期刊
DNA REPAIR
卷 117, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.dnarep.2022.103370
关键词
Zygote; Cell cycle; Radiosensitivity; DNA damage response; Checkpoint
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [17K19318, 18H03970, 19H05752, 21H04752]
- Japan Society for the Promotion of Science [202012040]
Mammalian zygotes have higher sensitivity to radiation due to defective DNA damage response (DDR) at G1, S, and M phases. This study irradiated mouse zygotes at different cell cycle phases and found that DNA damage checkpoints were activated only at the G2 phase. The absence of DNA damage checkpoints at G1 and M phases may be due to low phosphorylated CHK2 levels. The low developmental rates of embryos irradiated at G1, S, and M phases suggest that these embryos are prone to developmental failure due to chromatin abnormalities.
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 gamma-rays at all four cell cycle phases. DNA damage checkpoints were activated by gamma-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.
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