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

DNA依赖性蛋白激酶（DNA-PK）的多功能性与辐射敏感性的关联

• 批准号: 08458155
• 负责人: KOMATSU Kenshi
• 金额: $ 5.44万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08458155/
• 关键词: DNA dependent protein kinase; murine scid; V (D) J recombination; hyperthermia; teratogenesis protein; genetic instability; double strand break; DNA repair; DNA-PK; scid; DNA2重鎖切断; 放射線感受性; 温熱感受性; OK1035; Ku80

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.

严重的合并免疫缺陷（SCID）小鼠在DSB修复中异常，因此对电离辐射敏感。 Komatsu在人类8q11中绘制了一种鼠SCID的基因，并被鉴定为DNA依赖性蛋白激酶（DNA-PK）的催化亚基。 DNA-PK复合物（例如KU70，KU80和DNA-PKC）在DNA损伤后重新加入辐射诱导的DSB和信号转导的关键作用，但该机制尚不清楚。最近，SCID小鼠还显示出对胸腺淋巴瘤的易感性。在这项研究中，我们使用玻璃体和体内测定系统证明了DNA-PK的多功能功能。 （1）SCID突变中的编码接头形成异常，但信号关节形成正常。此外，（2）ku80在43°C处的热量不稳定，它可能导致辐射诱导的细胞杀死的高温感。另一方面，（3）DNA-PK（SCID突变）在PC-1微卫星的基础上有助于基因组不稳定性。最后，（4）我们的结果表明DNA-PK参与了小鼠胚胎发生，其中辐射诱导的SCID小鼠的胞胎发生明显高于对照小鼠的胞胎。

项目成果

S. Matsuura, K. Komatsu, et. al.: "Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen Brakage Syndrome at chromosome 8q21-24." Am. J. Hum. Genet.(in press). (1997)

S.松浦，K.小松，等。

K. Komatsu, et. al.: "Inhibitory action of (-) -epigallocatechin gallate on radiation-induced mouse oncogenic transformation." Canser Lett.(in press). (1997)

K.小松等。

Matsuura, K.: "Radiation induction of p53 in cells from Nijmegen breakage syndrome is defective but not similar to ataxia-telahgiectasia." Biochem.Biophys.Res.Commun.242. 602-607 (1998)

Matsuura, K.：“奈梅亨断裂综合征细胞中 p53 的辐射诱导是有缺陷的，但与共济失调-四肢扩张症不同。”

Komatsu, K.: "The Gene for Nijmegen Beakage Syndrome (V2) is not located on chromosome 11." Am.J.Hum.Genet.58. 885-888 (1996)

Komatsu, K.：“奈梅亨喙综合症 (V2) 的基因并不位于 11 号染色体上。”

Komatsu,K.: "The Gene for Nijmegen Breakage Syndrome(V2) is not located on chromosome 11." Am.J.Hum.Genet.58. 885-888 (1996)

Komatsu,K.：“奈梅亨断裂综合征 (V2) 的基因并不位于 11 号染色体上。”