Xpd/Ercc2 regulates CAK activity and mitotic progression
Xpd/Ercc2 regulates CAK activity and mitotic progression
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DOI：
10.1038/nature01746
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发表时间：
2003-07-10
期刊：
影响因子：
64.8
通讯作者：
Suter, B
中科院分区：
文献类型：
--
作者：
Chen, J;Larochelle, S;Suter, B
一般转录因子IIH（TFIIH）由9个亚基组成：细胞周期蛋白依赖性激酶7（Cdk 7）、细胞周期蛋白H和MAT 1（形成Cdk激活激酶或CAK复合物）、两个解旋酶Xpb/Hay和Xpd以及p34、p44、p52和p62（参考文献1 - 3）。作为TFIIH的激酶亚基，Cdk 7通过磷酸化RNA聚合酶II最大亚基的羧基末端结构域参与基础转录1，4，5。作为CAK的一部分，Cdk 7也磷酸化其他Cdk，这是其活化的重要步骤（6-9）。在这里，我们表明，果蝇TFIIH组件XPD负调控Cdk 7的细胞周期功能，CAK活性。过量的Xpd抑制CAK活性，导致Cdk T环磷酸化降低、有丝分裂缺陷和致死性，而Xpd降低导致CAK活性增加和细胞增殖。此外，Xpd在有丝分裂开始时下调，此时Cdk 7的细胞周期靶标Cdk 1最活跃。因此，Xpd的下调似乎有助于有丝分裂CAK活性的上调，并积极调节有丝分裂进程。同时，Xpd的下调可能是有丝分裂沉默基础转录的主要机制。
General transcription factor IIH (TFIIH) consists of nine subunits: cyclin-dependent kinase 7 (Cdk7), cyclin H and MAT1 ( forming the Cdk-activating-kinase or CAK complex), the two helicases Xpb/Hay and Xpd, and p34, p44, p52 and p62 (refs 1 - 3). As the kinase subunit of TFIIH, Cdk7 participates in basal transcription by phosphorylating the carboxy-terminal domain of the largest subunit of RNA polymerase II1,4,5. As part of CAK, Cdk7 also phosphorylates other Cdks, an essential step for their activation(6-9). Here we show that the Drosophila TFIIH component Xpd negatively regulates the cell cycle function of Cdk7, the CAK activity. Excess Xpd titrates CAK activity, resulting in decreased Cdk T-loop phosphorylation, mitotic defects and lethality, whereas a decrease in Xpd results in increased CAK activity and cell proliferation. Moreover, Xpd is downregulated at the beginning of mitosis when Cdk1, a cell cycle target of Cdk7, is most active. Downregulation of Xpd thus seems to contribute to the upregulation of mitotic CAK activity and to regulate mitotic progression positively. Simultaneously, the downregulation of Xpd might be a major mechanism of mitotic silencing of basal transcription.