DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks
Abstract
:1. Introduction
2. The Physical Characteristics of Low-Versus High-LET IR Determine Differences in Complexity of Induced DSBs
3. Exposure to High-LET IR Activates Signaling Networks Mainly Regulated by ATR
4. DSB Repair Pathways
4.1. Classical Non-Homologous End Joining
4.2. Homologous Recombination (HR)
4.3. Alternative End-Joining (Alt-EJ)
4.4. Single Strand Annealing (SSA)
5. Specific Processing Characteristics of High-LET-Induced DSBs and DSB Clusters
5.1. DSB Clusters Compromise c-NHEJ
5.2. Engagement of Resection-Dependent DSB Repair Pathways
5.3. Contribution of Homologous Recombination to the Processing of DSB Clusters
5.4. Promotion of Error-Prone Alt-EJ by DSB Clusters Results in Enhanced Genomic Instability
6. Concluding Remarks
- To elucidate the parameters that determine the engagement of resection-dependent DSB repair pathways following exposure to high-LET IR and establish the connection between resection and the engagement of HR.
- To establish the factors and activities that determine the switch from high-fidelity HR to error-prone repair mechanisms as a function of dose and LET.
- To investigate whether active or passive changes or disruptions in chromatin organization in the vicinity of the DSB regulate the response with increasing LET and to identify the molecular underpinnings of candidate molecular mechanisms.
- To establish whether distinct chromatin marks drive/force/stimulate the switch to resection with increasing LET.
- To explore whether pharmacological targeting or genetic modulation of such activities offers means to improve the clinical application of different IR modalities in cancer therapy and radiation protection during space travel.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Mladenova, V.; Mladenov, E.; Stuschke, M.; Iliakis, G. DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks. Molecules 2022, 27, 1540. https://doi.org/10.3390/molecules27051540
Mladenova V, Mladenov E, Stuschke M, Iliakis G. DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks. Molecules. 2022; 27(5):1540. https://doi.org/10.3390/molecules27051540
Chicago/Turabian StyleMladenova, Veronika, Emil Mladenov, Martin Stuschke, and George Iliakis. 2022. "DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks" Molecules 27, no. 5: 1540. https://doi.org/10.3390/molecules27051540