Sequential posttranslational modifications program FEN1 degradation during cell-cycle progression.
Sequential posttranslational modifications program FEN1 degradation during cell-cycle progression.
复制标题
DOI：
10.1016/j.molcel.2012.05.042
复制
发表时间：
2012-08-10
期刊：
影响因子：
16
通讯作者：
Shen, Binghui
中科院分区：
文献类型：
--
作者：
Guo, Zhigang;Kanjanapangka, Julie;Liu, Na;Liu, Songbai;Liu, Changwei;Wu, Zhenxing;Wang, Yingjie;Loh, Tiffany;Kowolik, Claudia;Jamsen, Joonas;Zhou, Mian;Khue Truong;Chen, Yuan;Zheng, Li;Shen, Binghui
我们认为，细胞周期依赖的FEN1核酸酶活性的时间对于细胞周期进程和维持基因组的稳定性是必不可少的。在S期的出口点完成DNA复制后，去除多余的FEN1可能是至关重要的。在这里，我们报告了一种机制，通过一系列翻译后修饰来控制FEN1的程序性降解。我们发现，FEN1的磷酸化刺激其SUMO化，进而刺激其泛素化，并最终通过蛋白酶体途径导致其降解。在这个途径中的任何一步阻止修饰的突变或抑制剂都会抑制FEN1的降解。关键的是，存在泛素化缺陷的FEN1突变蛋白会导致Cyclin B的积聚、G1和G2/M期的延迟以及多倍体。这些发现可能代表了细胞用来确保精确的细胞周期进程和防止转化的一种新的调控机制。
We propose that cell cycle-dependent timing of FEN1 nuclease activity is essential for cell cycle progression and the maintenance of genome stability. After DNA replication is complete at the exit point of the S-phase, removal of excess FEN1 may be crucial. Here, we report a mechanism that controls the programmed degradation of FEN1 via a sequential cascade of post-translational modifications. We found that FEN1 phosphorylation stimulated its SUMOylation, which, in turn, stimulated its ubiquitination and ultimately led to its degradation via the proteasome pathway. Mutations or inhibitors that blocked the modification at any step in this pathway suppressed FEN1 degradation. Critically, the presence of SUMOylation- or ubiquitination- defective, non-degradable FEN1 mutant protein caused accumulation of Cyclin B, delays in the G1 and G2/M phases and polyploidy. These findings may represent a newly identified regulatory mechanism used by cells to ensure precise cell cycle progression and to prevent transformation.
登录
查看更多内容
影响因子：
14.8
作者：
Guo, Zhigang;Zheng, Li;Xu, Hong;Dai, Huifang;Zhou, Mian;Pascua, Mary Rose;Chen, Qin M.;Shen, Binghui
通讯作者：
Shen, Binghui
影响因子：
5.3
作者：
Guo, Zhigang;Qian, Limin;Shen, Binghui
通讯作者：
Shen, Binghui
影响因子：
9.2
作者：
Saharia, Abhishek;Guittat, Lionel;Stewart, Sheila A.
通讯作者：
Stewart, Sheila A.
影响因子：
8
作者：
Henneke, G;Koundrioukoff, S;Hübscher, U
通讯作者：
Hübscher, U
影响因子：
4.5
作者：
Bernkop-Schnürch, A;Kirchmayer, R;Kratzel, M
通讯作者：
Kratzel, M