Defined Biological Models of High-Let Radiation Lesions

Iliakis, George; Mladenova, Veronika; Mortoga, Sharif; Chaudhary, Shipra; Mavragani, Ifigeneia V.; Soni, Aashish; Saha, Janapriya; Schipler, Agnes; Mladenov, Emil

doi:10.1093/rpd/ncy248

Cited by 17 publications

(18 citation statements)

References 26 publications

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“…Instead, the altered biology of the DNA damage observed upon proton irradiation may cause a higher dependency on HRR [28,29]. Herein, others revealed that clustered DNA damage induces chromatin destabilization resulting in exclusion of HRR as a possible DNA repair pathway and strongly increasing the contribution and importance of alt-EJ to DSB repair [76]. Following this, cells that failed in HRR used alt-EJ as a backup for DNA DSBs repair [77].…”

Section: Discussionmentioning

confidence: 99%

Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

Szymonowicz

Krysztofiak

Linden

et al. 2020

Cells

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Technical improvements in clinical radiotherapy for maximizing cytotoxicity to the tumor while limiting negative impact on co-irradiated healthy tissues include the increasing use of particle therapy (e.g., proton therapy) worldwide. Yet potential differences in the biology of DNA damage induction and repair between irradiation with X-ray photons and protons remain elusive. We compared the differences in DNA double strand break (DSB) repair and survival of cells compromised in non-homologous end joining (NHEJ), homologous recombination repair (HRR) or both, after irradiation with an equal dose of X-ray photons, entrance plateau (EP) protons, and mid spread-out Bragg peak (SOBP) protons. We used super-resolution microscopy to investigate potential differences in spatial distribution of DNA damage foci upon irradiation. While DNA damage foci were equally distributed throughout the nucleus after X-ray photon irradiation, we observed more clustered DNA damage foci upon proton irradiation. Furthermore, deficiency in essential NHEJ proteins delayed DNA repair kinetics and sensitized cells to both, X-ray photon and proton irradiation, whereas deficiency in HRR proteins sensitized cells only to proton irradiation. We assume that NHEJ is indispensable for processing DNA DSB independent of the irradiation source, whereas the importance of HRR rises with increasing energy of applied irradiation.

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Section: Discussionmentioning

confidence: 99%

Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

Szymonowicz

Krysztofiak

Linden

et al. 2020

Cells

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“…Α fluorescent macromolecule is then synthesized, producing enough fluorescence to be visualized under a conventional fluorescence microscope. PLA assay has the ability to make the proximity of two single molecules visible [94,95,96].…”

Section: Detection Of Complex Dna Damagementioning

confidence: 99%

“…To study the biological consequences of DSB clustering in a cogent manner, cell lines harboring DNA sequences, at which single DSBs and DSB clusters of known constitution are enzymatically generated, can be constructed. Efficient activation of the DDR has been demonstrated using this model system, as well as a significantly increased potential of DSB clusters, as compared to single DSBs, to kill cells and generate PARP1-dependent chromosomal translocations [87,95]. Increasing formation of chromosomal translocations is also observed at numbers and complexities, with increasing DSB-clustering.…”

Section: Biological Response To Clustered Dna Damage and Its Signimentioning

confidence: 99%

Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance

Mavragani

Nikitaki

Kalospyros

et al. 2019

Cancers

143

107

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Biological responses to ionizing radiation (IR) have been studied for many years, generally showing the dependence of these responses on the quality of radiation, i.e., the radiation particle type and energy, types of DNA damage, dose and dose rate, type of cells, etc. There is accumulating evidence on the pivotal role of complex (clustered) DNA damage towards the determination of the final biological or even clinical outcome after exposure to IR. In this review, we provide literature evidence about the significant role of damage clustering and advancements that have been made through the years in its detection and prediction using Monte Carlo (MC) simulations. We conclude that in the future, emphasis should be given to a better understanding of the mechanistic links between the induction of complex DNA damage, its processing, and systemic effects at the organism level, like genomic instability and immune responses.

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“…I-SceI is a double stranded DNase with a large and asymmetric recognition site that is not included in human genome. Thus, upon the expression of I-SceI, DSB clusters are induced at specific locations in the genome, by defining the position of I-SceI recognition sites in the transfected plasmid [42][43][44]. The CRISPR/Cas9-based system is another genome engineering tool that can induce DSBs at specific genomic locations [45].…”

Section: Damage Inductionmentioning

confidence: 99%

“…In the Proximity Ligation Assay (PLA), a fluorescent signal is produced only when the molecules of interest are located in close proximity. In this case, the secondary antibodies, i.e., PLA probes, are not fluorescent by themselves, but they carry single stranded oligonucleotides that can synthesize fluorescent macromolecule in the simultaneous presence of the target enzymes [44,[72][73][74]. PLA in principle works when the proteins of interest are located in distances smaller than 40 nm, making it a competitive assay in terms of complex DNA damage detection.…”

Section: Proximity Ligation Assaymentioning

confidence: 99%

In Situ Detection of Complex DNA Damage Using Microscopy: A Rough Road Ahead

Nikitaki

Pariset

Sudar

et al. 2020

Cancers

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Complexity of DNA damage is considered currently one if not the primary instigator of biological responses and determinant of short and long-term effects in organisms and their offspring. In this review, we focus on the detection of complex (clustered) DNA damage (CDD) induced for example by ionizing radiation (IR) and in some cases by high oxidative stress. We perform a short historical perspective in the field, emphasizing the microscopy-based techniques and methodologies for the detection of CDD at the cellular level. We extend this analysis on the pertaining methodology of surrogate protein markers of CDD (foci) colocalization and provide a unique synthesis of imaging parameters, software, and different types of microscopy used. Last but not least, we critically discuss the main advances and necessary future direction for the better detection of CDD, with important outcomes in biological and clinical setups.

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Defined Biological Models of High-Let Radiation Lesions

Cited by 17 publications

References 26 publications

Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance

In Situ Detection of Complex DNA Damage Using Microscopy: A Rough Road Ahead

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