Cell cycle-dependent radiosensitivity in mouse zygotes

Abstract

Mammalian zygotes are hypersensitive to radiation exposure compared with later-stage embryos and somatic cells, which may be due to an unusual DNA damage response (DDR). DNA damage checkpoints are an essential part of the DDR, allowing for faithful replication of cells. Although the DDR and radiosensitivity of somatic cells are dependent on the cell cycle phase, it remains largely unclear how the irradiation of zygotes at different phases affects cell cycle progression and preimplantation development. Here, mouse zygotes were irradiated with 10 Gy γ-rays at all four cell cycle phases. DNA damage checkpoints were activated by γ-irradiation at the G2 phase, but not at the G1, S, and M phases. The absence of DNA damage checkpoints at the G1 and M phases seems to be due to the low abundance of phosphorylated CHK2, which plays a key role in checkpoint activation in response to ionizing radiation. The cause of the inoperative S phase checkpoint may lie downstream of CHK2 activation. The inactive DNA damage checkpoints at the G1 and S phases contributed to micronucleus formation in the subsequent 2-cell stage, whereas irradiation at the M phase led to the highest incidence of chromatin bridges. The low developmental rates of embryos irradiated at the G1, S, and M phases suggest that embryos with these two types of chromatin abnormalities are prone to developmental failure. Taken together, these results suggest that the radiosensitivity of zygotes can be ascribed to a defective DDR at the G1, S, and M phases.