Shimizu Naoto, Ooka Masato, Takagi Tokiyo, Takeda Shunichi, Hirota Kouji
a Department of Chemistry, Graduate School of Science and Engineering, Tokyo Metropolitan University, Minamiosawa 1-1, Hachioji-shi, Tokyo 192-0397, Japan; and.
b Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe, Sakyo-ku, Kyoto 606-8501, Japan.
Radiat Res. 2015 Oct;184(4):442-8. doi: 10.1667/RR14117.1. Epub 2015 Oct 2.
Ionizing radiation induces more cell death under normoxic conditions than under hypoxic conditions. This phenomenon, which is known as the oxygen enhancement effect, occurs primarily because ionizing radiation causes more DNA lesions in the presence of oxygen than in its absence. However, the roles these lesions play in terms of cell survival and chromosome damage have not been fully characterized. We exposed a panel of chicken DT40 mutant cells to ionizing radiation to categorize the type of lesion induced and the DNA-repair pathway involved under both normoxic and hypoxic conditions. Among the mutant panel, RAD54(-/-)/KU70(-/-) cells exhibited the greatest radiosensitivity, which was found to be significantly higher under normoxic conditions. This indicates that double-strand breaks (DSBs) were the major cause of cell death and that ionizing radiation induces more DSBs under normoxic condition. Interestingly, the sensitivity of the REV3(-/-) cells increased under hypoxic conditions. Indeed, the REV3(-/-) mutant exhibited a greater number of chromosomal aberrations under hypoxic conditions than under normoxic conditions. These results suggest that the Rev3-mediated translesion-synthesis pathway is more critical for cellular tolerance to ionizing radiation in hypoxic cells than in normoxic cells, and that more chemically modified DNA might be induced under hypoxic conditions. In this study, we identify a previously unappreciated radiation-induced pattern of DNA damage under hypoxic conditions.
与低氧条件相比，电离辐射在常氧条件下诱导更多细胞死亡。这种现象被称为氧增强效应，主要是因为电离辐射在有氧存在时比无氧时会导致更多的DNA损伤。然而，这些损伤在细胞存活和染色体损伤方面所起的作用尚未完全明确。我们将一组鸡DT40突变细胞暴露于电离辐射下，以对常氧和低氧条件下诱导的损伤类型及涉及的DNA修复途径进行分类。在该突变细胞组中，RAD54(-/-)/KU70(-/-)细胞表现出最大的放射敏感性，发现在常氧条件下其放射敏感性显著更高。这表明双链断裂（DSBs）是细胞死亡的主要原因，且电离辐射在常氧条件下诱导更多的双链断裂。有趣的是，REV3(-/-)细胞在低氧条件下的敏感性增加。实际上，REV3(-/-)突变体在低氧条件下比在常氧条件下表现出更多的染色体畸变。这些结果表明，Rev3介导的跨损伤合成途径对低氧细胞比对常氧细胞在电离辐射耐受性方面更为关键，并且在低氧条件下可能诱导更多化学修饰的DNA。在本研究中，我们鉴定出一种在低氧条件下先前未被认识到的辐射诱导的DNA损伤模式。
