Yvonne Lorat1, Sara Timm1, Burkhard Jakob2, Gisela Taucher-Scholz2, Claudia E Rübe3. 1. Department of Radiation Oncology, Saarland University, Homburg/Saar, Germany. 2. Department of Biophysics, GSI Helmholtz Center for Heavy Ion Research, Darmstadt, Germany. 3. Department of Radiation Oncology, Saarland University, Homburg/Saar, Germany. Electronic address: claudia.ruebe@uks.eu.
Abstract
BACKGROUND AND PURPOSE: High linear energy transfer (LET) radiotherapy offers superior dose conformity and biological effectiveness compared with low-LET radiotherapy, representing a promising alternative for radioresistant tumours. A prevailing hypothesis is that energy deposition along the high-LET particle trajectories induces DNA lesions that are more complex and clustered and therefore more challenging to repair. The precise molecular mechanisms underlying the differences in radiobiological effects between high-LET and low-LET radiotherapies remain unclear. MATERIAL AND METHODS: Human fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.5h and 5h post exposure, the DNA-damage pattern in the chromatin ultrastructure was visualised using gold-labelled DNA-repair factors. The induction and repair of single-strand breaks, double-strand breaks (DSBs), and clustered lesions were analysed in combination with terminal dUTP nick-end labelling of DNA breaks. RESULTS: High-LET irradiation induced clustered lesions with multiple DSBs along ion trajectories predominantly in heterochromatic regions. The cluster size increased over time, suggesting inefficient DSB repair. Low-LET irradiation induced many isolated DSBs throughout the nucleus, most of which were efficiently rejoined. CONCLUSIONS: The clustering of DSBs in heterochromatin following high-LET irradiation perturbs efficient DNA repair, leading to greater biological effectiveness of high-LET irradiation versus that of low-LET irradiation.
BACKGROUND AND PURPOSE: High linear energy transfer (LET) radiotherapy offers superior dose conformity and biological effectiveness compared with low-LET radiotherapy, representing a promising alternative for radioresistant tumours. A prevailing hypothesis is that energy deposition along the high-LET particle trajectories induces DNA lesions that are more complex and clustered and therefore more challenging to repair. The precise molecular mechanisms underlying the differences in radiobiological effects between high-LET and low-LET radiotherapies remain unclear. MATERIAL AND METHODS:Human fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.5h and 5h post exposure, the DNA-damage pattern in the chromatin ultrastructure was visualised using gold-labelled DNA-repair factors. The induction and repair of single-strand breaks, double-strand breaks (DSBs), and clustered lesions were analysed in combination with terminal dUTP nick-end labelling of DNA breaks. RESULTS: High-LET irradiation induced clustered lesions with multiple DSBs along ion trajectories predominantly in heterochromatic regions. The cluster size increased over time, suggesting inefficient DSB repair. Low-LET irradiation induced many isolated DSBs throughout the nucleus, most of which were efficiently rejoined. CONCLUSIONS: The clustering of DSBs in heterochromatin following high-LET irradiation perturbs efficient DNA repair, leading to greater biological effectiveness of high-LET irradiation versus that of low-LET irradiation.
Authors: Tiffany G Kornberg; Todd A Stueckle; Jayme Coyle; Raymond Derk; Philip Demokritou; Yon Rojanasakul; Liying W Rojanasakul Journal: Chem Res Toxicol Date: 2019-11-11 Impact factor: 3.739
Authors: Scott J Bright; David B Flint; Sharmistha Chakraborty; Conor H McFadden; David S Yoon; Lawrence Bronk; Uwe Titt; Radhe Mohan; David R Grosshans; Pavel Sumazin; Simona F Shaitelman; Aroumougame Asaithamby; Gabriel O Sawakuchi Journal: Int J Radiat Oncol Biol Phys Date: 2019-08-16 Impact factor: 7.038