DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus
DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus
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DOI：
10.1038/ng1297-483
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发表时间：
1997-12-01
期刊：
影响因子：
30.8
通讯作者：
Merlino, G
中科院分区：
文献类型：
--
作者：
Jhappan, C;Morse, HC;Merlino, G
严重联合免疫缺陷（SCID）小鼠(1)在重新排列其可变(V)、多样性(D)和连接(J)遗传元件以产生功能性免疫球蛋白(g)和t细胞受体（TCR）分子的能力方面存在缺陷；因此，他们缺乏成熟的B细胞和T细胞(2)。这些小鼠对电离辐射高度敏感，表明scid基因的产物在V(D)I重组和DNA双链断裂修复中都起着关键作用（3-5）。最近的研究表明，SCID缺陷在于编码dna依赖性蛋白激酶（DNA-PK；参考文献6-8）催化亚基的基因，DNA-PK是一种由ku70和ku86亚基以及大催化亚基DNA-PKcs组成的核蛋白（9,10）。其他报道暗示SCID表型与Prkdc （DNA-PKcs基因）的极端3'端无义突变相关（11-14）。然而，该基因的身份仍然存在疑问，因为Prkdc基因失活的后果尚未确定。值得注意的是，DNA- pkcs缺失的小鼠表现出胸腺淋巴母细胞淋巴瘤的完全外显性，这强烈表明Prkdc在小鼠中作为t细胞肿瘤抑制因子起作用，并且由于其与DNA修复和重组的关联，属于肿瘤抑制基因的“看守”类，包括ATM，BRCA1和BRCA2（参考文献15）。
Severe combined immunodeficiency (SCID) mice(1) are defective in their ability to rearrange their variable (V), diversity (D) and joining (J) genetic elements to generate functional immuno-globulin tig) and T-cell receptor (TCR) molecules; as a result, they lack mature B and T cells(2). These mice are highly sensitive to ionizing radiation, suggesting that the product of the scid gene plays a critical role in both V(D)I recombination and DNA double-strand break repair(3-5). Recent studies suggest that the SCID defect lies in the gene encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PK; refs 6-8), a nuclear protein made up of the Ku 70 and Ku 86 subunits as well as the large catalytic subunit, DNA-PKcs(9,10). Other reports have implied that the SCID phenotype correlates with nonsense mutations at the extreme 3' end of Prkdc, the DNA-PKcs gene(11-14). The identity of the gene remains in doubt, however, because the consequences of genetic inactivation of Prkdc have not been determined. This study shows that complete inactivation of Prkdc in a novel insertional mouse mutant recapitulates the SCID phenotype and that Prkdc and scid are allelic, Significantly, DNA-PKcs null mice demonstrate complete penetrance of thymic lymphoblastic lymphomas, strongly suggesting that Prkdc functions in mice as a T-cell tumour suppressor and, by virtue of its association with DNA repair and recombination, belongs to the 'caretaker' class of tumour-suppressor genes that includes ATM, BRCA1 and BRCA2 (ref. 15).