damage (64,65) with different levels of complexity (i.e., different types of DNA lesions in the same DNA region) and clustering (i.e., accumulation of DNA damage in the same DNA region) (66,67). Apart from DNA lesions directly induced by direct interaction with the DNA molecule, ionizing radiation (IR) also creates reactive species (i.e., reactive oxygen or nitrogen species, ROS or RNS) by interacting with other molecules, such as water, proteins, etc… (68)(69)(70), which then also contribute to further formation of DNA damage within irradiated cells.…”

“…Apart from DNA lesions directly induced by direct interaction with the DNA molecule, ionizing radiation (IR) also creates reactive species (i.e., reactive oxygen or nitrogen species, ROS or RNS) by interacting with other molecules, such as water, proteins, etc… (68)(69)(70), which then also contribute to further formation of DNA damage within irradiated cells. Computational approaches (66,67) showed that irradiations with α-particles lead to a small number of DNA damage sites with concentrated clusters of complex DNA lesions compared to irradiations with protons, which give a higher number of DNA damage sites containing less clusters of complex DNA lesions. Here, with the use of the MIRCOM ion microbeam, we induce, whatever the particle delivered, protons or α-particles, DNA lesions within a very localized subnuclear area, thus potentially more clustered.…”

Mutagenesis and Repair of γ-Radiation- and Radical-Induced Tandem DNA Lesions

“…In addition to isolated single DNA lesions, single-and double-strand breaks, and apurinic/apyrimidinic sites, formation of clustered DNA lesions within a short stretch of DNA is a well-established characteristic of ionizing radiation [4][5][6][7][8][9]. For the sake of convenience, MDS have been defined as two or more lesions within ~20 base pairs, of which tandem lesions, with damage to two contiguous bases, constitute an important fraction [7,[10][11][12]. Generation of radicals by metal ions also results in MDS [13,14].…”