Analysis of Immunodeficiencies with defective DNA damage response

DNA 损伤反应缺陷的免疫缺陷分析

• 批准号: 18591184
• 负责人: MORIO Tomohiro
• 金额: $ 2.43万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591184/
• 关键词: DNA damage response; Immunodeficiency; Malignancy; Ataxia telangiectasia; Artemis; KU70; 80; DNA ligase IV; Cernunnos; 原発性免疫不全症; DNA損傷修復異常; 毛細血管拡張性小脳失調症; ATM; V(D)J再構成; 免疫グロブリンクラススイッチ; 悪性腫瘍; リン酸化

We sought to analyze molecular mechanism of immunodeficiency caused by defective DNA damage response working on cells from disorders including ataxia-telangiectasia (AT), Artemis deficiency, and Nijmegen breakage syndrome (NBS1 deficiency).We have so far revealed that S645 of Artemis is phosphorylated by ATM upon DNA damaging reagent. Through this study, we have shown 70-kDa molecule is associated with Artemis and controls stability of Artemis. The interaction requires phosphorylation of Artemis, but the site is not in the hitherto-known region. A new role of Artemis was also demonstrated. Endonuclease activity of Artemis was shown to be required for double strand DNA break when DNA replication is stalled in a ragging strand. This process was dependent on ATM. Further investigation is currently in progress.DNA damage response (DDR) is absolutely required for diversification of immune receptors; and disrupted DDR during the process leads to chromosomal aberration. We analyzed involvement of the DDR molecules in tumorigenesis, and found that DDR is activated in pre-malignant stage. The loss of DDR led to malignant transformation of the cells with mutation in p53 in some cases (Leukemia 2006).ATM and Ku70/80 were shown to be degraded upon oxidative stress leading to cellular apoptosis (Ann NY Acad Sci 2006, Int J Biochem Cell Biol. 2008)。 The cells escaped from apoptosis may lead to acquisition of chromosomal aberration.We diagnosed 14 patients with AT, 2 DNA ligase IV deficiency, 2 Mre11deficiency (ATLD) and one Cernunnos deficiency. Finally, we carried out the first nation-wide survey for AT. We observed phenotypic variety between sibling cases with AT. Hyper-IgM was noted in 10% of the patients indicating involvement of ATM in class switch recombination.

到目前为止，我们已经透露，在DNA损伤灾害试剂上，ATM磷酸化S645。通过这项研究，我们显示了70 kDa分子与阿耳emis虫有关，并控制着artemis的稳定性。这种相互作用需要阿耳震症的磷酸化，但该部位不在隐藏的区域。还展示了阿耳emi弥斯的新作用。当DNA复制停滞在破烂的链中时，ARTEMIS的核酸酶活性是双链DNA断裂所必需的。此过程取决于ATM。目前正在进行进一步的调查。DNA损伤响应（DDR）绝对需要免疫接收器的多样化；在此过程中破坏了DDR会导致染色体像差。我们分析了DDR分子在肿瘤发生中的参与，并发现DDR在预防阶段被激活。 DDR的丧失导致细胞在p53中突变的恶性转化（白血病2006）。ATM和KU70/80在氧化应激后被降解，导致细胞凋亡（Ann Ny Acad Sci Sci 2006，Int J Biochem Cell Biol.2008）。从凋亡中抗凋亡的细胞可能会导致染色体像差。最后，我们对AT进行了首次全国范围的调查。我们观察到与AT的同胞病例之间的表型变化。在10％的患者中发现了超基因，表明ATM参与类转换重组。

项目成果

Ataxia-telangiectasia-mutated-dependent activation of Ku in human fibroblasts exposed to hydrogen peroxide

接触过氧化氢的人成纤维细胞中共济失调毛细血管扩张突变依赖性 Ku 激活

• 发表时间: 2006
• 期刊: Ann N Y Acad Sci 1091
• 作者: Lee JH;Kim KH;Morio T;Kim H.
• 通讯作者: Kim H.

骨髄異形成症候群(MDS)の白血病への進展過程におけるDNA損傷応答の関与

DNA 损伤反应参与骨髓增生异常综合征 (MDS) 向白血病的进展

• 发表时间: 2006
• 作者: 高木正稔;堀部志保;森尾友宏;北川昌伸;水谷修紀
• 通讯作者: 水谷修紀

XAB2を標的とした癌の分化誘導療法

靶向XAB2的癌症分化诱导治疗

• 发表时间: 2006
• 作者: 大沼久美子;森尾友宏;長澤正之;細井創;大沼圭;水谷修紀
• 通讯作者: 水谷修紀

関連学会合同シンポジウム「細胞移植・再生医療における品質管理のあり方」細胞移植の立場から(増殖リンパ球治療を中心として)

相关学会联合研讨会：从细胞移植的角度看“细胞移植与再生医学的质量控制应该如何”（聚焦增殖淋巴细胞治疗）

• 发表时间: 2008
• 作者: 森尾友宏;清水則夫;伊藤仁也
• 通讯作者: 伊藤仁也

The First Infant Case With Hepatosplenic gammadelta T-cell Lymphoma After Acute Disseminated Encephalomyelitis (ADEM)-like Exacerbation.

首例急性播散性脑脊髓炎 (ADEM) 样恶化后患有肝脾 γδ T 细胞淋巴瘤的婴儿病例。

• 发表时间: 2006
• 期刊: J Pediatr Hematol Oncol 28
• 作者: Koga SY;Kumaki S;Ichinohasama R;Numakata M;Haginoya K;Ohashi Y;Tanaka Y;Sakamoto O;Minegishi M;Morio T;Iinuma K;Tsuchiya S.
• 通讯作者: Tsuchiya S.