Absence of Ku70 Gene Obliterates X-Ray-Induced lacZ Mutagenesis of Small Deletions in Mouse Tissues
Absence of Ku70 Gene Obliterates X-Ray-Induced lacZ Mutagenesis of Small Deletions in Mouse Tissues
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DOI：
10.1667/rr1283.1
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发表时间：
2008-08
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通讯作者：
Y. Uehara;H. Ikehata;J. Komura;A. Ito;Masaki Ogata;T. Itoh;R. Hirayama;Y. Furusawa;K. Ando;T. Paunesku;G. Woloschak;K. Komatsu;S. Matsuura;T. Ikura;K. Kamiya;T. Ono
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作者：
Y. Uehara;H. Ikehata;J. Komura;A. Ito;Masaki Ogata;T. Itoh;R. Hirayama;Y. Furusawa;K. Ando;T. Paunesku;G. Woloschak;K. Komatsu;S. Matsuura;T. Ikura;K. Kamiya;T. Ono
摘要Uehara，Y.，Ikehata，H.，Komura，J-I.，伊藤，A.，Ogata，M.，伊托，T.，平山河，Furusawa，Y.，Ando，K.，Paunesku，T.，Woloschak，G. E.，小松，K.，Matsuura，S.，Ikura，T.，Kamiya，K.和Ono，T. Ku 70基因缺失消除X射线诱导的小鼠组织中小缺失的lacZ突变Radiat. Res. 170，216-223（2008）。为了了解非同源末端连接修复在组织水平上维持遗传信息的作用，我们研究了Ku 70基因缺陷lacZ转基因小鼠中辐射诱导的突变和随后的DNA双链断裂修复。局部突变频率和突变类型进行了分析的lacZ基因，已染色体整合，这使我们能够监测DNA序列的变化在这3.1 kbp的区域。在Ku 70 −/−小鼠中，暴露于20戈伊X射线后，导致野生型小鼠中最常见的小缺失发生的致突变过程在检查的三个组织（脾、肝和脑）中得到抑制。Ku 70缺陷小鼠和正常小鼠的DNA断裂重接和组蛋白H2 AX磷酸化的检测表明，Ku 70缺陷降低了DNA重接的频率，这表明DNA重接是辐射诱导的缺失突变的原因之一。有限的，但统计学上显着的DNA重连接被发现在肝脏和大脑的Ku 70缺陷小鼠照射后3.5天，显示存在的DNA双链断裂修复系统以外的非同源末端连接。这些数据表明，在体内辐射诱导突变的生产中，非同源末端连接的主要作用。
Abstract Uehara, Y., Ikehata, H., Komura, J-I., Ito, A., Ogata, M., Itoh, T., Hirayama, R., Furusawa, Y., Ando, K., Paunesku, T., Woloschak, G. E., Komatsu, K., Matsuura, S., Ikura, T., Kamiya, K. and Ono, T. Absence of Ku70 Gene Obliterates X-Ray-Induced lacZ Mutagenesis of Small Deletions in Mouse Tissues. Radiat. Res. 170, 216–223 (2008). With the goal of understanding the role of non-homologous end-joining repair in the maintenance of genetic information at the tissue level, we studied mutations induced by radiation and subsequent repair of DNA double-strand breaks in Ku70 gene-deficient lacZ transgenic mice. The local mutation frequencies and types of mutations were analyzed on a lacZ gene that had been chromosomally integrated, which allowed us to monitor DNA sequence alterations within this 3.1-kbp region. The mutagenic process leading to the development of the most frequently observed small deletions in wild-type mice after exposure to 20 Gy of X rays was suppressed in Ku70−/− mice in the three tissues examined: spleen, liver and brain. Examination of DNA break rejoining and the phosphorylation of histone H2AX in Ku70-deficient and -proficient mice revealed that Ku70 deficiency decreased the frequency of DNA rejoining, suggesting that DNA rejoining is one of the causes of radiation-induced deletion mutations. Limited but statistically significant DNA rejoining was found in the liver and brain of Ku70-deficient mice 3.5 days after irradiation, showing the presence of a DNA double-strand break repair system other than non-homologous end joining. These data indicate a predominant role of non-homologous end joining in the production of radiation-induced mutations in vivo.