Cyclin E-dependent localization of MCM5 regulates centrosome duplication
Cyclin E-dependent localization of MCM5 regulates centrosome duplication
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DOI：
10.1242/jcs.034702
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发表时间：
2008-10-01
影响因子：
4
通讯作者：
Maller, James L.
中科院分区：
文献类型：
--
作者：
Ferguson, Rebecca L.;Maller, James L.
中心体是动物细胞中主要的微管组织中心，是有丝分裂过程中双极纺锤体组装所必需的。中心体数量的扩增在人类癌细胞中常见，可能导致基因组不稳定。细胞周期蛋白 E-Cdk2 参与调节非洲爪蟾胚胎和提取物以及哺乳动物细胞中的中心体复制。细胞周期蛋白 E 在中心体上的定位是由称为中心体定位序列 (CLS) 的 20 个氨基酸结构域介导的。在本文中，细胞周期蛋白 E 以 CLS 依赖性但不依赖 Cdk2 的方式与 DNA 复制因子 MCM5 直接相互作用并共定位于中心体。 MCM5 中负责与细胞周期蛋白 E 相互作用的结构域与之前描述的 MCM5 功能不同，并且在从酵母到哺乳动物的 MCM5 蛋白中高度保守。 MCM5 或其细胞周期蛋白 E 相互作用结构域（而非 MCM2）的表达显着抑制停滞在 S 期的 CHO 细胞中中心体的过度复制。这些结果表明参与 DNA 复制的蛋白质也可能调节中心体的复制。
Centrosomes are the primary microtubule-organizing centers in animal cells and are required for bipolar spindle assembly during mitosis. Amplification of centrosome number is commonly observed in human cancer cells and might contribute to genomic instability. Cyclin E-Cdk2 has been implicated in regulating centrosome duplication both in Xenopus embryos and extracts and in mammalian cells. Localization of cyclin E on centrosomes is mediated by a 20-amino acid domain termed the centrosomal localization sequence (CLS). In this paper, cyclin E is shown to directly interact with and colocalize on centrosomes with the DNA replication factor MCM5 in a CLS-dependent but Cdk2-independent manner. The domain in MCM5 that is responsible for interaction with cyclin E is distinct from any previously described for MCM5 function and is highly conserved in MCM5 proteins from yeast to mammals. Expression of MCM5 or its cyclin E-interacting domain, but not MCM2, significantly inhibits over-duplication of centrosomes in CHO cells arrested in S-phase. These results indicate that proteins involved in DNA replication might also regulate centrosome duplication.