Phosphorylation of Mcm2 by Cdc7 promotes pre-replication complex assembly during cell-cycle re-entry.
Phosphorylation of Mcm2 by Cdc7 promotes pre-replication complex assembly during cell-cycle re-entry.
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DOI：
10.1016/j.molcel.2009.06.014
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发表时间：
2009-07-31
期刊：
影响因子：
16
通讯作者：
Reed, Steven I.
中科院分区：
文献类型：
--
作者：
Chuang, Li-Chiou;Teixeira, Leonardo K.;Wohlschlegel, James A.;Henze, Martha;Yates, John R.;Mendez, Juan;Reed, Steven I.
细胞周期蛋白 E 已被证明在从静止状态重新进入细胞周期的细胞的复制前复合物 (Pre-RC) 组装中发挥作用。预复制复合体的组装涉及 6 个 MCM 亚基 (Mcm2-7) 的装载，是 DNA 复制的先决条件。我们发现细胞周期蛋白 E 通过激活 Cdk2 促进 Mcm2 装载到染色质上。该功能部分是通过促进 Cdc7 mRNA 和蛋白质的积累来介导的，然后磷酸化 Mcm2。与此一致的是，Mcm2 的磷酸模拟突变体可以在 Mcm2 负载方面绕过 Cdc7 的要求。此外，Cdc6 和 Cdc7 的异位表达可以挽救与显性失活 Cdk2 表达相关的 MCM 加载缺陷。这些结果与细胞周期蛋白 E-Cdk2 在促进 Cdc6 和 Cdc7 积累中的作用一致，这是细胞从静止状态重新进入细胞周期时加载 Mcm2 所必需的。
Cyclin E has been shown to have a role in pre-replication complex (Pre-RC) assembly in cells reentering the cell cycle from quiescence. The assembly of the pre-replication complex, which involves the loading of 6 MCM subunits (Mcm2–7), is a prerequisite for DNA replication. We found that cyclin E, through activation of Cdk2, promotes Mcm2 loading onto chromatin. This function is mediated in part by promoting the accumulation of Cdc7 mRNA and protein, which then phosphorylates Mcm2. Consistent with this, a phosphomimetic mutant of Mcm2 can bypass the requirement for Cdc7 in terms of Mcm2 loading. Furthermore, ectopic expression of both Cdc6 and Cdc7 can rescue the MCM loading defect associated with expression of dominant-negative Cdk2. These results are consistent with a role for cyclin E-Cdk2 in promoting the accumulation of Cdc6 and Cdc7, which is required for Mcm2 loading when cells re-enter the cell cycle from quiescence.
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