期刊
RADIOTHERAPY AND ONCOLOGY
卷 121, 期 1, 页码 154-161出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.radonc.2016.08.028
关键词
Double-strand breaks (dsbs); Single-strand breaks (ssbs); High-LET irradiation; Non-homologous end joining (NHEJ); Ku-heterodimer; Transmission electron microscopy
资金
- research program of the Medical Faculty of the University of Saarland [HOMFOR-2013]
- German Cancer Aid [701122999]
- German Federal Ministry of Education and Research [02NUK037A, 02NUK035A]
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 0.5 h and 5 h 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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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