Abstract
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.
Highlights
Radiotherapy is a part of the standard treatment for more than 50% of cancer patients and has a documented contribution to local tumor control and improved overall survival
stimulated emission depletion (STED) microscopy analysis of γH2A.X foci upon spread-out Bragg peak (SOBP) proton irradiation revealed that the pattern of DNA damage foci consisted of several small sub clusters of γH2A.X foci in close proximity to each other and with larger distance to neighboring γH2A.X foci accumulations yielding a pattern of larger cluster formations within the nucleus; we termed the γH2A.X foci with the larger appearance “foci clusters” throughout the manuscript (Figure 1B)
We speculate that the suggested increasing importance of repair by homologous recombination repair (HRR) in cancer cells irradiated with SOBP protons compared to X-ray photon irradiation might be due to the induction of more clustered DNA lesions composed of multiple DNA damage sites in close proximity, as demonstrated in MEFs by visualizing γH2A.X foci using STED microscopy
Summary
Radiotherapy is a part of the standard treatment for more than 50% of cancer patients and has a documented contribution to local tumor control and improved overall survival. Clinical radiotherapy aims to achieve maximal tumor control rates while reducing the risk for dose-limiting adverse late effects in normal tissues [1,2]. Overcoming dose-limiting toxicity to normal tissues is still a major challenge in clinical radiotherapy, when tumors grow adjacent to critical structures or within tissues or organs with pronounced radiation sensitivity. Enhancing the accuracy of dose delivery to the tumor volume, e.g., by stereotactic radiotherapy or intensity-modulated radiation therapy, has allowed clinicians to improve the safety profile of radiotherapy for many solid tumors [4]. Recent technical developments have led to broader application of particle therapy in clinical practice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
