DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation
DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation
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DOI：
10.1038/35006670
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发表时间：
2000-03-30
期刊：
影响因子：
64.8
通讯作者：
Nussenzweig, A
中科院分区：
文献类型：
--
作者：
Difilippantonio, MJ;Zhu, J;Nussenzweig, A
癌症易感基因被分为两类：守门人和看门人(1)。看门人是控制细胞增殖和死亡的基因，而看护人是DNA修复基因，其失活导致遗传不稳定。同时取消照顾者和看门人的功能会显著增加癌症的易感性。虽然Ku80在DNA双链断裂修复中的重要性已经得到证实，但Ku80和其他非同源末端连接途径的成分都不知道在维持基因组稳定性方面具有看守作用。在这里，我们发现缺乏Ku80的小鼠细胞显示出染色体畸变的显著增加，包括断裂、易位和非整倍体。尽管观察到染色体不稳定，但Ku80（-/-）小鼠的癌症发病时间仅略早（2,3）。p53的缺失与Ku80协同促进肿瘤发生，使得所有Ku80(-/-) p53（-/-）小鼠在3个月大前死于弥散性前b细胞淋巴瘤。肿瘤是由一组特定的染色体易位和涉及IgH和c-Myc的基因扩增引起的，让人想起伯基特淋巴瘤。我们得出结论，Ku80是一个看守基因，通过抑制染色体重排的机制维持基因组的完整性。
Cancer susceptibility genes have been classified into two groups: gatekeepers and caretakers(1). Gatekeepers are genes that control cell proliferation and death, whereas caretakers are DNA repair genes whose inactivation leads to genetic instability. Abrogation of both caretaker and gatekeeper function markedly increases cancer susceptibility. Although the importance of Ku80 in DNA double-strand break repair is well established, neither Ku80 nor other components of the non-homologous end-joining pathway are known to have a caretaker role in maintaining genomic stability. Here we show that mouse cells deficient for Ku80 display a marked increase in chromosomal aberrations, including breakage, translocations and aneuploidy. Despite the observed chromosome instabilities, Ku80(-/-) mice have only a slightly earlier onset of cancer(2,3). Loss of p53 synergizes with Ku80 to promote tumorigenesis such that all Ku80(-/-) p53(-/-) mice succumb to disseminated pro-B-cell lymphoma before three months of age. Tumours result from a specific set of chromosomal translocations and gene amplications involving IgH and c-Myc, reminiscent of Burkitt's lymphoma. We conclude that Ku80 is a caretaker gene that maintains the integrity of the genome by a mechanism involving the suppression of chromosomal rearrangements.