Impaired DNA Double-Strand Break Repair in Irradiated Sheep Lung Fibroblasts: Late Effects of Previous Irradiation of the Spinal Thecal Sac
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. The Sheep Treatment
- -
- Low-dose (LD) region: area of the sheep that received a total dose lower than 2 Gy.
- -
- High-dose (HD) region: area of the sheep that received a total dose higher than 70% of the total dose to the thecal sac, i.e., more than 18 Gy.
2.2. Sheep Euthanasia and Lung Tissue Sampling
2.3. Primary Cell Culture
2.4. Cell Line Irradiation
2.5. Trypan Blue Exclusion Assay
2.6. Immunofluorescence
2.7. Cell Survival Clonogenic Assay
2.8. Statistical Analysis
3. Results
3.1. Fibroblastic Nature of the Established Cell Lines
3.2. Previous Irradiation Does Not Affect Cellular Viability
3.3. Previous Irradiation Impairs DNA DSB Signaling and Repair
3.4. ATM Nucleoshuttling Is Delayed in Previously Treated Cells
3.5. Previous Irradiation Did Not Affect the Percentage of Radio-Induced Micronuclei or Cell Survival
4. Discussion
4.1. Pediatric Radiotherapy: Long-Term Consequences
- Animal size: This study required an animal model the size of a very young human, in order to have the most relevant treatment plan. It is noteworthy that the bone structure and composition of sheep are very similar to those of the human body [40].
- Life expectancy: This study required an animal model with a life expectancy long enough to observe any effects, but not too long for technical considerations. The life expectancy of sheep ranges between 8 and 10 years, which made them ideal for this project.
- Adult age: This study required an animal that reaches adulthood at ages 2–4 years in order to assess the effect of early pediatric treatment at adulthood.
- Radiosensitivity and DNA repair: The non-homologous end-joining and the homologous recombination repair pathways, which involved ATM and H2AX, are assumed to be the two DSB repair pathways present in mammalian cells [41,42]. Specifically, γH2AX is detected in all tested mammalian cells [43,44,45]. This justifies our focus on these two proteins. Moreover, as highlighted in [15], and as confirmed in our results, the cellular and molecular radiosensitivity of sheep was shown to be comparable to that of humans.
4.2. Previous Irradiation Can Radiosensitize Cells by Impairing DNA DSB Signaling and Repair
- Group I: radioresistant. Cells from this group show efficient DNA DSB repair and fast ATM nucleoshuttling. The usual number of residual γH2AX foci in this group ranges between 0 and 2, and the number of pATM foci at 10 min is higher than 35.
- Group II: moderately radiosensitive. Cells show less efficient DNA DSB repair and slower ATM nucleoshuttling. These can be radiosensitive and/or with high cancer proneness. The number of residual γH2AX foci is between 2 and 8 and the number of pATM foci is between 25 and 35.
- Group III: hyper-radiosensitive. These usually include DNA repair genetic mutation, such as that present in ataxia telangiectasia. This group has a high risk of cancer and more than eight residual γH2AX foci.
- A small but significant increase in the number of basal DNA DSBs was detected, as highlighted by the number of γH2AX foci without irradiation (Figure 3). Although the increase was small, the significant difference shows that the previously irradiated cells can continuously have remaining DNA DSBs, even without any exposure to genotoxic stress. Many factors contribute to this phenomenon, for example, the unrepaired DSBs from environmental stress, or an increase in the activity of reactive oxygen species. Studies have shown that this can also be a sign of cell aging [46].
- A significant decrease in the number of recognized DSBs, highlighted by the number of γH2AX foci 10 min after irradiation. Knowing that the number of radio-induced DSBs should be the same, this shows that LD and HD cells might have a DSB signaling problem.
- A significant decrease in the ATM activity 10 min after irradiation. Knowing that ATM acts early after exposure to genotoxic stress, multiple studies have shown that any decrease or delay in ATM activity can lead to genomic instability and increased radiosensitivity.
- A significant increase in the number of residual γH2AX foci 24 h after irradiation. This means that previous irradiation might have affected the capacity of the treated cells to repair their DNA DSBs upon re-irradiation.
4.3. Clinical Relevance
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
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Youssef, B.; Feghaly, C.; Al Choboq, J.; Bou-Gharios, J.; Challita, R.; Azzi, J.; Bou Hadir, H.; Abi Antoun, F.; Araji, T.; Taddei, P.J.; et al. Impaired DNA Double-Strand Break Repair in Irradiated Sheep Lung Fibroblasts: Late Effects of Previous Irradiation of the Spinal Thecal Sac. Cancers 2024, 16, 2968. https://doi.org/10.3390/cancers16172968
Youssef B, Feghaly C, Al Choboq J, Bou-Gharios J, Challita R, Azzi J, Bou Hadir H, Abi Antoun F, Araji T, Taddei PJ, et al. Impaired DNA Double-Strand Break Repair in Irradiated Sheep Lung Fibroblasts: Late Effects of Previous Irradiation of the Spinal Thecal Sac. Cancers. 2024; 16(17):2968. https://doi.org/10.3390/cancers16172968
Chicago/Turabian StyleYoussef, Bassem, Charbel Feghaly, Joelle Al Choboq, Jolie Bou-Gharios, Rafka Challita, Joyce Azzi, Hanine Bou Hadir, Fabienne Abi Antoun, Tarek Araji, Phillip J. Taddei, and et al. 2024. "Impaired DNA Double-Strand Break Repair in Irradiated Sheep Lung Fibroblasts: Late Effects of Previous Irradiation of the Spinal Thecal Sac" Cancers 16, no. 17: 2968. https://doi.org/10.3390/cancers16172968