Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance
Abstract
:1. Introduction
2. Radiobiological Modeling and Simulations: A Useful Tool for Prediction and Experimental Data Interpretation
2.1. Monte Carlo Simulations for DNA Damage
2.2. Modeling of Radiation Effects in Biological Material
2.3. Radiation Transport and Track-Structure Codes for Radiation-Induced Damage
2.4. Key Conclusions
- The majority of damage events are of simple type containing an SSB. Strand breaks of greater complexity appear at high frequencies.
- The complexity of damage increases with LET.
- The yield of both single- and double-strand breaks per gray and per Dalton is nearly constant over a wide range of LETs.
- For low-LET radiations, nearly 20% of the DSBs are of complex type. The proportion of this clustered damage increases with LET, reaching ~70% or higher for high-LET radiations.
- When base damage is also taken into account, the proportion of complex DSBs increases for all radiations, reaching more than 90% for the higher LETs.
- Experiments show a slower rate of repair of DSBs produced by high-LET radiations.
3. Detection of Complex DNA Damage
3.1. The In Situ Detection of Complex DNA Damage and the Colocalization Concept
- The damaging factor (irradiation, chemical reagent, or genetically engineered clones);
- The visualization target (the damage itself or a participating repair enzyme);
- The labeling method (immuno-labeling or fluorescent labeling);
- The imaging apparatus (static or live cell imaging);
- The image analysis (static or tracking).
3.2. Damage Induction
3.3. Damage Visualization: Direct or Indirect
3.4. Labeling Techniques
3.4.1. Immunolabeling—Fixed Cells
In Situ Immunofluorescence-Fluorophore Conjugated Antibodies
Transmission Electron Microscopy (TEM) Analysis—Nanoparticle Conjugated Antibodies
Proximity Ligation Assay―In Situ PLA
3.4.2. Live Cell Imaging
Encoding Fluorescence Labeled Proteins
Fluorogenic Dyes
3.5. Imaging: Microscopy and Image Analysis
3.5.1. Microscopy: TEM and Fluorescence Microscopy
Conventional (Widefield) Fluorescence Microscopy
Confocal Microscopy: Scanning Laser or Spinning Disk
Super Resolution Microscopy (SRM): Beyond the Diffraction Limit
3.5.2. Image Analysis: Co-Localization Coefficients, Parameters, and Methods
Defining an Extra Type of Foci
3.6. DNA Sequencing for Genome-Wide Nucleotide-Resolution DNA Damage Identification
- NGR detects and labels the nick-gaps, induced during DNA replication [118].
- BLISS can detect DSBs induced by endonucleases, using their corresponding unique molecular identifiers (UMIs) [119].
- BLESS is able to detect DSBs at nucleotide resolution. It is independent of proteins that bind to DNA or single-stranded DNA, which are both sources of bias. BLESS’ innovation is that it uses an amplification step for the fragments created by two DSBs [120].
- i-BLESS is a BLESS adaptation that is suitable for very small and fragile cell genomes (yeast), while it achieves the incredible detection accuracy of one DSB per 105 cells [121].
4. Biological Response to Clustered DNA Damage and Its Significance
4.1. The Role of Delayed Repair
4.2. Double-Strand Break Clustering
4.3. Carcinogenesis Associated with Clustered DNA Damage
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Code | Particles | Pros | Cons | Ref. |
---|---|---|---|---|
EGS4 | photons & e- | Developed specifically for dose calculations in RT applications | Not applicable at the nanoscale due to limitations of the physics models | [47] |
FLUKA | Large set of particles | Multipurpose code covering medical, space, nuclear, and high-energy applications | Closed-source code. Not applicable at the nanoscale due to limitations of the physics models | [48,49] |
Geant4 | large set of particles | Open-source toolkit covering medical, space, nuclear, and high-energy applications. Contains powerful visualization packages. Includes low-energy physics models for sub-keV transport. Maintained by a large international collaboration | Complex toolkit. Computationally intensive. Requires users with advanced programming skills. | [41,50] |
Geant4-DNA | Large set of particles | Performs event-by-event simulation for track-structure applications in liquid water. Includes a variety of low-energy electron models. Includes chemistry (water radiolysis) and biology (DNA damage and repair models) Maintained by a large international collaboration and continuously upgraded | Complex toolkit. Computationally intensive. Requires users with advanced programming skills. | [51,52] |
KURBUC | Photons, neutrons, electrons, protons, alpha, carbon ions | Performs event-by-event simulations down to very low energies for track-structure applications. Includes physics models for both gaseous and liquid water medium. Includes chemistry (water radiolysis) and biology (DNA damage and repair models) | Proprietary code. Specific to water medium. | [53,54] |
MC4 | e-, protons, α-particles | Performs event-by-event simulations down to low-energies for track-structure applications. Includes physics models for both gaseous and liquid water medium. Known for its upgraded models for the liquid phase. | Proprietary code. Specific to water. Does not extend to relativistic energies. | [55,56,57,58] |
MCDS | e-, p, alpha particles & ions | Simulates in a very fast way (ranging from seconds to minutes) the induction and clustering of DNA lesions. | Lacks accuracy. Impossible to generate damage configurations for e- with energy lower than 80 eV. | [59] |
MCNP | Large set of particles | Multipurpose code covering nuclear and medical applications. Known for its accurate neutron models. | Not a free access code. | [60] |
PARTRAC | e- & ions | Performs event-by-event simulation for track-structure applications. Uses physics models specifically developed for liquid water. Includes chemistry (water radiolysis) and biology (DNA damage and repair models) | Proprietary code. Specific to water. Does not include relativistic energies. The parameterization of the DNA model does not consider the DNA atomic composition. | [17,61] |
PENELOPE | Photons, e- & e+ | Developed for dose calculations in radiotherapy applications. Known for its electron models that extend to low-energies. Event-by-event simulations possible for application to microdosimetry | Limited track-structure applications due the incomplete simulation of electron track ends. Requires users with advanced programming skills to develop their own applications. | [62] |
PEREGRINE | Large set of particles | Developed for radiotherapy treatment planning. | Gives results through a computer cluster. Not applicable at the nanoscale due to limitations of the physics models | [63] |
RITRACKS | e- & ions | Performs event-by-event simulation up to relativistic energies. Simulation of radiation tracks without the need of extensive knowledge of computer programming. Simple in use. | Distributed only to authorized users. Specific to water. Uses atomic cross sections that are not reliable for nanoscale transport in liquid water. | [64] |
Topas-nBio | large set of particles | Uses Geant4-DNA as its transport engine. Simply to use software specifically developed for radiobiological applications at the (sub) cellular level. | Not (yet) open-sourced. Specific to water medium. | [65] |
TRAX | e- & ions | Performs event-by-event simulation for track-structure applications in various media. | Uses atomic cross sections that are not reliable for nanoscale transport in condensed-phase media. | [66] |
Cell Type | Radiation Type | Biological Response | Ref. |
---|---|---|---|
HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A and UMSCC6) cells | High-LET α-particles (121 keV/μm) or protons (12 keV/μm), versus low-LET protons (1 keV/μm) and X-rays | Τhe signaling and repair of complex DNA damage, particularly induced by high-LET IR is coordinated through the specific induction of H2Bub catalyzed by MSL2 and RNF20/40, a mechanism that contributes to decreased cell survival after irradiation. | [125,130] |
Human peripheral blood lymphocytes | Mixed beam of alpha-particles (241Am source, 0.223 Gy/min, LET: 90.9 keV/μm) and X-rays (190 kV, 4.0 mA, 0-2 Gy) | Induced DNA damage was above the level predicted by assuming additivity. The activation levels of DDR proteins and mRNA levels of the studied genes were highest in cells exposed to mixed beams. The repair of damage occurs with a delay. | [131] |
Human dermal fibroblasts | High-LET IR with carbon ions (9.5 MeV/n; LET 190 keV/μm; calculated mean dose: 1.52 Gy) or calcium ions (7.7 MeV/n; LET 1800 keV/μm; calculated mean dose: 14.4 Gy), versus low-LET IR with 6-MV photons (10 Gy) | High-LET-IR induced clustered DNA damage and triggered profound changes in chromatin structure along particle trajectories. DSBs exhibited delayed repair despite cooperative activity of 53BP1, pATM, pKap-1. | [26] |
Normal human skin fibroblasts | 60Co γ-rays (LET=0.3 keV/μm), accelerated 11B (E = 8.1 MeV/nucleon, LET=138 keV/μm) ions | It has been found that heavy charged particles induce clustered DNA damage in the genome of cells that can lead not only to gene mutations, but also to large deletions. | [132] |
HeLa Kyoto cells | Pulsed UV laser (micro-irradiation, IR) | Recruitment and dissociation of 70 DNA repair proteins to laser-induced complex DNA lesions. | [83] |
Human uveal melanoma (92–1) cells | Carbon ions (LET: 80 keV/μm) and iron ions (LET: 400 keV/μm) at different doses, versus X-rays (LET: 4 keV/μm) | Heavy ions were more effective at inducing senescence than X-rays. Less-efficient repair was observed when DNA damage was induced by heavy ions compared to X-rays and most of the irreparable damage was complex of SSBs and DSBs, while DNA damage induced by X-rays was mostly repaired in 24 h. Results suggest that DNA damage induced by heavy ion is complex and difficult to repair, thus presenting as persistent DNA damage, and pushes the cell into senescence. | [128] |
Human dermal fibroblasts, NFFh-TERT foreskin fibroblasts | Low-LET irradiation with 6 MV photons, versus high-LET irradiation with carbon ions (9.5 MeV/n; LET = 190 keV/μm) | High-LET irradiation caused localized energy deposition within the particle tracks and generated highly clustered DNA lesions with multiple DSBs in close proximity. Ηuge DSB clusters predominantly localized in condensed heterochromatin. High-LET irradiation-induced clearly higher DSB yields than low-LET irradiation, and large fractions of these heterochromatic DSBs remained unrepaired. | [24] |
Human osteosarcoma cell line (U2-OS) | X-rays (250 keV, 16 mA; LET: 2 keV/μm), versus heavy ions: 238U ions (LET: 15,000 keV/μm), 207Pb ions (LET: 13,500 keV/μm), 197Au ions (LET: 13,000 keV/μm), 119Sn ions (LET: 7,880 keV/μm), 59Ni (LET: 3,430 keV/μm), 48Ti (LET: 2,180 keV/μm), 14N ions (LET: 400 keV/μm), and 12C ions (LET: 170 keV/μm) | DSB complexity plays a critical role in the decision for DSB end-resection in G1-cells. CtIP, MRE11, and EXO1 are required for the resection of complex DSBs in G. Repair of complex DSBs relies on resection independent of the cell cycle stage. | [133] |
Human cells (fibroblasts, HBECs) | 1 Gy of Si (LET: 44 keV/μm) or Fe (LET: 150 keV/μm) ions | Direct visualization of clustered DNA lesions at the single-cell level using 53BP1, XRCC1, and hOGG1 as surrogate markers for DSBs, SSBs, and base damage, respectively, reveals that most complex DNA damage is not repaired in human cells. Unrepaired clustered DNA lesions result in the generation of a spectrum of chromosome aberrations. Checkpoint release before the completion of clustered DNA damage repair is a major cause of chromosomal aberrations. | [23] |
Human Lung Adenocarcinoma (A5490) cells | 12C ions (62 MeV, LET: 290 keV/μm), versus 60Co γ-rays (1–3 Gy) | Carbon ions were three times more cytotoxic than γ-rays. The observed decrease in number of γ-H2AX foci 4 h after γ-rays irradiation indicates repair of damage and is supported by nearly 100% survival, whilst the decrease in γ-H2AX foci after carbon ion irradiation was not indicative of repair. | [134] |
HF12 primary male human fibroblast cells | 238Pu α-particles (range, ∼20 μm; peak energy, 3.26 MeV; LET=121.4 keV/μm) | Many α-particle-induced mutations are large deletions. Rejoining at microhomologies characterizes large deletion junctions. Intra- and interchromosomal insertions and inversions occur at the sites of some large deletions. Novel fragments found in complex rearrangements derive from other sites of radiation damage in the same cell. | [135] |
Biological System/Cell Type | Radiation Type | Immune Response | Ref. |
---|---|---|---|
Peripheral blood mononuclear cells (PBMCs) of head and neck (HNSCC) cancer patients | Intensity modulated radiotherapy (IMRT), (51–74 Gy total dose, 1.6–3 Gy dose/fraction) | Expression of the FXDR, SESN1, GADD45, DDB2, and MDM2 radiation-response genes were altered in the PBMCs of patients after RT. All changes were long-lasting, detectable one month after RT. Local tumor irradiation induces systemic changes in the level of immune and inflammation-related plasma proteins. RT induces changes in the immune phenotype of PBMCs of HNSCC patients. | [168] |
Murine CT26 colorectal cancer cells | 8 Gy proton beams at 1.09 keV/μm (low), 2.58 keV/μm (medium) and 7.7 keV/μm (high) LET. | Increase in percentage expression of immune markers (OX40L, CD40, ICAM-1, and MHC-I) in high-LET irradiated cells. High-LET proton radiation can be used to stimulate better immunogenic phenotype in tumor cells compared to low LET proton radiation. | [169] |
Human cancer cell lines: TE2, KYSE70, A549, NCI-H460 and WiDr | Carbon ions (290 MeV/n, LET 30 keV/µm) | Carbon-ion beams significantly increased HMGB1 (a damage-associated molecular pattern—DAMP) levels in the culture supernatants. | [170] |
NCI-H446 (lung tumor cells) | Carbon ions (290 MeV/n, LET 13 keV/µm) | Cyto- and chemokine response release by tumor cells after irradiation. (TNF-α) | [171] |
Tumor-bearing mice (C3H/He, Balb/c nude mice) | Carbon ion irradiation (290 MeV/n, LET=77 keV/µm) | Increased cytotoxic T-lymphocytes (CTL)-associated lysis of isolated tumor splenocytes after carbon ion irradiation treatment with supplementary intratumoral dendritic cell (DC) injection. | [172] |
Tumors of mouse squamous cell carcinoma (NR-S1) cells inoculated in the legs of C3H/HeSlc mice | Carbon ions (290 MeV/n, 6-cm spread-out Bragg peak, 6 Gy) | Even when exposed to the same equivalent doses, carbon ion therapy might activate the immune system to a greater extent than conventional RT. | [173] |
NR-S1 and SCCVII (squamous cell carcinoma), NFSa, #8520 (fibrosarcoma) | Carbon ions (290 MeV/n, LET 50 keV/µm) | Significant C-ion induced upregulation of stress-responsive and cell-communication genes common to different tumor types. | [174] |
Rat skin | 56Fe ions (1.01 GeV/n) | 56Fe ion radiation significantly induced inflammation-related genes, including many in the categories of ‘immune response’, ‘response to stress’, ‘signal transduction’, and ‘response to biotic stress’, that contribute to carcinogenesis. | [175] |
Highly aggressive HT1080 human fibrosarcoma and LM8 mouse osteosarcoma cells | Carbon ion beams (290 MeV/n), versus X-rays | When compared with photon irradiation, carbon ion exposure reduced the number of distant lung metastasis in carcinoma models in immunocompetent mice. | [176] |
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Mavragani, I.V.; Nikitaki, Z.; Kalospyros, S.A.; Georgakilas, A.G. Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance. Cancers 2019, 11, 1789. https://doi.org/10.3390/cancers11111789
Mavragani IV, Nikitaki Z, Kalospyros SA, Georgakilas AG. Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance. Cancers. 2019; 11(11):1789. https://doi.org/10.3390/cancers11111789
Chicago/Turabian StyleMavragani, Ifigeneia V., Zacharenia Nikitaki, Spyridon A. Kalospyros, and Alexandros G. Georgakilas. 2019. "Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance" Cancers 11, no. 11: 1789. https://doi.org/10.3390/cancers11111789