Analytical formulas representing track-structure simulations on DNA damage induced by protons and light ions at radiotherapy-relevant energies

Abstract Track structure based simulations valuably complement experimental research on biological effects of ionizing radiation. They provide information at the highest level of detail on initial DNA damage induced by diverse types of radiation. Simulations with the biophysical Monte Carlo code PARTRAC have been used for testing working hypotheses on radiation action mechanisms, for benchmarking other damage codes and as input for modelling subsequent biological processes. To facilitate such applications and in particular to enable extending the simulations to mixed radiation field conditions, we present analytical formulas that capture PARTRAC simulation results on DNA single- and double-strand breaks and their clusters induced in cells irradiated by ions ranging from hydrogen to neon at energies from 0.5 GeV/u down to their stopping. These functions offer a means by which radiation transport codes at the macroscopic scale could easily be extended to predict biological effects, exploiting a large database of results from micro-/nanoscale simulations, without having to deal with the coupling of spatial scales and running full track-structure calculations.

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Coupling Radiation Transport and Track-Structure Simulations: Strategy Based on Analytical Formulas Representing DNA Damage Yields

Frontiers in Physics ◽

10.3389/fphy.2021.719682 ◽

2021 ◽

Vol 9 ◽

Author(s):

Pavel Kundrát ◽

Werner Friedland ◽

Andrea Ottolenghi ◽

Giorgio Baiocco

Keyword(s):

Dna Damage ◽

Radiation Transport ◽

Scale Effects ◽

Biological Effects ◽

Spatial Scales ◽

Dose Calculation ◽

Particle Energy ◽

Track Structure ◽

Dose Calculation Algorithms ◽

Analytical Formulas

Existing radiation codes for biomedical applications face the challenge of dealing with largely different spatial scales, from nanometer scales governing individual energy deposits to macroscopic scales of dose distributions in organs and tissues in radiotherapy. Event-by-event track-structure codes are needed to model energy deposition patterns at cellular and subcellular levels. In conjunction with DNA and chromatin models, they predict radiation-induced DNA damage and subsequent biological effects. Describing larger-scale effects is the realm of radiation transport codes and dose calculation algorithms. A coupling approach with a great potential consists in implementing into radiation transport codes the results of track-structure simulations captured by analytical formulas. This strategy allows extending existing transport codes to biologically relevant endpoints, without the need of developing dedicated modules and running new computationally expensive simulations. Depending on the codes used and questions addressed, alternative strategies can be adopted, reproducing DNA damage in dependence on different parameters extracted from the transport code, e.g., microdosimetric quantities, average linear energy transfer (LET), or particle energy. Recently, a comprehensive database on DNA damage induced by ions from hydrogen to neon, at energies from 0.5 GeV/u down to their stopping, has been created with PARTRAC biophysical simulations. The results have been captured as a function of average LET in the cell nucleus. However, the formulas are not applicable to slow particles beyond the Bragg peak, since these can have the same LET as faster particles but in narrower tracks, thus inducing different DNA damage patterns. Particle energy distinguishes these two cases. It is also more readily available than LET from some transport codes. Therefore, a set of new analytical functions are provided, describing how DNA damage depends on particle energy. The results complement the analysis of the PARTRAC database, widening its potential of application and use for implementation in transport codes.

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Impact of the Lorentz Force on Electron Track Structure and Early DNA Damage Yields in Magnetic Resonance-Guided Radiotherapy

10.21203/rs.3.rs-1248701/v1 ◽

2022 ◽

Author(s):

Yoshie Yachi ◽

Takeshi Kai ◽

Yusuke Matsuya ◽

Yuho Hirata ◽

Yuji Yoshii ◽

...

Keyword(s):

Dna Damage ◽

Magnetic Resonance ◽

Lorentz Force ◽

Dose Distribution ◽

Biological Effects ◽

Low Energy ◽

Track Structure ◽

Monte Carlo Code ◽

Electron Track ◽

The Impact

Abstract Magnetic resonance-guided radiotherapy (MRgRT) has been developed and installed in recent decades for external radiotherapy in several clinical facilities. The Lorentz force modulates dose distribution by charged particles in MRgRT; however, the impact by this force on low-energy electron track structure and early DNA damage induction remain unclear. In this study, we estimated features of electron track structure and biological effects in a static magnetic field (SMF) using a general-purpose Monte Carlo code, Particle and Heavy Ion Transport code System (PHITS) that enables us to simulate low-energy electrons down to 1 meV by track-structure mode. The macroscopic dose distributions by electrons above approximately 300 keV initial energy in liquid water are changed by both perpendicular and parallel SMFs against the incident direction, indicating that the Lorentz force plays an important role in calculating dose within tumours. Meanwhile, DNA damage estimation based on the spatial patterns of atomic interactions indicates that the initial yield of DNA double-strand breaks (DSBs) is independent of the SMF intensity. The DSB induction is predominantly attributed to the secondary electrons below a few tens of eV, which are not affected by the Lorentz force. Our simulation study suggests that treatment planning for MRgRT can be made with consideration of only changed dose distribution.

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Comprehensive track-structure based evaluation of DNA damage by light ions from radiotherapy-relevant energies down to stopping

Scientific Reports ◽

10.1038/srep45161 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 82

Author(s):

W. Friedland ◽

E. Schmitt ◽

P. Kundrát ◽

M. Dingfelder ◽

G. Baiocco ◽

...

Keyword(s):

Dna Damage ◽

Track Structure ◽

Light Ions

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Stochastic multicellular modeling of x-ray irradiation, DNA damage induction, DNA free-end misrejoining and cell death

Scientific Reports ◽

10.1038/s41598-019-54941-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Jake C. Forster ◽

Michael J. J. Douglass ◽

Wendy M. Phillips ◽

Eva Bezak

Keyword(s):

Dna Damage ◽

Cell Death ◽

Cell Killing ◽

Track Structure ◽

Linear Component ◽

X Rays ◽

Dna Double Strand Breaks ◽

Cell Nuclei ◽

Strand Breaks ◽

X Ray

AbstractThe repair or misrepair of DNA double-strand breaks (DSBs) largely determines whether a cell will survive radiation insult or die. A new computational model of multicellular, track structure-based and pO2-dependent radiation-induced cell death was developed and used to investigate the contribution to cell killing by the mechanism of DNA free-end misrejoining for low-LET radiation. A simulated tumor of 1224 squamous cells was irradiated with 6 MV x-rays using the Monte Carlo toolkit Geant4 with low-energy Geant4-DNA physics and chemistry modules up to a uniform dose of 1 Gy. DNA damage including DSBs were simulated from ionizations, excitations and hydroxyl radical interactions along track segments through cell nuclei, with a higher cellular pO2 enhancing the conversion of DNA radicals to strand breaks. DNA free-ends produced by complex DSBs (cDSBs) were able to misrejoin and produce exchange-type chromosome aberrations, some of which were asymmetric and lethal. A sensitivity analysis was performed and conditions of full oxia and anoxia were simulated. The linear component of cell killing from misrejoining was consistently small compared to values in the literature for the linear component of cell killing for head and neck squamous cell carcinoma (HNSCC). This indicated that misrejoinings involving DSBs from the same x-ray (including all associated secondary electrons) were rare and that other mechanisms (e.g. unrejoined ends) may be important. Ignoring the contribution by the indirect effect toward DNA damage caused the DSB yield to drop to a third of its original value and the cDSB yield to drop to a tenth of its original value. Track structure-based cell killing was simulated in all 135306 viable cells of a 1 mm3 hypoxic HNSCC tumor for a uniform dose of 1 Gy.

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Bestimmung der DNA-Schädigung in vitro

Nuklearmedizin ◽

10.1055/s-0038-1626526 ◽

2010 ◽

Vol 49 (S 01) ◽

pp. S64-S68

Author(s):

E. Dikomey

Keyword(s):

Dna Damage ◽

Cell Lines ◽

Chromosome Aberrations ◽

Genetic Factors ◽

Double Strand Breaks ◽

Strand Breaks ◽

Cell Inactivation ◽

Repair Mechanisms ◽

Break Repair

SummaryIonising irradiation acts primarily via induction of DNA damage, among which doublestrand breaks are the most important lesions. These lesions may lead to lethal chromosome aberrations, which are the main reason for cell inactivation. Double-strand breaks can be repaired by several different mechanisms. The regulation of these mechanisms appears be fairly different for normal and tumour cells. Among different cell lines capacity of doublestrand break repair varies by only few percents and is known to be determined mostly by genetic factors. Knowledge about doublestrand break repair mechanisms and their regulation is important for the optimal application of ionising irradiation in medicine.

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PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome

Nature Communications ◽

10.1038/s41467-019-13641-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Deepti Sharma ◽

Louis De Falco ◽

Sivaraman Padavattan ◽

Chang Rao ◽

Susana Geifman-Shochat ◽

...

Keyword(s):

Dna Damage ◽

Mutational Analysis ◽

Catalytic Efficiency ◽

Double Strand Breaks ◽

Genomic Integrity ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Nucleosome Core ◽

Epigenetic Marker ◽

Kinetics Of

AbstractThe poly(ADP-ribose) polymerase, PARP1, plays a key role in maintaining genomic integrity by detecting DNA damage and mediating repair. γH2A.X is the primary histone marker for DNA double-strand breaks and PARP1 localizes to H2A.X-enriched chromatin damage sites, but the basis for this association is not clear. We characterize the kinetics of PARP1 binding to a variety of nucleosomes harbouring DNA double-strand breaks, which reveal that PARP1 associates faster with (γ)H2A.X- versus H2A-nucleosomes, resulting in a higher affinity for the former, which is maximal for γH2A.X-nucleosome that is also the activator eliciting the greatest poly-ADP-ribosylation catalytic efficiency. The enhanced activities with γH2A.X-nucleosome coincide with increased accessibility of the DNA termini resulting from the H2A.X-Ser139 phosphorylation. Indeed, H2A- and (γ)H2A.X-nucleosomes have distinct stability characteristics, which are rationalized by mutational analysis and (γ)H2A.X-nucleosome core crystal structures. This suggests that the γH2A.X epigenetic marker directly facilitates DNA repair by stabilizing PARP1 association and promoting catalysis.

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Transcriptome profiling of cells exposed to particular and intense electromagnetic radiation emitted by the "SG-III" prototype laser facility

Scientific Reports ◽

10.1038/s41598-021-81642-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jiangbin Wei ◽

Qiwu Shi ◽

Lidan Xiong ◽

Guang Xin ◽

Tao Yi ◽

...

Keyword(s):

Dna Damage ◽

Pc12 Cells ◽

Inertial Confinement Fusion ◽

Biological Effects ◽

Harmful Effect ◽

Transcriptome Profiling ◽

Target Chamber ◽

Target Range ◽

Inertial Confinement ◽

Laser Facility

AbstractThe experiment of inertial confinement fusion by the “ShengGuang (SG)-III” prototype laser facility is a transient and extreme reaction process within several nanoseconds, which could form a very complicated and intense electromagnetic field around the target chamber of the facility and may lead to harmful effect on people around. In particular, the biological effects arising from such specific environment field could hardly be ignored and have never been investigated yet, and thus, we reported on the investigation of the biological effects of radiation on HaCat cells and PC12 cells to preliminarily assess the biological safety of the target range of the "SG-III" prototype laser facility. The viability revealed that the damage of cells was dose-dependent. Then we compared the transcriptomes of exposed and unexposed PC12 cells by RNA-Seq analysis based on Illumina Novaseq 6000 platform and found that most significantly differentially expressed genes with corresponding Gene Ontology terms and pathways were strongly involved in proliferation, transformation, necrosis, inflammation response, apoptosis and DNA damage. Furthermore, we find increase in the levels of several proteins responsible for cell-cycle regulation and tumor suppression, suggesting that pathways or mechanisms regarding DNA damage repair was are quickly activated. It was found that "SG-III" prototype radiation could induce DNA damage and promote apoptotic necrosis.

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RepID-deficient cancer cells are sensitized to a drug targeting p97/VCP segregase

Molecular & Cellular Toxicology ◽

10.1007/s13273-021-00121-0 ◽

2021 ◽

Author(s):

Sang-Min Jang ◽

Christophe E. Redon ◽

Haiqing Fu ◽

Fred E. Indig ◽

Mirit I. Aladjem

Keyword(s):

Dna Damage ◽

Cancer Cells ◽

Cell Sorting ◽

Clonogenic Survival ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Ubiquitinated Proteins ◽

Damage Response ◽

Survival Assay

Abstract Background The p97/valosin-containing protein (VCP) complex is a crucial factor for the segregation of ubiquitinated proteins in the DNA damage response and repair pathway. Objective We investigated whether blocking the p97/VCP function can inhibit the proliferation of RepID-deficient cancer cells using immunofluorescence, clonogenic survival assay, fluorescence-activated cell sorting, and immunoblotting. Result p97/VCP was recruited to chromatin and colocalized with DNA double-strand breaks in RepID-deficient cancer cells that undergo spontaneous DNA damage. Inhibition of p97/VCP induced death of RepID-depleted cancer cells. This study highlights the potential of targeting p97/VCP complex as an anticancer therapeutic approach. Conclusion Our results show that RepID is required to prevent excessive DNA damage at the endogenous levels. Localization of p97/VCP to DSB sites was induced based on spontaneous DNA damage in RepID-depleted cancer cells. Anticancer drugs targeting p97/VCP may be highly potent in RepID-deficient cells. Therefore, we suggest that p97/VCP inhibitors synergize with RepID depletion to kill cancer cells.

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Boon and Bane of DNA Double-Strand Breaks

International Journal of Molecular Sciences ◽

10.3390/ijms22105171 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5171

Author(s):

Ingo Schubert

Keyword(s):

Negative Impact ◽

Biological Effects ◽

Double Strand Breaks ◽

Immunoglobulin Gene ◽

Dna Double Strand Breaks ◽

Endogenous Factors ◽

Strand Breaks ◽

Chromatin Elimination ◽

Evolutionary Consequences ◽

Cell Lethality

DNA double-strand breaks (DSBs), interrupting the genetic information, are elicited by various environmental and endogenous factors. They bear the risk of cell lethality and, if mis-repaired, of deleterious mutation. This negative impact is contrasted by several evolutionary achievements for DSB processing that help maintaining stable inheritance (correct repair, meiotic cross-over) and even drive adaptation (immunoglobulin gene recombination), differentiation (chromatin elimination) and speciation by creating new genetic diversity via DSB mis-repair. Targeted DSBs play a role in genome editing for research, breeding and therapy purposes. Here, I survey possible causes, biological effects and evolutionary consequences of DSBs, mainly for students and outsiders.

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Escherichia coli MutM Suppresses Illegitimate Recombination Induced by Oxidative Stress

Genetics ◽

10.1093/genetics/151.2.439 ◽

1999 ◽

Vol 151 (2) ◽

pp. 439-446 ◽

Cited By ~ 2

Author(s):

Masaaki Onda ◽

Katsuhiro Hanada ◽

Hirokazu Kawachi ◽

Hideo Ikeda

Keyword(s):

Oxidative Stress ◽

Escherichia Coli ◽

Hydrogen Peroxide ◽

Dna Damage ◽

Double Strand Breaks ◽

Illegitimate Recombination ◽

Recombination Analysis ◽

Wild Type ◽

Strand Breaks ◽

In The Wild

Abstract DNA damage by oxidative stress is one of the causes of mutagenesis. However, whether or not DNA damage induces illegitimate recombination has not been determined. To study the effect of oxidative stress on illegitimate recombination, we examined the frequency of λbio transducing phage in the presence of hydrogen peroxide and found that this reagent enhances illegitimate recombination. To clarify the types of illegitimate recombination, we examined the effect of mutations in mutM and related genes on the process. The frequency of λbio transducing phage was 5- to 12-fold higher in the mutM mutant than in the wild type, while the frequency in the mutY and mutT mutants was comparable to that of the wild type. Because 7,8-dihydro-8-oxoguanine (8-oxoG) and formamido pyrimidine (Fapy) lesions can be removed from DNA by MutM protein, these lesions are thought to induce illegitimate recombination. Analysis of recombination junctions showed that the recombination at Hotspot I accounts for 22 or 4% of total λbio transducing phages in the wild type or in the mutM mutant, respectively. The preferential increase of recombination at nonhotspot sites with hydrogen peroxide in the mutM mutant was discussed on the basis of a new model, in which 8-oxoG and/or Fapy residues may introduce double-strand breaks into DNA.

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