Nicole Grosse1, Andrea O Fontana1, Eugen B Hug2, Antony Lomax2, Adolf Coray2, Marc Augsburger1, Harald Paganetti3, Alessandro A Sartori4, Martin Pruschy5. 1. Laboratory for Molecular Radiobiology, University Hospital Zurich, Zurich, Switzerland. 2. Center for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland. 3. Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 4. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland. 5. Laboratory for Molecular Radiobiology, University Hospital Zurich, Zurich, Switzerland. Electronic address: martin.pruschy@usz.ch.
Abstract
PURPOSE: To investigate the impact of the 2 major DNA repair machineries on cellular survival in response to irradiation with the 2 types of ionizing radiation. METHODS AND MATERIALS: The DNA repair and cell survival endpoints in wild-type, homologous recombination (HR)-deficient, and nonhomologous end-joining-deficient cells were analyzed after irradiation with clinically relevant, low-linear energy transfer (LET) protons and 200-keV photons. RESULTS: All cell lines were more sensitive to proton irradiation compared with photon irradiation, despite no differences in the induction of DNA breaks. Interestingly, HR-deficient cells and wild-type cells with small interfering RNA-down-regulated Rad51 were markedly hypersensitive to proton irradiation, resulting in an increased relative biological effectiveness in comparison with the relative biological effectiveness determined in wild-type cells. In contrast, lack of nonhomologous end-joining did not result in hypersensitivity toward proton irradiation. Repair kinetics of DNA damage in wild-type cells were equal after both types of irradiation, although proton irradiation resulted in more lethal chromosomal aberrations. Finally, repair kinetics in HR-deficient cells were significantly delayed after proton irradiation, with elevated amounts of residual γH2AX foci after irradiation. CONCLUSION: Our data indicate a differential quality of DNA damage by proton versus photon irradiation, with a specific requirement for homologous recombination for DNA repair and enhanced cell survival. This has potential relevance for clinical stratification of patients carrying mutations in the DNA damage response pathways.
PURPOSE: To investigate the impact of the 2 major DNA repair machineries on cellular survival in response to irradiation with the 2 types of ionizing radiation. METHODS AND MATERIALS: The DNA repair and cell survival endpoints in wild-type, homologous recombination (HR)-deficient, and nonhomologous end-joining-deficient cells were analyzed after irradiation with clinically relevant, low-linear energy transfer (LET) protons and 200-keV photons. RESULTS: All cell lines were more sensitive to proton irradiation compared with photon irradiation, despite no differences in the induction of DNA breaks. Interestingly, HR-deficient cells and wild-type cells with small interfering RNA-down-regulated Rad51 were markedly hypersensitive to proton irradiation, resulting in an increased relative biological effectiveness in comparison with the relative biological effectiveness determined in wild-type cells. In contrast, lack of nonhomologous end-joining did not result in hypersensitivity toward proton irradiation. Repair kinetics of DNA damage in wild-type cells were equal after both types of irradiation, although proton irradiation resulted in more lethal chromosomal aberrations. Finally, repair kinetics in HR-deficient cells were significantly delayed after proton irradiation, with elevated amounts of residual γH2AX foci after irradiation. CONCLUSION: Our data indicate a differential quality of DNA damage by proton versus photon irradiation, with a specific requirement for homologous recombination for DNA repair and enhanced cell survival. This has potential relevance for clinical stratification of patients carrying mutations in the DNA damage response pathways.
Authors: Qi Liu; Tracy S A Underwood; Jong Kung; Meng Wang; Hsiao-Ming Lu; Harald Paganetti; Kathryn D Held; Theodore S Hong; Jason A Efstathiou; Henning Willers Journal: Int J Radiat Oncol Biol Phys Date: 2016-02-01 Impact factor: 7.038
Authors: Neil G Burnet; Ranald I Mackay; Ed Smith; Amy L Chadwick; Gillian A Whitfield; David J Thomson; Matthew Lowe; Norman F Kirkby; Adrian M Crellin; Karen J Kirkby Journal: Br J Radiol Date: 2020-01-14 Impact factor: 3.039