Jiangsu Key Laboratory for Molecular and Medical Biotechnology and College of Life Sciences, Nanjing Normal University, Nanjing 210046, China.
Mol Cell. 2012 Aug 10;47(3):444-56. doi: 10.1016/j.molcel.2012.05.042. Epub 2012 Jun 30.
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 posttranslational 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, nondegradable 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.
我们提出，FEN1 核酸内切酶活性的细胞周期依赖性定时对于细胞周期进程和基因组稳定性的维持是必不可少的。在 S 期的出口点完成 DNA 复制后，去除多余的 FEN1 可能至关重要。在这里，我们报告了一种通过翻译后修饰的级联反应来控制 FEN1 程序化降解的机制。我们发现 FEN1 磷酸化刺激其 SUMO 化，进而刺激其泛素化，最终导致其通过蛋白酶体途径降解。在该途径中的任何步骤阻断修饰的突变或抑制剂均抑制 FEN1 降解。至关重要的是，SUMOylation 或泛素化缺陷、不可降解的 FEN1 突变蛋白的存在导致 Cyclin B 的积累、G1 和 G2/M 期的延迟以及多倍体形成。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发现的调节机制。
