Upstream eventEnergy Deposition
Increase, DNA strand breaks
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Direct deposition of ionizing energy onto DNA leading to lung cancer||adjacent||High||High|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Direct deposition of ionizing energy refers to imparted energy interacting directly with the DNA double helix and producing randomized damage in the form of strand breaks. Among the different types of damage, the most detrimental type of DNA damage to a cell is the double-strand break (DSB). DSBs are caused by the breaking of the sugar-phosphate backbone on both strands of the DNA double helix molecule, either directly across from each other or several nucleotides apart (Ward, 1988; Iliakis et al., 2015). The number of DSBs produced and the complexity of the breaks is highly dependent on the amount of energy deposited on and absorbed by the cell. This can vary as a function of the dose-rate (Brooks et al., 2016) and the radiation quality which is a function of its linear energy transfer (LET) (Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012). LET describes the amount of energy that an ionizing particle transfers to media per unit distance (Smith et al., 2003; Okayasu, 2012a; Christensen et al., 2014). High LET radiation, such as alpha particle radiation, can deposit larger quantities of energy within a single track than low LET radiation, such as gamma-ray radiation (Kadhim et al., 2006). As such, radiation with higher LETs tends to produce more complex, dense structural damage, particularly in the form of clustered damage, in comparison to lower LET radiation (Nikjoo et al., 2001; Terato and Ide, 2005; Hada and Georgakilas, 2008; Okayasu, 2012; Lorat et al., 2015; Nikitaki et al., 2016). Thus, the complexity and yield of clustered DNA damage increases with ionizing density (Ward, 1988; Goodhead, 2006). However, clustered damage can also be induced even by a single radiation track through a cell.
Evidence Supporting this KER
The biological rationale linking the direct deposition of energy on DNA with an increase in DSB formation is strongly supported by numerous literature reviews that are available on this topic (J .F. Ward, 1988; Terato & Ide, 2005; Goodhead, 2006; Asaithamby et al., 2008; Hada & Georgakilas, 2008; Okayasu, 2012b; M. E. Lomax et al., 2013; Moore et al., 2014; Desouky et al., 2015; Sage & Shikazono, 2017; Jeggo, 2009). Ionizing radiation can be in the form of high energy particles (such as alpha particles, beta particles, or charged ions) or high energy waves (such as gamma-rays or X-rays). Ionizing radiation can break the DNA within chromosomes both directly and indirectly, as shown through using velocity sedimentation of DNA through neutral and alkaline sucrose gradients. The most direct path entails a collision between a high-energy particle or photon and a strand of DNA. The high-energy subatomic particles can interact with the orbital electrons of the DNA causing ionization (where electrons are ejected from atoms) and excitation (where electrons are raised to higher energy levels) (Joiner, 2009). These processes ultimately break the phosphodiester backbone.
Additionally, excitation of secondary electrons in the DNA allows for a cascade of ionization events to occur, which can lead to the formation of multiple damage sites (Joiner, 2009). As an example, high-speed electrons will traverse a DNA molecule in a mammalian cell within 10-18 s and 10-14 s, resulting in 100,000 ionizing events per 1 Gy dose in a 10 μm cell (Joiner, 2009). The amount of damage can be influenced by factors such as the cell cycle stage and chromatin structure. It has been shown that in more condensed, packed chromatin structures such as those present in intact cells and heterochromatin, it is more difficult for the DNA to be damaged (Radulescu et al., 2006; Agrawala et al., 2008; Falk et al., 2008; Venkatesh et al., 2016). In contrast, DNA damage is more easily induced in lightly-packed chromatin such as euchromatin, nucleoids, and naked genome DNA (Radulescu et al., 2006; Falk et al., 2008; Venkatesh et al., 2016).
DNA damage can be in the form of DSBs, single-strand breaks, base damage, or the crosslinking of DNA to other molecules (Smith et al., 2003; Joiner, 2009; Christensen, 2014; Sage and Shikazono, 2017). Of the possible radiation-induced DNA damage types, DSB is considered to be the most harmful to the cell, as there may be severe consequences if this damage is not adequately repaired (Khanna & Jackson, 2001; Smith et al., 2003; Okayasu, 2012; M. E. Lomax et al., 2013; Rothkamm et al., 2015).
A considerable fraction of DSBs can also be formed in cells through indirect mechanisms. In this case, deposited energy can split water molecules near DNA, which can generate a significant quantity of reactive oxygen species in the form of hydroxyl free radicals (Ward, 1988; Desouky et al., 2015; Maier et al., 2016). Estimates using models and experimental results suggest that hydroxyl radicals may be present within nanoseconds of energy deposition by radiation (Yamaguchi et al., 2005). These short-lived but highly reactive hydroxyl radicals may react with nearby DNA. This will produce DNA damage, including single-strand breaks and DSBs (Ward, 1988; Desouky et al., 2015; Maier et al., 2016). DNA breaks are especially likely to be produced if the sugar moiety is damaged, and DSBs occur when two single-strand breaks are in close proximity to each other (Ward, 1988).
Empirical data strongly supports this KER. The evidence presented below is summarized in table 1, here (click link). The types of DNA damage produced by ionizing radiation and the associated mechanisms, including the induction of DSBs, are reviewed by Lomax et al. (2013) and documents produced by international radiation governing frameworks (Valentine, 1998; UNSCEAR, 2000). Other reviews also highlight the relationship between DSB induction and the deposition of energy by radiation, and discuss the various methods available to detect these DSBs (Terato & Ide, 2005; Rothkamm et al., 2015; Sage & Shikazono, 2017). A visual respresentation of the time frames and dose ranges probed by the dedicated studies discussed here is shown in Figures 1 & 2 below.
Figure 1: Plot of studies (y-axis) against equivalent dose (Sv) used to determine the empircal link between direct deposition of energy and DSBs. The z-axis denotes the equivalent dose rate used in each study. The y-axis is ordered from low LET to high LET from top to bottom.
Figure 2: Plot of studies (y-axis) against time scales used to determine the empircal link between direct deposition of energy and DSBs. The z-axis denotes the equivalent dose rate used in each study. The y-axis is ordered from low LET to high LET from top to bottom.
Dose and Incidence Concordance
There is evidence in the literature suggesting a dose/incidence concordance between the direct deposition of energy by ionizing radiation and the incidence (Grudzenski et al., 2010) of DNA DSBs. Results from in vitro (Rogakou et al., 1999; Sutherland et al., 2000; Lara et al., 2001; Rothkamm and Lo, 2003; Kuhne et al., 2005; Sudprasert et al., 2006; Beels et al., 2009; Grudzenski et al., 2010; Shelke & Das, 2015; Antonelli et al., 2015), in vivo (Sutherland et al., 2000; Rube et al., 2008; Beels et al., 2009; Grudzenski et al., 2010), ex vivo (Rube et al., 2008; Flegal et al., 2015) and simulation studies (Charlton et al., 1989) suggest that there is a dose-dependent increase in DSBs with increasing deposition of energy across a wide range of radiation types (iron ions, X-rays, ultrasoft X-rays, gamma-rays, photons, and alpha particles) and radiation doses (1 mGy - 100 Gy). DSBs have been predicted to occur at energy deposition levels as low as 75 eV (Charlton et al., 1989). Although all the radiation types studied were able to induce DSBs, some types were found to be more damaging in terms of the number of DSBs induced per dose (Lara et al., 2001; Kuhne et al., 2005; Antonelli et al., 2015).
There is evidence suggesting a time concordance between the direct deposition of energy and the incidence of DSBs. A number of different models and experiments have provided evidence of DSBs seconds (Mosconi et al., 2011) or minutes after radiation exposure (Rogakou et al., 1999; Rothkamm and Lo, 2003; Rube et al., 2008; Beels et al., 2009; Kuefner et al., 2009; Grudzenski et al., 2010; Antonelli et al., 2015).
Results from a number of antioxidant studies found that pre-treatment of in vitro and in vivo lymphocytes with various antioxidants resulted in reduced DNA damage in response to radiation exposure (results summarized in a review by (Kuefner et al., 2015)). Similar results were also found in numerous in vitro and in vivo studies using various cell types, rodents, and humans exposed to antioxidants prior to radiation (reviewed by (Smith et al., 2017)). This suggests that deposition of energy on DNA by ionizing radiation is required to produce DNA DSBs.
Uncertainties and Inconsistencies
Uncertainties and inconsistencies in this KER are as follows:
- Studies have shown that dose-rates (Brooks et al., 2016) and radiation quality (Sutherland et al., 2000; Nikjoo et al., 2001; Jorge et al., 2012) are factors that can influence the dose-response relationship.
- Low-dose radiation has been observed to have beneficial effects and may even invoke protection against spontaneous genomic damage (Feinendegen, 2005; Day et al., 2007; Feinendegen et al., 2007; Shah et al., 2012; Nenoi et al., 2015). This protective effect has been documented in in vivo and in vitro, as reviewed by ICRP (2007) and UNSCEAR (2008) and can vary depending on the cell type, the tissue, the organ, or the entire organism (Brooks et al., 2016).
- Depositing ionizing energy is a stochastic event; as such this can influence the location, degree and type of DNA damage imparted on a cell. As an example, studies have shown that mitochondrial DNA may also be an important target for genotoxic effects of ionizing radiation (Wu et al., 1999).
Quantitative Understanding of the Linkage
Quantitative understanding of this linkage suggests that DSBs can be predicted upon exposure to ionizing radiation. This is dependent on the biological model, the type of radiation and the radiation dose. In general, 1 Gy of radiation is thought to result in 3000 damaged bases (Maier et al., 2016), 1000 single-strand breaks, and 40 DSBs (Ward, 1988; Maier et al., 2016) . The table below provides representative examples of the calculated DNA damage rates across different model systems, most of which are examining DNA DSBs.
Under the assumption of 6 pg of DNA per cell. 60 eV of energy deposited per event over a total of 1 Gy. Deoxyribose (2.3 pg/cell): 14,000 eV deposited, 235 events. Bases (2.4 pg/cell): 14,700 eV deposited, 245 events. Phosphate (1.2 pg/cell): 7,300 eV deposited, 120 events. Bound water (3.1 pg/cell): 19,000 eV deposited, 315 events. Inner hydration shell (4.2 pg/cell): 25,000 eV deposited 415 events.
|Charlton, 1989||Simulated dose-concordance prediction of increase in number of DSBs/54 nucleotide pairs as direct deposition of energy increases in the range 75-400 eV. In the range 100 - 150 eV: 0.38 DSBs/54 nucleotide pairs and at 400 eV: ~0.80 DSBs per 64 nucleotide pairs.|
|Sutherland, 2000||Using isolated bacteriophage T7 DNA and 0-100 Gy of gamma radiations, observed a response of 2.4 DSBs per megabase pair per Gy.|
|Rogakou et al., 1999||Radiation doses of 0.6 Gy & 2 Gy to normal human fibroblasts (IMR90) and MCF7 cells resulted in 10.1 & 12.2 DSBs per nucleus on average (0.6 Gy), respectively; increasing to 24 & 27.1 DSBs per nucleus (2 Gy). DSBs present at 3 min, persisted from 15 - 60 min, and then were decreased to almost baseline levels by 180 min.|
|Kuhne et al., 2005||Gamma-ray and X-ray irradiation of primary human skin gibroblasts (HSF2) at 0 - 70 Gy. Gamma-rays: (6.1 ± 0.2) x 10-9 DSBs per base pair per Gy, X-rays: (7.0 ± 0.2) x 10-9 DSBs per base pair per Gy. C_k X-rays: (12.1 ± 1.9) x 10-9 DSBs per base pair per Gy.|
|Rothkamm, 2003||X-ray irradiation of primary human fibroblasts (MRC-5) in the range 1 mGy - 100 Gy, 35 DSBs per cell per Gy.|
|Grudzenski et al, 2010||X-rays irradiating primary human fibroblasts (HSF1) in the range 2.5 - 100 mGy yielded a response of 21 foci per gy. When irradiating adult C57BL/6NCrl mice with photons a response of 0.07 foci per cell at 10 mGy was found. At 100 mGy the response was 0.6 foci per cell and finally, at 1 Gy; 8 foci per cell.|
|de Lara, 2001||V79-4 cells irradiated with gamma-rays and ultrasoft x-rays (carbon K-shell, copper L-shell, aluminium K-shell and titanum K-shell) in the range 0 - 20 Gy. Response (DSBs per Gy per cell): Gamma-rays: 41, carbon K-shell: 112, copper L-shell: 94, aluminum K-shell: 77, titanium K-shell: 56.|
|Rube et al., 2008||Linear dose-dependent increase in DSBs in the brain, small intestine, lung and heart of C57BL/6CNrl mice after whole-body irradiation with 0.1 - 1.0 Gy of radiation. 0.8 foci per cell (0.1 Gy) and 8 foci per cell (1 Gy)|
|Antonelli et al., 2015||Linear dose-dependent increase in the number of DSBs from 0 - 1 Gy for gamma-rays and alpha particles as follows: Gamma-rays: 24.1 foci per Gy per cell nucleus, alpha particles: 8.8 foci per Gy per cell nucleus.|
|Dubrova & Plumb, 2002||At 1 Gy observe 70 DSBs, 1000 single-strange breaks and 2000 damaged DNA bases per cell per Gy.|
There is evidence of a response-response relationship between the deposition of energy and the frequency of DSBs. In studies encompassing a variety of biological models, radiation types and radiation doses, a positive, linear relationship was found between the radiation dose and the number of DSBs (Sutherland et al., 2000; de Lara et al., 2001; Rothkamm & Lo, 2003; Kuhne et al., 2005; Rube et al., 2008; Grudzenski et al., 2010; Shelke & Das, 2015; Antonelli et al., 2015). There were, however, two exceptions reported. When human blood lymphocytes were irradiated with X-rays in vitro, a linear relationship was only found for doses ranging from 6 - 500 mGy; at low doses from 0 - 6 mGy, there was a quadratic relationship reported (Beels et al., 2009). Secondly, simulation studies predicted that there would be a non-linear increase in DSBs as energy deposition increased, with a saturation point at higher LETs (Charlton et al., 1989).
Data from temporal response studies suggests that DSBs likely occur within seconds to minutes of energy deposition by ionizing radiation. In a variety of biological models, the presence of DSBs has been well documented within 10 - 30 minutes of radiation exposure (Rogakou et al., 1999; Rube et al., 2008; Beels et al., 2009; Kuefner et al., 2009; Grudzenski et al., 2010; Antonelli et al., 2015); there is also evidence that DSBs may actually be present within 3 - 5 minutes of irradiation (Rogakou et al., 1999; Rothkamm & Lo, 2003; Rube et al., 2008; Grudzenski et al., 2010). Interestingly, one study that focussed on monitoring the cells before, during and after irradiation by taking photos every 5, 10 or 15 seconds found that foci indicative of DSBs were present 25 and 40 seconds after collision of the alpha particles and protons with the cell, respectively. The number of foci were found to increase over time until plateauing at approximately 200 seconds after alpha particle exposure and 800 seconds after proton exposure (Mosconi et al., 2011).
After the 30 minute mark, DSBs have been shown to rapidly decline in number. By 24 hours post-irradiation, DSB numbers had declined substantially in systems exposed to radiation doses between 40 mGy and 80 Gy (Rothkamm & Lo, 2003; Rube et al., 2008; Grudzenski et al., 2010; Russo et al., 2015; Antonelli et al., 2015), with the sharpest decrease documented within the first 5 hours (Rogakou et al., 1999; Rube et al., 2008; Kuefner et al., 2009; Grudzenski et al., 2010; Shelke and Das, 2015). Interestingly, DSBs were found to be more persistent when they were induced by higher LET radiation (Antonelli et al., 2015).
Known modulating factors
Some common clinical radiation modifiers include cisplatin, 5-fluorouracil, thiols, and nitroxides (reviewed in (Citrin and Mitchel, 2014)). Clinical approaches have identified many modulating radiation factors, which are often categorized as either sensitizers or protectors. Sensitizers enhance radiation-induced tumour cell killing, and protectors protect normal tissues from the deleterious effects of ionizing radiation (Citrin & Mitchel, 2014).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability relates to all eukaryotic species that contain genetic information in the form of a double strand helix of DNA (Parris et al., 2015; Cannan & Pederson, 2016).
Agrawala, P. K. et al., (2008), Induction and repairability of DNA damage caused by ultrasoft X-rays: Role of core events. Int J Radiat Biol. 84(12):1093–1103. doi:10.1080/09553000802478083.
Antonelli, A. F. et al., (2015), Induction and Repair of DNA DSB as Revealed by H2AX Phosphorylation Foci in Human Fibroblasts Exposed to Low- and High-LET Radiation : Relationship with Early and Delayed Reproductive Cell Death Induction and Repair of DNA DSB as Revealed by H2AX Phosphor. doi:10.1667/RR13855.1.
Asaithamby, A. et al., (2008), Repair of HZE-Particle-Induced DNA Double-Strand Breaks in Normal Human Fibroblasts. Radiat Res. 169(4):437–446. doi:10.1667/RR1165.1.
Beels, L. et al., (2009), g-H2AX Foci as a Biomarker for Patient X-Ray Exposure in Pediatric Cardiac Catheterization Are We Underestimating Radiation Risks ? :1903–1909. doi:10.1161/CIRCULATIONAHA.109.880385.
Brooks, A. L., D. G. Hoel & R. J. Preston, (2016), The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation. Int J Radiat Biol. 92(8):405–426. doi:10.1080/09553002.2016.1186301.
Cannan, W. J. & D. S. Pederson, (2016), Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin. J Cell Physiol. 231(1):3–14. doi:10.1002/jcp.25048.
Charlton, D. E., H. Nikjoo & J. L. Humm, (1989), Calculation of initial yields of single- and double-strand breaks in cell nuclei from electrons , protons and alpha particles.
Christensen, D. M., (2014), Management of Ionizing Radiation Injuries and Illnesses, Part 3: Radiobiology and Health Effects of Ionizing Radiation. 114(7):556–565. doi:10.7556/jaoa.2014.109.
Citrin, D. E., J. B. Mitchel. (2014), Public Access NIH Public Access. 71(2):233–236. doi:10.1038/mp.2011.182.doi.
Day, T. K. et al., (2007), Adaptive Response for Chromosomal Inversions in pKZ1 Mouse Prostate Induced by Low Doses of X Radiation Delivered after a High Dose. Radiat Res. 167(6):682–692. doi:10.1667/rr0764.1.
Desouky, O., N. Ding, G. Zhou, (2015), ScienceDirect Targeted and non-targeted effects of ionizing radiation. J Radiat Res Appl Sci. 8(2):247–254. doi:10.1016/j.jrras.2015.03.003.
Dubrova, Y. E., M. A. Plumb, (2002), Ionising radiation and mutation induction at mouse minisatellite loci The story of the two generations ଝ. 499:143–150.
Falk, M., E. Lukášová and S. Kozubek, (2008), Chromatin structure influences the sensitivity of DNA to γ-radiation. Biochim Biophys Acta - Mol Cell Res. 1783(12):2398–2414. doi:10.1016/j.bbamcr.2008.07.010.
Feinendegen, L. E., (2005), UKRC 2004 debate Evidence for beneficial low level radiation effects and radiation hormesis. Radiology. 78:3–7. doi:10.1259/bjr/63353075.
Feinendegen, L. E., M. Pollycove & R. D. Neumann, (2007), Whole-body responses to low-level radiation exposure: New concepts in mammalian radiobiology. Exp Hematol. 35(4 SUPPL.):37–46. doi:10.1016/j.exphem.2007.01.011.
Flegal, M., M. S. Blimkie, H. Wyatt, M. Bugden, J. Surette, D. Klokov, (2015), Measuring DNA Damage and Repair in Mouse Splenocytes After Chronic In Vivo Exposure to Very Low Doses of Beta- and Gamma-Radiation. (July):1–9. doi:10.3791/52912.
Goodhead, D. T., (2006), Energy deposition stochastics and track structure: What about the target? Radiat Prot Dosimetry. 122(1–4):3–15. doi:10.1093/rpd/ncl498.
Grudzenski, S. et al., (2010), Inducible response required for repair of low-dose radiation damage in human fi broblasts. doi:10.1073/pnas.1002213107.
Hada, M. & A.G. Georgakilas, (2008), Formation of Clustered DNA Damage after High-LET Irradiation : A Review. 49(3):203–210. doi:10.1269/jrr.07123.
Iliakis, G. T. Murmann & A. Soni, (2015), Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations. Mutat Res - Genet Toxicol Environ Mutagen. 793:166–175. doi:10.1016/j.mrgentox.2015.07.001.
Joiner, M, (2009), Basic Clinical Radiobiology Edited by.  PJ Sadler, Next-Generation Met Anticancer Complexes Multitargeting via Redox Modul Inorg Chem 52 21.:375. doi:10.1201/b13224.
Jorge, S.-G. et al., (2012), Evidence of DNA double strand breaks formation in Escherichia coli bacteria exposed to alpha particles of different LET assessed by the SOS response. Appl Radiat Isot. 71(SUPPL.):66–70. doi:10.1016/j.apradiso.2012.05.007.
Kadhim, M. A., M. A. Hill & S. R. Moore, (2006), Genomic instability and the role of radiation quality. Radiat Prot Dosimetry. 122(1–4):221–227. doi:10.1093/rpd/ncl445.
Khanna, K. K., S. P. Jackson, (2001), DNA double-strand breaks : signaling , repair and the cancer connection. Nature Genetics. 27(3):247-54. doi:10.1038/85798.
Kuefner, M. A. et al., (2009), DNA Double-Strand Breaks and Their Repair in Blood Lymphocytes of Patients Undergoing Angiographic Procedures. Investigative radiology. 44(8):440-6. doi:10.1097/RLI.0b013e3181a654a5.
Kuefner, M. A. et al., (2015), Chemoprevention of Radiation-Induced DNA Double-Strand Breaks with Antioxidants. :1–6. doi:10.1007/s40134-014-0081-9.
Kuhne, M., G. Urban & M. Lo, (2005), DNA Double-Strand Break Misrejoining after Exposure of Primary Human Fibroblasts to C K Characteristic X Rays , 29 kVp X Rays and Co g Rays. Radiation Research. 164(5):669-676. doi:10.1667/RR3461.1.
Lara CM De, Hill MA, Jenner TJ, Papworth D. 2001. Dependence of the Yield of DNA Double-Strand Breaks in Chinese Hamster V79-4 Cells on the Photon Energy of Ultrasoft X Rays. Radiation Research. 155(3):440-8. doi:10.1667/0033-7587(2001)155[0440:DOTYOD]2.0.CO;2.
Lomax M E, Folkes LK, Neill PO. 2013. Biological Consequences of Radiation-induced DNA Damage : Relevance to Radiotherapy Statement of Search Strategies Used and Sources of Information Why Radiation Damage is More Effective than Endogenous Damage at Killing Cells Ionising Radiation-induced Do. 25:578–585. doi:10.1016/j.clon.2013.06.007.
Lomax M. E., Folkes LK, O’Neill P. 2013. Biological consequences of radiation-induced DNA damage: Relevance to radiotherapy. Clin Oncol. 25(10):578–585.doi:10.1016/j.clon.2013.06.007.
Lorat Y, Brunner CU, Schanz S, Jakob B, Taucher-scholz G, Rübe CE. 2015. Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy – The heavy burden to repair. DNA Repair (Amst). 28:93–106. doi:10.1016/j.dnarep.2015.01.007.
Maier P, Hartmann L, Wenz F, Herskind C. 2016. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization. doi:10.3390/ijms17010102.
Moore S, Stanley FKT, Goodarzi AA. 2014. The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation – No simple task. DNA repair. 17:64–73. doi: 10.1016/j.dnarep.2014.01.014.
Mosconi M, Giesen U, Langner F. 2011. 53BP1 and MDC1 foci formation in HT-1080 cells for low- and high-LET microbeam irradiations. :345–352. doi:10.1007/s00411-011-0366-9.
Nenoi M, Wang B, Vares G. 2015. In vivo radioadaptive response: A review of studies relevant to radiation-induced cancer risk. Hum Exp Toxicol. 34(3):272–283. doi:10.1177/0960327114537537.
Nikitaki Z, Nikolov V, Mavragani I V, Mladenov E, Mangelis A, Laskaratou DA, Fragkoulis GI, Hellweg E, Martin OA, Emfietzoglou D, et al. 2016. Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer ( LET ). 5762. doi:10.1080/10715762.2016.1232484.
Nikjoo H, O’Neill P, Wilson WE, Goodhead DT. 2001. Computational approach for determining the spectrum of DNA damage induced by ionizing radiation. Radiat Res. 156(5 Pt 2):577–83.
Okayasu R. 2012a. Repair of DNA damage induced by accelerated heavy ions-A mini review. Int J Cancer. 130(5):991–1000. doi:10.1002/ijc.26445.
Okayasu R. 2012b. heavy ions — a mini review. 1000:991–1000. doi:10.1002/ijc.26445.
Parris CN, Adam Zahir S, Al-Ali H, Bourton EC, Plowman C, Plowman PN. 2015. Enhanced γ-H2AX DNA damage foci detection using multimagnification and extended depth of field in imaging flow cytometry. Cytom Part A. 87(8):717–723. doi:10.1002/cyto.a.22697.
Radulescu I, Elmroth K, Stenerlöw B. 2006. Chromatin Organization Contributes to Non-randomly Distributed Double-Strand Breaks after Exposure to High-LET Radiation. Radiat Res. 161(1):1–8. doi:10.1667/rr3094.
Rogakou EP, Boon C, Redon C, Bonner WM. 1999. Megabase Chromatin Domains Involved in DNA Double-Strand Breaks In Vivo. The Journal of Cell Biology. 146(5):905-16. doi: 10.1083/jcb.146.5.905.
Rothkamm K, Barnard S, Moquet J, Ellender M, Rana Z, Burdak-rothkamm S. 2015. Review DNA Damage Foci : Meaning and Significance. 504(March). doi:10.1002/em.
Rothkamm K, Lo M. 2003. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proceedings of the National Academy of Sciences. 100(9):5057-62. doi: 10.1073/pnas.0830918100.
Rube CE, Grudzenski S, Ku M, Dong X, Rief N, Lo M, Ru C. 2008. Cancer Therapy : Preclinical DNA Double-Strand Break Repair of Blood Lymphocytes and Normal Tissues Analysed in a Preclinical Mouse Model : Implications for Radiosensitivity Testing. 14(20):6546–6556. doi:10.1158/1078-0432.CCR-07-5147.
Russo A, Pacchierotti F, Cimini D, Ganem NJ, Genesc A, Natarajan AT, Pavanello S, Valle G, Degrassi F. 2015. Review Article Genomic Instability : Crossing Pathways at the Origin of Structural and Numerical Chromosome Changes. 580(March). doi:10.1002/em.
Sage E, Shikazono N. 2017. Free Radical Biology and Medicine Radiation-induced clustered DNA lesions : Repair and mutagenesis. Free Radic Biol Med. 107(December 2016):125–135. doi:10.1016/j.freeradbiomed.2016.12.008.
Shah DJ, Sachs RK, Wilson DJ. 2012. Radiation-induced cancer: A modern view. Br J Radiol. 85(1020):1166–1173. doi:10.1259/bjr/25026140.
Shelke S, Das B. 2015. Dose response and adaptive response of non- homologous end joining repair genes and proteins in resting human peripheral blood mononuclear cells exposed to γ radiation. (December 2014):365–379. doi:10.1093/mutage/geu081.
Smith J, Riballo E, Kysela B, Baldeyron C, Manolis K, Masson C, Lieber MR, Papadopoulo D, Jeggo P. 2003. Impact of DNA ligase IV on the delity of end joining in human cells. Nucleic Acids Research. 31(8):2157-2167.doi:10.1093/nar/gkg317.
Smith TA, Kirkpatrick DR, Smith S, Smith TK, Pearson T, Kailasam A, Herrmann KZ, Schubertv J, Agrawal DK. 2017. Radioprotective agents to prevent cellular damage due to ionizing radiation. Journal of Translational Medicine .15(1).doi:10.1186/s12967-017-1338-x.
Sudprasert W, Navasumrit P, Ruchirawat M. 2006. Effects of low-dose gamma radiation on DNA damage , chromosomal aberration and expression of repair genes in human blood cells. 209:503–511. doi:10.1016/j.ijheh.2006.06.004.
Sutherland BM, Bennett P V, Sidorkina O, Laval J. 2000. Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation. Journal of Radiation Research. 43 Suppl(S):S149-52. doi: 10.1269/jrr.43.S149
Terato H, Ide H. 2005. Clustered DNA damage induced by heavy ion particles. Biol Sci Sp. 18(4):206–215. doi:10.2187/bss.18.206.
Valentin JDJ. 1998. Chapter 1. Ann ICRP. 28(4):5–7. doi:10.1016/S0146-6453(00)00002-6. http://www.ncbi.nlm.nih.gov/pubmed/10882804.
Venkatesh P, Panyutin I V., Remeeva E, Neumann RD, Panyutin IG. 2016. Effect of chromatin structure on the extent and distribution of DNA double strand breaks produced by ionizing radiation; comparative study of hESC and differentiated cells lines. Int J Mol Sci. 17(1). doi:10.3390/ijms17010058.
Ward, J. F. 1988. DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Reparability. Prog Nucleic Acid Res Mol Biol. 35(C):95–125. doi:10.1016/S0079-6603(08)60611-X.
Wu L-J, Randers-Pehrson G, Xu A, Waldren CA, Geard CR, Yu Z, Hei TK. 1999. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci. 96(9):4959–4964. doi:10.1073/pnas.96.9.4959.
Yamaguchi H, Uchihori Y, Yasuda N, Heavy E. 2005. Estimation of Yields of OH Radicals in Water Irradiated by Ionizing Radiation. Journal of Radiation Research. 46(3):333-41. doi: 10.1269/jrr.46.333.