Characteristics of DNA-binding proteins determine the biological sensitivity to high-linear energy transfer radiation.
Non-homologous end-joining (NHEJ) and homologous recombination repair (HRR), contribute to repair ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Mre11 binding to DNA is the first step for activating HRR and Ku binding to DNA is the first step for initiating NHEJ. High-linear energy transfer (LET) IR (such as high energy charged particles) killing more cells at the same dose as compared with low-LET IR (such as X or gamma rays) is due to inefficient NHEJ. However, these phenomena have not been demonstrated at the animal level and the mechanism by which high-LET IR does not affect the efficiency of HRR remains unclear. In this study, we showed that although wild-type and HRR-deficient mice or DT40 cells are more sensitive to high-LET IR than to low-LET IR, NHEJ deficient mice or DT40 cells are equally sensitive to high- and low-LET IR. We also showed that Mre11 and Ku respond differently to shorter DNA fragments in vitro and to the DNA from high-LET irradiated cells in vivo. These findings provide strong evidence that the different DNA DSB binding properties of Mre11 and Ku determine the different efficiencies of HRR and NHEJ to repair high-LET radiation induced DSBs.
Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
Hongyan
H
Wang
Xiangming
X
Zhang
Ping
P
Wang
Xiaoyan
X
Yu
Jeroen
J
Essers
David
D
Chen
Roland
R
Kanaar
Shunichi
S
Takeda
Ya
Y
Wang
D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D000072200:Ku Autoantigen; D018499:Linear Energy Transfer; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011995:Recombination, Genetic
D034961:Antigens, Nuclear; D002843:Chromatin; D004268:DNA-Binding Proteins; D004247:DNA; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen