Dose, LET and Strain Dependence of Radiation-Induced 53BP1 Foci in 15Mouse Strains Ex Vivo Introducing Novel DNA Damage Metrics

Sébastien Penninckx, Egle Cekanaviciute, Charlotte Degorre, Elodie Guiet, Louise Viger, Stéphane Lucas, Sylvain V Costes

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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
langue originaleAnglais
Pages (de - à)1-12
Nombre de pages12
journalRadiation Research
Numéro de publication1
Les DOIs
Etat de la publicationPublié - 13 mai 2019

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