Evidence for DNA Double-Strand Breaks as the Critical Lesions in Yeast Cells Irradiated with Sparsely or Densely Ionizing Radiation under Oxic or Anoxic Conditions

Frankenberg, D.; Frankenberg-Schwager, M.; Blöcher, Detlef; Harbich, R.

doi:10.2307/3575641

Cited by 247 publications

(76 citation statements)

References 13 publications

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“…Corresponding RBE values obtained using the biological weighting function for the intestinal crypt regeneration are also plotted in this figure. It is seen that RBE values increase rapidly at the distal edge of the Bragg peak, reaching a For DNA DSB, the MCDS program simulates the fluence-averaged RBE according to Equations (4)(5)(6). Figure 9 shows the depth-dose distributions calculated using the FLUKA code for 160 MeV proton beam in the water phantom.…”

Section: Resultsmentioning

confidence: 99%

“…Experimental results demonstrated that deoxyribonucleic acid (DNA) double strand break (DSB) plays a key role in biological damages of the irradiated cell. [4] Therefore, those particles with inelastic (ionization and excitation) mean free paths close to a few nanometers (the width of opposite DNA strands) are considered the most critical for the induction of lethal lesions. Such particles with linear energy transfer (LET) close to 100 keV/µm are most effective in inducing the biological effects.…”

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Microdosimetric relative biological effectiveness of therapeutic proton beams

Tung

2015

Biomed J

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I n particle (proton or heavy-ion) therapy, the patient treatment planning includes assessments of radiation dose and radiation quality. Distributions of the absorbed dose and the relative biological effectiveness (RBE), a quality index, in the patient provide essential information in the treatment planning. To facilitate these assessments, the International Atomic Energy Agency and the International Commission on Radiation Units and Measurements (ICRU) have jointly recommended the reporting and recording of isoeffective doses in the treatment plan.[1] The isoeffective dose, that is, the product of absorbed dose and isoeffective weighting factor, of particle beam is defined as the equivalent dose of photon beam under the same irradiation conditions (e.g., 2 Gy per fraction, 5 daily fractions per week, etc.). The key factor determining the isoeffective weighting factor is the RBE. While absorbed dose relates to the total energy deposition in a macroscopic volume of the irradiated tissue, radiation quality regards the single-event energy deposition in a microscopic volume of the biologically sensitive target. [2] When compared to photon beams, particle beams have distinct spatial distributions on the energy depositions in both the macroscopic and microscopic volumes. [3] Such distributions are responsible for the different biological consequences in the tumor and healthy cells during radiotherapy. The macroscopic distribution, that When compared to photon beams, particle beams have distinct spatial distributions on the energy depositions in both the macroscopic and microscopic volumes. In a macroscopic volume, the absorbed dose distribution shows a rapid increase near the particle range, that is, Bragg peak, as particle penetrates deep inside the tissue. In a microscopic volume, individual particle deposits its energy along the particle track by producing localized ionizations through the formation of clusters. These highly localized clusters can induce complex types of deoxyribonucleic acid (DNA) damage which are more difficult to repair and lead to higher relative biological effectiveness (RBE) as compared to photons. To describe the biological actions, biophysical models on a microscopic level have been developed. In this review, microdosimetric approaches are discussed for the determination of RBE at different depths in a patient under particle therapy. These approaches apply the microdosimetric lineal energy spectra obtained from measurements or calculations. Methods to determine these spectra will be focused on the tissue equivalent proportional counter and the Monte Carlo program. Combining the lineal energy spectrum and the biological model, RBE can be determined. Three biological models are presented. A simplified model applies the dose-mean lineal energy and the measured RBE (linear energy transfer) data. A more detailed model makes use of the full lineal energy spectrum and the biological weighting function spectrum. A comprehensive model calculates the spectrum-averaged yields of DNA damages caused by ...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Microdosimetric relative biological effectiveness of therapeutic proton beams

Tung

2015

Biomed J

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“…Radiation-induced DSBs are also potentially lethal in yeast based on evidence that a single double strand break can be lethal in repair deficient mutants (8)(9)(10). Two major pathways for DNA double strand break repair have been identified in eukaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

Use of a Genome-Wide Approach to Identify New Genes that Control Resistance of Saccharomyces cerevisiae to Ionizing Radiation

et al. 2003

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of a genome-wide approach to identify new genes that control resistance of Saccharomyces cerevisiae to ionizing radiation. Radiat ResWe have used the recently completed set of all homozygous diploid deletion mutants in budding yeast, S. cerevisiae, to screen for new mutants conferring sensitivity to ionizing radiation (IR). In each strain a different open reading frame (ORF) has been replaced with a cassette containing unique 20-mer sequences that allow the relative abundance of each strain in a pool to be determined by hybridization to a high-density oligonucleotide array. Putative radiation-sensitive mutants were identified as having a reduced abundance in the pool of 4,627 individual deletion strains following irradiation. Of the top 33 strains most sensitive to IR in this assay, 14 contained genes known to be involved in DNA repair. Eight of the remaining deletion mutants were studied in detail. Only one, that deleted for the ORF YDR014W (which we name RAD61), conferred reproducible radiation sensitivity both in the haploid and diploid deletions and had no problem with spore viability when the haploid was backcrossed to wild-type. The rest showed only marginal sensitivity as haploids, and many had problems with spore viability when backcrossed, suggesting the presence of gross aneuploidy or polyploidy in strains initially presumed haploid. Our results emphasize that secondary mutations or deviations from euploidy can be a problem in screening this resource for sensitivity to IR. Keywords:Saccharomyces cerevisiae, radiosensitive mutants, genome-wide, RAD61, ionizing radiation 3 INTRODUCTIONFor many years the budding yeast Saccharomyces cerevisiae has been an important model system for understanding DNA repair in eukaryotic cells (1). This is primarily a result of the ease of genetic manipulations of this organism and of the remarkable conservation of pathways and genes from yeast to man in the area of DNA repair (2-4).In mammalian cells the most important lesions leading to cell death by ionizing radiation (IR) are believed to be DNA double strand breaks (DSBs), and mutants defective in the repair of these lesions are highly sensitive to radiation-induced cell killing (5-7). Radiation-induced DSBs are also potentially lethal in yeast based on evidence that a single double strand break can be lethal in repair deficient mutants (8-10). Two major pathways for DNA double strand break repair have been identified in eukaryotic cells. The first, homologous recombination (HR), involves exchange of DNA between broken and non-broken DNA strands. This is the major pathway of repair in S. cerevisiae but plays a lesser role in mammalian cells. The second pathway, non-homologous end-joining (NHEJ), which involves direct ligation of the broken ends, is the major pathway for repair of IR-induced DSBs in mammalian cells but plays at most a minor role in repair of IR damage in S. cerevisiae. Despite the lesser importance of HR in repairing radiation induced DSBs in mammalian cells (11,12), it is clearly a pathway of major impo...

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“…To date, there are evidences that DNA is the privileged target giving rise to irradiation damages to cells [1]. The energy deposited by the ionising particles produces critical DNA damages such as base damages or strand breaks, nevertheless it is generally accepted that DNA double strand breaks (DSB) are the main responsible for chromosomal aberrations and cell death [2]. Nowadays, Monte Carlo track calculations are the only method to accurately simulate the energy deposition by ionizing radiation in such small biological structures.…”

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confidence: 99%