Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability.
Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability.
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DOI：
10.1084/jem.20082396
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发表时间：
2009-04-13
期刊：
影响因子：
--
通讯作者：
Sekiguchi J
中科院分区：
文献类型：
--
作者：
Huang Y;Giblin W;Kubec M;Westfield G;St Charles J;Chadde L;Kraftson S;Sekiguchi J
Artemis最初是作为人类放射敏感性T−B−严重联合免疫缺陷症中失活的基因被发现的，这是一种以缺乏B和T淋巴细胞以及对电离辐射的细胞超敏性为特征的综合征。亚型Artemis等位基因也已在患者中鉴定，并与不同严重程度的联合免疫缺陷相关。我们研究的分子机制，潜在的一个亚型Artemis等位基因引起的部分免疫缺陷综合征使用小鼠作为模型系统。这种突变P70导致过早的翻译终止，删除了大部分非保守的C末端。我们发现纯合子Artemis-P70小鼠表现出B和T淋巴细胞数量减少，从而重现了患者的表型。亚型突变导致淋巴特异性DNA重排（称为V（D）J重组）过程中末端加工受损、双链断裂修复缺陷和染色体不稳定性增加。生物化学分析表明，Artemis-P70突变蛋白与DNA依赖性蛋白激酶催化亚基相互作用，并保留显着的，虽然减少，外切和内切核酸酶活性，但不进行磷酸化。总之，我们的研究结果表明，Artemis C末端在确保有效的V（D）J重排和维持基因组完整性方面具有关键的体内功能。
Artemis was initially discovered as the gene inactivated in human radiosensitive T−B− severe combined immunodeficiency, a syndrome characterized by the absence of B and T lymphocytes and cellular hypersensitivity to ionizing radiation. Hypomorphic Artemis alleles have also been identified in patients and are associated with combined immunodeficiencies of varying severity. We examine the molecular mechanisms underlying a syndrome of partial immunodeficiency caused by a hypomorphic Artemis allele using the mouse as a model system. This mutation, P70, leads to premature translation termination that deletes a large portion of a nonconserved C terminus. We find that homozygous Artemis-P70 mice exhibit reduced numbers of B and T lymphocytes, thereby recapitulating the patient phenotypes. The hypomorphic mutation results in impaired end processing during the lymphoid-specific DNA rearrangement known as V(D)J recombination, defective double-strand break repair, and increased chromosomal instability. Biochemical analyses reveal that the Artemis-P70 mutant protein interacts with the DNA-dependent protein kinase catalytic subunit and retains significant, albeit reduced, exo- and endonuclease activities but does not undergo phosphorylation. Together, our findings indicate that the Artemis C terminus has critical in vivo functions in ensuring efficient V(D)J rearrangements and maintaining genome integrity.
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