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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.

我们试图分析包括共济失调毛细血管扩张症(AT)、Artemis缺乏症和Nijmegen断裂综合征(NBS1缺乏症)在内的疾病细胞的DNA损伤反应缺陷导致免疫缺陷的分子机制。到目前为止，我们已经揭示了Artemis的S645是通过DNA损伤剂被ATM磷酸化的。通过本研究，我们发现70 kDa的分子与Artemis相关，并且控制Artemis的稳定性。这种相互作用需要Artemis的磷酸化，但该位点不在迄今已知的区域。还展示了阿耳特弥斯的新角色。当DNA复制在一条碎屑链上停滞时，双链DNA断裂需要卤虫的内切酶活性。这个过程依赖于自动取款机。目前进一步的研究正在进行中。DNA损伤反应(DDR)是免疫受体多样化所必需的，在这个过程中，DDR的中断会导致染色体的异常。我们分析了DDR分子在肿瘤发生中的作用，发现DDR在癌前阶段被激活。在某些情况下，DDR的缺失导致了带有p53突变的细胞的恶性转化(白血病，2006年)。ATM和Ku70/80被证明在氧化应激导致细胞凋亡时被降解(Ann NY Acad Sci2006，Int J Biochem Cell Biol)。2008年)。我们诊断出14例AT，2例DNA连接酶IV缺乏症，2例Mre11缺乏症，1例Cernunnos缺乏症。最后，我们为AT进行了第一次全国范围的调查。我们观察了患有AT的同胞病例之间的表型变化。在10%的患者中发现了高IgM，表明ATM参与了类交换重组。