TY - JOUR
T1 - Dose, LET and Strain Dependence of Radiation-Induced 53BP1 Foci in 15Mouse Strains Ex Vivo Introducing Novel DNA Damage Metrics
AU - Penninckx, Sébastien
AU - Cekanaviciute, Egle
AU - Degorre, Charlotte
AU - Guiet, Elodie
AU - Viger, Louise
AU - Lucas, Stéphane
AU - Costes, Sylvain V
N1 - Funding Information:
This work was supported by the National Aeronautics and Space Administration (grant no. NNJ16HP241 to SVC, principal investigator). S. Penninckx is a PhD fellow funded by the Belgian Fund for Scientific Research (FRS-FNRS, Belgium). We thank Dr. Afshin Beheshti for comments, suggestions and discussion during preparation of this article. We also thank Drs. Adam Rusek, Michael Sivert and I-Hung Chang for the many years of support at NSRL.
Publisher Copyright:
© 2019 by Radiation Research Society.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/5/13
Y1 - 2019/5/13
N2 - We present a comprehensive comparative analysis on therepair of radiation-induced DNA damageex vivoin 15 strainsof mice, including 5 inbred reference strains and 10collaborative-cross strains, of both sexes, totaling 5 millionskin fibroblast cells imaged by three-dimensional high-throughput conventional microscopy. Non-immortalized pri-mary skin fibroblasts derived from 76 mice were subjected toincreasing doses of both low- and high-LET radiation (Xrays; 350 MeV/n40Ar; 600 MeV/n56Fe), which are relevant tocarcinogenesis and human space exploration. Automatedimage quantification of 53BP1 radiation-induced foci (RIF)formation and repair during the first 4–48 h postirradiationwas performed as a function of dose and LET. Since multipleDNA double-strand breaks (DSBs) are induced in a dose- andLET-dependent manner, our data suggest that when DSBsare formed within the same discrete nuclear region, referredto as the ‘‘repair domain’’, novel mathematical formalismsused to report RIF allowed us to conclude that multiple DSBscan be present in single RIF. Specifically, we observed thatthe number of RIF per Gy was lower for higher X-ray dosesor higher LET particles (i.e., 600 MeV/n56Fe), suggestingthere are more DSBs per RIF when the local absorbed doseincreases in the nucleus. The data also clearly show that withmore DSBs per RIF, it becomes more difficult for cells to fullyresolve RIF. All 15 strains showed the same dose and LETdependence, but strain differences were preserved undervarious experimental conditions, indicating that the numberand sizes of repair domains are modulated by the geneticbackground of each strain
AB - We present a comprehensive comparative analysis on therepair of radiation-induced DNA damageex vivoin 15 strainsof mice, including 5 inbred reference strains and 10collaborative-cross strains, of both sexes, totaling 5 millionskin fibroblast cells imaged by three-dimensional high-throughput conventional microscopy. Non-immortalized pri-mary skin fibroblasts derived from 76 mice were subjected toincreasing doses of both low- and high-LET radiation (Xrays; 350 MeV/n40Ar; 600 MeV/n56Fe), which are relevant tocarcinogenesis and human space exploration. Automatedimage quantification of 53BP1 radiation-induced foci (RIF)formation and repair during the first 4–48 h postirradiationwas performed as a function of dose and LET. Since multipleDNA double-strand breaks (DSBs) are induced in a dose- andLET-dependent manner, our data suggest that when DSBsare formed within the same discrete nuclear region, referredto as the ‘‘repair domain’’, novel mathematical formalismsused to report RIF allowed us to conclude that multiple DSBscan be present in single RIF. Specifically, we observed thatthe number of RIF per Gy was lower for higher X-ray dosesor higher LET particles (i.e., 600 MeV/n56Fe), suggestingthere are more DSBs per RIF when the local absorbed doseincreases in the nucleus. The data also clearly show that withmore DSBs per RIF, it becomes more difficult for cells to fullyresolve RIF. All 15 strains showed the same dose and LETdependence, but strain differences were preserved undervarious experimental conditions, indicating that the numberand sizes of repair domains are modulated by the geneticbackground of each strain
UR - http://www.scopus.com/inward/record.url?scp=85068402907&partnerID=8YFLogxK
U2 - 10.1667/rr15338.1
DO - 10.1667/rr15338.1
M3 - Article
SN - 0033-7587
VL - 192
SP - 1
EP - 12
JO - Radiation Research
JF - Radiation Research
IS - 1
ER -