Toyoshima Megumi
Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi, Minami-ku, Hiroshima, Japan.
J Radiat Res. 2009 Jan;50(1):11-7. doi: 10.1269/jrr.08099.
Ionizing radiation activates a series of DNA damage response, cell cycle checkpoints to arrest cells at G1/S, S and G2/M, DNA repair, and apoptosis. The DNA damage response is thought to be the major determinant of cellular radiosensitivity and thought to operate in all higher eukaryotic cells. However, the radiosensitivity is known to differ considerably during ontogeny of mammals and early embryos of mouse for example are much more sensitive to radiation than adults. We have focused on the radiation-induced damage response during pre-implantation stage of mouse embryo. Our study demonstrates a hierarchy of damage responses to assure the genomic integrity in early embryonic development. In the sperm-irradiated zygotes, p53 dependent S-phase checkpoint functions to suppress erroneous replication of damaged DNA. The transcription-dependent function is not required and the DNA-binging domain of the protein is essential for this p53 dependent S-phase checkpoint. p21 mediated cleavage arrest comes next during early embryogenesis to prevent delayed chromosome damage at morula/ blastocyst stages. Apoptosis operates even later only in the cells of ICM at the blastocyst stage to eliminate deleterious cells. Thus, early development of sperm-irradiated embryos is protected at least by three mechanisms regulated by p53 and by p21.
电离辐射会激活一系列DNA损伤反应、细胞周期检查点，使细胞停滞在G1/S期、S期和G2/M期，启动DNA修复以及诱导细胞凋亡。DNA损伤反应被认为是细胞放射敏感性的主要决定因素，并且在所有高等真核细胞中都起作用。然而，众所周知，在哺乳动物个体发育过程中放射敏感性差异很大，例如小鼠的早期胚胎比成年个体对辐射更为敏感。我们聚焦于小鼠胚胎植入前阶段的辐射诱导损伤反应。我们的研究证明了损伤反应的层级关系，以确保早期胚胎发育中的基因组完整性。在精子受辐照的合子中，p53依赖的S期检查点发挥作用，抑制受损DNA的错误复制。转录依赖性功能并非必需，该蛋白的DNA结合结构域对于这种p53依赖的S期检查点至关重要。在早期胚胎发育过程中，接下来是p21介导的分裂停滞，以防止桑葚胚/囊胚阶段出现延迟的染色体损伤。细胞凋亡甚至更晚才发生，仅在囊胚期的内细胞团细胞中起作用，以清除有害细胞。因此，精子受辐照胚胎的早期发育至少受到由p53和p21调控的三种机制的保护。
