Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells
Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells
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DOI：
10.1073/pnas.0308757101
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发表时间：
2004-02-24
影响因子：
11.1
通讯作者：
Alt, FW
中科院分区：
文献类型：
--
作者：
Rooney, S;Sekiguchi, J;Alt, FW
非同源DNA末端连接(NHEJ)途径包含六个已知成分，包括Artemis，一种在人类严重联合免疫缺陷患者的子集中突变的核酸酶。先前分析的五种NHEJ因子和P53双重缺陷的小鼠不可避免地发生前体B淋巴瘤，携带der(12)t(12；15)易位和免疫球蛋白重链(IgH)/c-myc共扩增，通过断裂-融合-桥机制介导。在这份报告中，我们显示Artemis/P53基因缺陷的小鼠也可以复制地屈服于祖细胞B细胞肿瘤，这表明Artemis在小鼠中是一种肿瘤抑制因子。然而，大多数Artemis/p53缺陷肿瘤缺乏der(12)t(12；15)易位和c-myc扩增，而是通过12号染色体内或染色体间的断裂融合桥机制共扩增IgH和N-myc。我们在可能针对特定癌基因的IgH基因易位的机制的潜在含义的背景下讨论这一发现。
The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (IgH)/c-myc coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and c-myc amplification and instead coamplified IgH and N-myc through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target IgH locus translocations to particular oncogenes.