Multi-functions of DNA-dependent protein kinase (DNA-PK) and the association of radiation sensitivity

严重联合免疫缺陷（scid）小鼠DSB修复异常，因此对电离辐射敏感。小松在人类8q11染色体上定位了小鼠scid的一个潜在基因，并鉴定为dna依赖性蛋白激酶（DNA-PK）的一个催化亚基。DNA- pk复合物如Ku70、Ku80和DNA- pkcs可能在DNA损伤后辐射诱导的dsb和信号转导的重新连接中发挥关键作用，但其机制尚不清楚。最近，scid小鼠也表现出胸腺淋巴瘤的易感性。在本研究中，我们通过体外和体内实验系统证明了DNA-PK的多功能。(1) scid突变中编码关节形成异常，而信号关节形成正常。此外，(2)Ku80对43℃的高温不稳定，可能引起辐射诱导细胞死亡的热致敏。另一方面，(3)DNA-PK （scid突变）是造成Pc-1微卫星基因组不稳定的原因之一。最后，(4)我们的研究结果表明DNA-PK参与了小鼠胚胎发生，其中辐射诱导的胚胎畸形在scid小鼠中明显高于对照组小鼠。

Severe combined immunodeficient (scid) mice are aberrant in DSB repair and are thus sensitive to ionizing radiation. An underlying gene for murine scid was mapped in human chromosome 8q11 by Komatsu and identified as a catalytic subunit of DNA-dependent protein kinase (DNA-PK). The DNA-PK complex such as Ku70, Ku80, and DNA-PKcs, could play a critical role in rejoining radiation-induced dsb and signal transduction following DNA damage, but the mechanism remains unclear. Recently, scid mice also show predisposed to thymic lymphoma. In this study, we demonstrated the multi-function of DNA-PK using in vitron and in vivo assay system. (1) the coding joint formation is aberrant in scid mutation but signal joint formation is normal. Moreover, (2) Ku80 is labile for heat at 43ﾟC and it could cause the hyperthermic sensitization of radiation-induced cell killing. On the other hand, (3) DNA-PK (scid mutation) contributes to the genomic instability on the basis of Pc-1 micro-satellite. Finally, (4) our results showed the involvement of DNA-PK in mouse embryogenesis, where the radiation-induced teralogenesis in scid mice is significently high than that of control mice.