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，对电离辐射敏感。小松将小鼠SCID的一个潜在基因定位于人染色体8q11，鉴定为DNA依赖蛋白激酶(DNA-PK)的催化亚单位。DNA-PK复合体，如Ku70、Ku80和DNA-PKcs，在辐射诱导的DSB重联和DNA损伤后的信号转导中发挥关键作用，但其机制尚不清楚。近年来，SCID小鼠也表现出胸腺淋巴瘤的易感性。在本研究中，我们展示了DNA-PK在体外和体内检测系统中的多功能。(1)SCID突变时编码关节形态异常，信号关节形态正常。此外，KU80在43ﾟC时对热不稳定，可引起辐射诱导的细胞杀伤的热敏化。另一方面，DNA-PK(SCID突变)在Pc-1微卫星的基础上导致了基因组的不稳定性。最后，(4)我们的结果表明DNA-PK参与了小鼠胚胎的发生，其中SCID小鼠的辐射致畸率显著高于对照组。

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.