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Analysis of Immunodeficiencies with defective DNA damage response

DNA 损伤反应缺陷的免疫缺陷分析

基本信息

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

项目摘要

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.

我们试图分析由共济失调毛细血管扩张症 (AT)、Artemis 缺陷和奈梅亨断裂综合征 (NBS1 缺陷) 等疾病的细胞 DNA 损伤反应缺陷引起的免疫缺陷的分子机制。迄今为止，我们已经发现 Artemis 的 S645 在 DNA 损伤试剂的作用下被 ATM 磷酸化。通过这项研究，我们发现 70 kDa 分子与 Artemis 相关并控制 Artemis 的稳定性。这种相互作用需要 Artemis 的磷酸化，但该位点并不位于迄今为止已知的区域。阿尔忒弥斯的新角色也得到了展示。当 DNA 复制在一条不规则的链中停滞时，Artemis 的核酸内切酶活性是双链 DNA 断裂所必需的。这个过程依赖于ATM。进一步的研究目前正在进行中。DNA损伤反应（DDR）对于免疫受体的多样化是绝对必要的；在此过程中DDR被破坏会导致染色体畸变。我们分析了DDR分子在肿瘤发生中的参与，发现DDR在癌前阶段被激活。 DDR的缺失导致某些情况下p53突变的细胞发生恶性转化(Leukemia 2006)。ATM和Ku70/80被证明在氧化应激下降解导致细胞凋亡(Ann NY Acad Sci 2006, Int J Biochem Cell Biol. 2008)。逃离凋亡的细胞可能导致染色体畸变。我们诊断14 患有 AT、2 种 DNA 连接酶 IV 缺陷、2 种 Mre11 缺陷 (ATLD) 和 1 种 Cernunnos 缺陷的患者。最后，我们进行了第一次全国范围的AT调查。我们观察到患有 AT 的兄弟姐妹之间的表型变异。 10% 的患者出现高 IgM，表明 ATM 参与了类别转换重组。