Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis
Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis
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DOI：
10.1128/mcb.25.17.7569-7579.2005
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发表时间：
2005-09-01
影响因子：
5.3
通讯作者：
McGowan, CH
中科院分区：
文献类型：
--
作者：
Dendouga, N;Gao, H;McGowan, CH
Mus81-Eme1 核酸内切酶参与有效挽救酿酒酵母和粟酒裂殖酵母中断裂的复制叉。我们使用基因打靶来研究 Mus81-Eme1 核酸内切酶在哺乳动物细胞中的功能。 Mus81 缺陷小鼠发育正常并且具有生育能力。令人惊讶的是，来自 Mus81(-/-) 动物的胚胎成纤维细胞在体外无法增殖。这种增殖缺陷可以通过促进 p53 降解的乳头瘤病毒 E6 蛋白的表达来挽救。在培养物中生长时，Mus81(-/-) 细胞的 DNA 损伤水平升高，出现染色体畸变，并且对产生 DNA 交联的试剂高度敏感。与酵母中的情况相反，小鼠 Mus81 不需要在喜树碱处理后重新启动复制。 Mus81-/- 小鼠和细胞对 DNA 交联剂高度敏感。交联诱导的双链断裂形成在 Mus81(-/-) 细胞中是正常的，但修复中间体的解析则不然。 Mus81(-/-) 细胞中 Rad51 灶的持续存在表明 Mus81 在修复交联诱导的损伤中发挥作用。尽管存在这些缺陷，Mus81(-/-) 小鼠在生命的第一年并没有表现出罹患淋巴瘤或任何其他恶性肿瘤的倾向增加。
The Mus81-Eme1 endonuclease is implicated in the efficient rescue of broken replication forks in Saccharomyces cerevisiae and Schizosaccharomyces pombe. We have used gene targeting to study the function of the Mus81-Eme1 endonuclease in mammalian cells. Mus81-deficient mice develop normally and are fertile. Surprisingly, embryonic fibroblasts from Mus81(-/-) animals fail to proliferate in vitro. This proliferation defect can be rescued by expression of the papillomavirus E6 protein that promotes degradation of p53. When grown in culture, Mus81(-/-) cells have elevated levels of DNA damage, acquire chromosomal aberrations, and are hypersensitive to agents that generate DNA cross-links. In contrast to the situation in yeast, murine Mus81 is not required for replication restart following camptothecin treatment. Mus81-/- mice and cells are hypersensitive to DNA cross-linking agents. Cross-link-induced double-strand break formation is normal in Mus81(-/-) cells, but the resolution of repair intermediates is not. The persistence of Rad51 foci in Mus81(-/-) cells suggests that Mus81 acts at a late step in the repair of cross-link-induced lesions. Despite these defects, Mus81(-/-) mice do not show increased predisposition to lymphoma or any other malignancy in the first year of life.