scholarly journals Calculated relative biological effectiveness (RBE) for initial DNA double-strand breaks (DSB) from flattening filter and flattening filter-free 6 MV X-ray fields

BJR|Open ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 20200072
Author(s):  
Hisashi Nakano ◽  
Daisuke Kawahara ◽  
Satoshi Tanabe ◽  
Satoru Utsunomiya ◽  
Takeshi Takizawa ◽  
...  
Keyword(s):  
Relative Biological Effectiveness ◽  
Double Strand Breaks ◽  
Central Axis ◽  
X Rays ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Depth Measurement ◽  
Dna Dsbs ◽  
Flattening Filter ◽  
Biological Effectiveness

Objectives: We evaluated the radiobiological effectiveness based on the yields of DNA double-strand breaks (DSBs) of field induction with flattening filter (FF) and FF-free (FFF) photon beams. Methods: We used the particle and heavy ion transport system (PHITS) and a water equivalent phantom (30 × 30 × 30 cm3) to calculate the physical qualities of the dose-mean lineal energy (yD) with 6 MV FF and FFF. The relative biological effectiveness based on the yields of DNA-DSBs (RBEDSB) was calculated for standard radiation such as 220 kVp X-rays by using the estimating yields of SSBs and DSBs. The measurement points used to calculate the in-field yD and RBEDSB were located at a depth of 3, 5, and 10 cm in the water equivalent phantom on the central axis. Measurement points at 6, 8, and 10 cm in the lateral direction of each of the three depths from the central axis were set to calculate the out-of-field yD and RBEDSB. Results: The RBEDSB of FFF in-field was 1.7% higher than FF at each measurement depth. The RBEDSB of FFF out-of-field was 1.9 to 6.4% higher than FF at each depth measurement point. As the distance to out-of-field increased, the RBEDSB of FFF rose higher than those of FF. FFF has a larger RBEDSB than FF based on the yields of DNA-DSBs as the distance to out-of-field increased. Conclusions: The out-of-field radiobiological effect of FFF could thus be greater than that of FF since the spreading of the radiation dose out-of-field with FFF could be a concern compared to the FF. Advances in knowledge: The RBEDSB of FFF of out-of-field might be larger than FF.

scholarly journals Restrictions Limiting the Generation of DNA Double Strand Breaks during Chromosomal V(D)J Recombination

2002 ◽  
Vol 195 (3) ◽  
pp. 309-316 ◽  
Author(s):  
Robert E. Tillman ◽  
Andrea L. Wooley ◽  
Maureen M. Hughes ◽  
Tara D. Wehrly ◽  
Wojciech Swat ◽  
...  
Keyword(s):  
Dna Cleavage ◽  
Receptor Gene ◽  
Antigen Receptor ◽  
Double Strand Breaks ◽  
Recombination Reaction ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Recombination Signal Sequences ◽  
Dna Dsbs ◽  
Cleavage Step

Antigen receptor loci are composed of numerous variable (V), diversity (D), and joining (J) gene segments, each flanked by recombination signal sequences (RSSs). The V(D)J recombination reaction proceeds through RSS recognition and DNA cleavage steps making it possible for multiple DNA double strand breaks (DSBs) to be introduced at a single locus. Here we use ligation-mediated PCR to analyze DNA cleavage intermediates in thymocytes from mice with targeted RSS mutations at the endogenous TCRβ locus. We show that DNA cleavage does not occur at individual RSSs but rather must be coordinated between RSS pairs flanking gene segments that ultimately form coding joins. Coordination of the DNA cleavage step occurs over great distances in the chromosome and favors intra- over interchromosomal recombination. Furthermore, through several restrictions imposed on the generation of both nonpaired and paired DNA DSBs, this requirement promotes antigen receptor gene integrity and genomic stability in developing lymphocytes undergoing V(D)J recombination.

scholarly journals An Oligomerized 53BP1 Tudor Domain Suffices for Recognition of DNA Double-Strand Breaks

2008 ◽  
Vol 29 (4) ◽  
pp. 1050-1058 ◽  
Author(s):  
Omar Zgheib ◽  
Kristopher Pataky ◽  
Juergen Brugger ◽  
Thanos D. Halazonetis
Keyword(s):  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Checkpoint Proteins ◽  
Strand Breaks ◽  
Histone H2ax ◽  
Dna Dsbs ◽  
Tudor Domain ◽  
Histone Core ◽  
Histone H2ax Phosphorylation ◽  
Oligomerization Domain

ABSTRACT 53BP1, the vertebrate ortholog of the budding yeast Rad9 and fission yeast Crb2/Rhp9 checkpoint proteins, is recruited rapidly to sites of DNA double-strand breaks (DSBs). A tandem tudor domain in human 53BP1 that recognizes methylated residues in the histone core is necessary, but not sufficient, for efficient recruitment. By analysis of deletion mutants, we identify here additional elements in 53BP1 that facilitate recognition of DNA DSBs. The first element corresponds to an independently folding oligomerization domain. Replacement of this domain with heterologous tetramerization domains preserves the ability of 53BP1 to recognize DNA DSBs. A second element is only about 15 amino acids long and appears to be a C-terminal extension of the tudor domain, rather than an independently functioning domain. Recruitment of 53BP1 to sites of DNA DSBs is facilitated by histone H2AX phosphorylation and ubiquitination. However, none of the 53BP1 domains/elements important for recruitment are known to bind phosphopeptides or ubiquitin, suggesting that histone phosphorylation and ubiquitination regulate 53BP1 recruitment to sites of DNA DSBs indirectly.

Detecting, signalling and repairing DNA double-strand breaks

2001 ◽  
Vol 29 (6) ◽  
pp. 655-661 ◽  
Author(s):  
S. P. Jackson
Keyword(s):  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Double Strand Breaks ◽  
Model Organisms ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Site Specific ◽  
Strand Breaks ◽  
Dna Dsbs ◽  
Recombination Processes

DNA double-strand breaks (DSBs) can be generated by a variety of genotoxic agents, including ionizing radiation and radiomimetic chemicals. They can also occur when DNA replication complexes encounter other forms of DNA damage, and are produced as intermediates during certain site-specific recombination processes. It is crucial that cells recognize DSBs and bring about their efficient repair, because a single unrepaired cellular DSB can induce cell death, and defective DSB repair can lead to mutations or the loss of significant segments of chromosomal material. Eukaryotic cells have evolved a variety of systems to detect DNA DSBs, repair them, and signal their presence to the transcription, cell cycle and apoptotic machineries. In this review, I describe how work on mammalian cells and also on model organisms such as yeasts has revelaed that such systems are highly conserved throughout evolution, and has provided insights into the molecular mechanisms by which DNA DSBs are recognized, signalled and repaired. I also explain how defects in the proteins that function in these pathways are associated with a variety of human pathological states.

scholarly journals The Determinant of DNA Repair Pathway Choices in Ionising Radiation-Induced DNA Double-Strand Breaks

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Lei Zhao ◽  
Chengyu Bao ◽  
Yuxuan Shang ◽  
Xinye He ◽  
Chiyuan Ma ◽  
...  
Keyword(s):  
Dna Repair ◽  
Double Strand Breaks ◽  
Ionising Radiation ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Dna Dsbs ◽  
Repair Pathways

Ionising radiation- (IR-) induced DNA double-strand breaks (DSBs) are considered to be the deleterious DNA lesions that pose a serious threat to genomic stability. The major DNA repair pathways, including classical nonhomologous end joining, homologous recombination, single-strand annealing, and alternative end joining, play critical roles in countering and eliciting IR-induced DSBs to ensure genome integrity. If the IR-induced DNA DSBs are not repaired correctly, the residual or incorrectly repaired DSBs can result in genomic instability that is associated with certain human diseases. Although many efforts have been made in investigating the major mechanisms of IR-induced DNA DSB repair, it is still unclear what determines the choices of IR-induced DNA DSB repair pathways. In this review, we discuss how the mechanisms of IR-induced DSB repair pathway choices can operate in irradiated cells. We first briefly describe the main mechanisms of the major DNA DSB repair pathways and the related key repair proteins. Based on our understanding of the characteristics of IR-induced DNA DSBs and the regulatory mechanisms of DSB repair pathways in irradiated cells and recent advances in this field, We then highlight the main factors and associated challenges to determine the IR-induced DSB repair pathway choices. We conclude that the type and distribution of IR-induced DSBs, chromatin state, DNA-end structure, and DNA-end resection are the main determinants of the choice of the IR-induced DNA DSB repair pathway.

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