Department of Radiation Oncology and Molecular Radiation Sciences and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS Genet. 2010 Feb 26;6(2):e1000863. doi: 10.1371/journal.pgen.1000863.
The activation of phase-specific cyclin-dependent kinases (Cdks) is associated with ordered cell cycle transitions. Among the mammalian Cdks, only Cdk1 is essential for somatic cell proliferation. Cdk1 can apparently substitute for Cdk2, Cdk4, and Cdk6, which are individually dispensable in mice. It is unclear if all functions of non-essential Cdks are fully redundant with Cdk1. Using a genetic approach, we show that Cdk2, the S-phase Cdk, uniquely controls the G(2)/M checkpoint that prevents cells with damaged DNA from initiating mitosis. CDK2-nullizygous human cells exposed to ionizing radiation failed to exclude Cdk1 from the nucleus and exhibited a marked defect in G(2)/M arrest that was unmasked by the disruption of P53. The DNA replication licensing protein Cdc6, which is normally stabilized by Cdk2, was physically associated with the checkpoint regulator ATR and was required for efficient ATR-Chk1-Cdc25A signaling. These findings demonstrate that Cdk2 maintains a balance of S-phase regulatory proteins and thereby coordinates subsequent p53-independent G(2)/M checkpoint activation.
细胞周期时相特异性细胞周期蛋白依赖性激酶（Cdks）的激活与有序的细胞周期转变相关。在哺乳动物 Cdk 中，只有 Cdk1 对于体细胞增殖是必需的。Cdk1 显然可以替代在小鼠中各自不可或缺的 Cdk2、Cdk4 和 Cdk6。目前尚不清楚非必需 Cdk 的所有功能是否与 Cdk1 完全冗余。我们通过遗传方法表明，S 期 Cdk Cdk2 独特地控制 G2/M 检查点，该检查点可防止有 DNA 损伤的细胞启动有丝分裂。暴露于电离辐射的 CDK2 纯合缺失的人类细胞未能将 Cdk1 排斥出核，并表现出明显的 G2/M 期阻滞缺陷，这一缺陷被破坏 P53 所揭示。通常由 Cdk2 稳定的 DNA 复制许可蛋白 Cdc6 与检查点调节剂 ATR 发生物理关联，并需要其来有效激活 ATR-Chk1-Cdc25A 信号通路。这些发现表明 Cdk2 维持 S 期调节蛋白的平衡，从而协调随后不依赖 p53 的 G2/M 检查点激活。
