Presentation A study on the functions of XRCC4 and Artemis in the cellular response to heavy ion-beams

勝部, 孝則  ,  劉, 強  ,  王, 冰  ,  根井, 充  ,  森, 雅彦  ,  辻, 秀雄  ,  塩見, 忠博  ,  小野田, 眞

Artemis and XRCC4 are members of core factors for non-homologous end joining (NHEJ), a primary repair pathway of DNA double-strand breaks (DSBs). To better understand the roles of XRCC4 and Artemis in response to DNA damage in humans, we inactivated the Artemis and XRCC4 loci by gene targeting in the human adenocarcinoma somatic cell line HCT116. In the present study, we compared the cellular responses of these isogenic human cell lines (Artemis-/-, XRCC4-/- and HCT116 cells) to low- and high-LET ionizing radiations (IR), X-rays and carbon ion-beams, respectively. It is known that DNA damages induced by high-LET IR are qualitatively different from those induced by low-LET IR. Substantial increase in sensitivity of Artemis-/- and XRCC4-/- cells to both X-rays and carbon ion-beams as compared to HCT116 cells demonstrated participation of Artemis and XRCC4 in repair of DSBs induced by low- and high-LET IR. Remarkably, the values for relative biological effectiveness (RBE) of carbon ion-beams to X-rays on killing of the Artemis-/-, XRCC4-/- and HCT116 cells appeared to be 2.7, 2.8 and 3.0, respectively. This result is inconsistent with previous reports showing that high-LET IR is much effective as compared to low-LET IR on killing of most cell lines, but not on killing of NHEJ-deficient cells including Ku70, Ku80 and DNA-PKcs mutant lines. To address this discrepancy, we have started to examine induction and repair of DSBs in the Artemis-/-, XRCC4-/- and HCT116 cells following irradiation of carbon ion-beams by γH2AX nuclear foci analysis.

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