Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage
Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage
复制标题
DOI：
10.1038/nature02082
复制
发表时间：
2003-11-06
期刊：
影响因子：
64.8
通讯作者：
Draetta, GF
中科院分区：
文献类型：
--
作者：
Busino, L;Donzelli, M;Draetta, GF
Cdc 25 A磷酸酶是细胞周期进程所必需的，因为它的功能是去磷酸化细胞周期蛋白依赖性激酶。为了响应DNA损伤或复制停滞，ATM和ATR蛋白激酶激活检查点激酶Chk 1和Chk 2，从而导致Cdc 25 A过度磷酸化（1-3）。这些事件刺激泛素介导的Cdc 25 A蛋白水解（1，4，5），并有助于延迟细胞周期进程，从而防止基因组不稳定性（1-7）。在这里，我们报告说，β-TrCP是F-box蛋白，其靶向磷酸化Cdc 25 A，由Skp 1/Cul 1/F-box蛋白复合物降解。通过短干扰RNA下调β-TrCP 1和β-TrCP 2的表达，导致Cdc 25 A在S期细胞中积累，并阻止电离辐射诱导的Cdc 25 A降解，表明β-TrCP可能在S期内检查点发挥作用。与该假设一致，β-TrCP表达的抑制导致响应于DNA损伤的辐射抗性DNA合成-一种表型，其指示与不能正确调节Cdc 25 A相关的S期内检查点的缺陷。我们的研究结果表明，β-TrCP在介导的响应，通过Cdc 25 A降解DNA损伤中起着至关重要的作用。
The Cdc25A phosphatase is essential for cell-cycle progression because of its function in dephosphorylating cyclin-dependent kinases. In response to DNA damage or stalled replication, the ATM and ATR protein kinases activate the checkpoint kinases Chk1 and Chk2, which leads to hyperphosphorylation of Cdc25A(1-3). These events stimulate the ubiquitin-mediated proteolysis of Cdc25A(1,4,5) and contribute to delaying cell-cycle progression, thereby preventing genomic instability(1-7). Here we report that beta-TrCP is the F-box protein that targets phosphorylated Cdc25A for degradation by the Skp1/Cul1/F-box protein complex. Downregulation of beta-TrCP1 and beta-TrCP2 expression by short interfering RNAs causes an accumulation of Cdc25A in cells progressing through S phase and prevents the degradation of Cdc25A induced by ionizing radiation, indicating that beta-TrCP may function in the intra-S-phase checkpoint. Consistent with this hypothesis, suppression of beta-TrCP expression results in radioresistant DNA synthesis in response to DNA damage - a phenotype indicative of a defect in the intra-S-phase checkpoint that is associated with an inability to regulate Cdc25A properly. Our results show that beta-TrCP has a crucial role in mediating the response to DNA damage through Cdc25A degradation.