Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation

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• 作者：Yvonne Lorat^a ; Sara Timm^a ; Burkhard Jakob^b ; Gisela Taucher-Scholz^b ; Claudia E. Rü ; be^a ; ^{claudia.ruebe@uks.eu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Double-strand breaks (dsbs) ; Single-strand breaks (ssbs) ; High-LET irradiation ; Non-homologous end joining (NHEJ) ; Ku-heterodimer ; Transmission electron microscopy
• 刊名：Radiotherapy and Oncology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：121
• 期：1
• 页码：154-161
• 全文大小：4720 K

文摘

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.