Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression
Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression
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DOI：
10.1073/pnas.1113524108
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发表时间：
2011-10-25
影响因子：
11.1
通讯作者：
Schimenti, John C.
中科院分区：
文献类型：
--
作者：
Hartford, Suzanne A.;Luo, Yunhai;Schimenti, John C.
有效的 DNA 复制对于生物体的健康和繁殖成功至关重要。形成复制解旋酶的六种 MCM2-7 蛋白对于基因组的高保真复制至关重要。许多真核生物具有不同的旁系同源物 MCM9，据报道，MCM9 对于将 MCM2-7 加载到爪蟾卵母细胞提取系统中的复制起点至关重要。为了解决哺乳动物 MCM9 的体内作用，我们创建并分析了具有 MCM9 和内含子 DNA 复制相关基因 Asf1a 各种突变的小鼠的表型。 Mcm9 的消融与细胞增殖和小鼠活力相容，表明它对于 MCM2-7 加载或 DNA 复制不是必需的。 Mcm9突变体在两性中均经历了不依赖于p53的胚胎生殖细胞耗竭，而雄性也表现出有缺陷的精原干细胞更新。 MCM9缺陷细胞在复制应激后基因组不稳定性升高，细胞周期再进入缺陷，突变动物容易患性别特异性癌症，尤其是雄性肝细胞癌。突变小鼠和细胞的表型表明，MCM9 在 DNA 复制或复制相关质量控制机制中发挥了特殊但非必要的作用，这对于生殖系干细胞以及体细胞中的肿瘤抑制和基因组维护尤其重要。
Effective DNA replication is critical to the health and reproductive success of organisms. The six MCM2-7 proteins, which form the replicative helicase, are essential for high-fidelity replication of the genome. Many eukaryotes have a divergent paralog, MCM9, that was reported to be essential for loading MCM2-7 onto replication origins in the Xenopus oocyte extract system. To address the in vivo role of mammalian MCM9, we created and analyzed the phenotypes of mice with various mutations in Mcm9 and an intronic DNA replication-related gene Asf1a. Ablation of Mcm9 was compatible with cell proliferation and mouse viability, showing that it is nonessential for MCM2-7 loading or DNA replication. Mcm9 mutants underwent p53-independent embryonic germ-cell depletion in both sexes, with males also exhibiting defective spermatogonial stem-cell renewal. MCM9-deficient cells had elevated genomic instability and defective cell cycle reentry following replication stress, and mutant animals were prone to sex-specific cancers, most notably hepatocellular carcinoma in males. The phenotypes of mutant mice and cells suggest that MCM9 evolved a specialized but nonessential role in DNA replication or replication-linked quality-control mechanisms that are especially important for germ-line stem cells, and also for tumor suppression and genome maintenance in the soma.