Damaging-agent sensitivity of Artemis-deficient cell lines
Damaging-agent sensitivity of Artemis-deficient cell lines
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DOI：
10.1002/eji.200425555
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发表时间：
2005-04-01
影响因子：
5.4
通讯作者：
Villa, A
中科院分区：
文献类型：
--
作者：
Musio, A;Marrella, V;Villa, A
双链断裂修复缺陷可能导致基因组不稳定和肿瘤发生。在人类中，大多数 T-B 型严重联合免疫缺陷 (SCID) 患者的 RAG1 或 RAG2 基因存在缺陷，对放射不敏感，并且不表现出基因组不稳定。相反，少数 T-B-SCID 患者的 Artemis 基因异常，对放射线有中度敏感性。 Artemis 缺陷细胞在 RAG 裂解后无法处理发夹末端，但发夹打开活性本身并不能解释 Artemis 缺陷细胞的中等 X 射线敏感性。我们在此报告，与小鼠中的描述不同，Artemis(-/-) 患者的细胞系对丝裂霉素 C 中度敏感，并且在自发和暴露于电离辐射后，仅显示出低至中度的基因组不稳定性增加。 DNA 损伤敏感性和基因组不稳定性水平存在一些异质性，部分原因可能是所涉及的特定突变的不同影响或遗传背景，这可能并不总是代表无效等位基因。这些数据支持这样的假设：除了在 V(D)J 重组过程中的发夹打开中发挥作用外，Artemis 还参与修复 DNA 损伤的子集，其确切性质仍不确定。
Defects in repairing double-strand breaks can lead to genome instability and tumorigenesis. In humans, most T-B- severe combined immunodeficiencies (SCID) have a defect in either the RAG1 or RAG2 gene, are not radiosensitive and do not show genome instability. On the contrary, a minority of T-B- SCID patients have abnormalities in the Artemis gene and are moderately radiosensitive. Artemis-deficient cells are unable to process hairpin ends after RAG cleavage, but hairpin opening activity alone does not explain the moderate X-ray sensitivity of Artemis-deficient cells. We report here that, at variance with what has been described in mice, cell lines from Artemis(-/-) patients are moderately sensitive to mitomycin C and show only a low to moderate increase in genomic instability, both spontaneously and after exposure to ionizing radiations. There is some heterogeneity in the levels of DNA damage sensitivity and genome instability, which could in part be due to different effects of the specific mutation involved or to genetic background, which may not always represent null alleles. This data supports the hypothesis that, in addition to playing a role in hairpin opening during the V(D)J recombination process, Artemis is involved in the repair of a subset of DNA damage whose exact nature is still undefined.