Nuclear ATM responds to DNA double-strand breaks (DSBs), and upregulates cell cycle checkpoint pathways, including cell cycle arrest and DNA repair 4, 5. Ataxia telangiectasia mutated (ATM) serine/threonine kinase is a key regulator of the DDR system 4, 5. Therefore, the biological consequences of radiation exposure, including cell death, are highly influenced by pathways within the DNA damage response (DDR) system.
Thus, it is generally accepted that majority of biologically important damage produced by IR occurs to nuclear DNA, either by direct ionization or through reactions with free radicals produced nearby. In other experiments using radioactively-labeled compounds, cell death closely correlates with the dose administered to the nucleus, but not with doses administered to either the plasma membrane or the cytoplasm 2, 3. In contrast, cell death is induced when the nucleus is irradiated with one or two α-particles 1. In the case of irradiating individual cells with small polonium needles producing short-range α-particles, cell death is not observed with high-dose irradiation of the plasma membrane and cytoplasm 1. In the 1970s, DNA has been experimentally proven as a major target for radiation-induced cell death. Therefore, the consequences associated with permanent DNA damage are serious and often lethal for the cell. In contrast, DNA, which is central to all cellular functions, has only two copies in a cell and a very limited turnover. However, as most biomolecules, for example water, mRNA, and proteins, have multiple copies and a continuous, rapid turnover, they are not considered to contribute significantly to radiation effects. Ionized molecules are highly reactive, disrupting the structure of macromolecules. IR deposits energy randomly, thereby causing damage to all molecules in the cell. For example, even if a man is exposed to a 50% lethal dose of X-ray (4 Gy, or 4 J kg −1), the rise in body temperature is only ~ 0.001 ☌. Ionizing radiation (IR) exerts significant biological effects via imperceptible amounts of energy, compared with the energy deposition of life forms by other sources, such as thermal energy. Wilhelm Conrad Röntgen in 1895, many scientists have studied the nature of radiation. These data reveal that cytoplasmic radioresponses modify ATM-mediated DNA damage responses and determine the fate of cells irradiated at low doses. Furthermore, CDKN1A ( p21) is upregulated following whole-cell irradiation, indicating the induction of cell cycle arrest. ABL1 and p73 expression is upregulated following nucleus irradiation, suggesting the induction of p73-dependent cell death. Addition of an ataxia telangiectasia mutated (ATM) kinase inhibitor to whole-cell irradiations suppresses foci formation at ≤ 2 Gy. Phosphorylated histone H2AX foci, a surrogate marker for DNA double-strand breaks, in V79 and WI-38 cells are not observed in nucleus irradiations at ≤ 2 Gy, whereas they are observed in whole-cell irradiations. Here, we show changes in the DNA damage responses with or without X-ray microbeam irradiation of the cytoplasm. We recently showed that when a low X-ray dose is used, cell death is enhanced in nucleus-irradiated compared with whole-cell-irradiated cells however, the role of the cytoplasm remains unclear.