The cell division cycle 25A (CDC25A) phosphatase is a key regulator of cell cycle progression that acts on the phosphorylation status of Cyclin–Cyclin-dependent kinase complexes, with an emergent role in the DNA damage response and cell survival control. The regulation of CDC25A activity and its protein level is essential to control the cell cycle and maintain genomic integrity. Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. CDC25A in turn is able to control the phosphorylation of DYRK2 at several residues outside from its activation loop, thus affecting DYRK2 localization and activity. An inverse correlation between DYRK2 and CDC25A protein amounts was observed during cell cycle progression and in response to DNA damage, with CDC25A accumulation responding to the manipulation of DYRK2 levels or activity in either physiological scenario. Functional data show that the pro-survival activity of CDC25A and the pro-apoptotic activity of DYRK2 could be partly explained by the mutual regulation between both proteins. Moreover, DYRK2 modulation of CDC25A expression and/or activity contributes to the DYRK2 role in cell cycle regulation. Altogether, we provide evidence suggesting that DYRK2 and CDC25A mutually control their activity and stability by a feedback regulatory loop, with a relevant effect on the genotoxic stress pathway, apoptosis, and cell cycle regulation.

细胞分裂周期 25A (CDC25A) 磷酸酶是细胞周期进程的关键调节因子，作用于细胞周期蛋白-细胞周期蛋白依赖性激酶复合物的磷酸化状态，在 DNA 损伤反应和细胞存活控制中发挥着重要作用。 CDC25A 活性及其蛋白质水平的调节对于控制细胞周期和维持基因组完整性至关重要。在这里，我们描述了一种新的泛素/蛋白酶体介导的途径，该途径负调节 CDC25A 稳定性，依赖于丝氨酸/苏氨酸激酶 DYRK2 的磷酸化。 DYRK2 在至少 7 个残基上磷酸化 CDC25A，导致其降解不依赖于已知的 CDC25A E3 泛素连接酶。 CDC25A 反过来能够控制 DYRK2 在其激活环之外的几个残基处的磷酸化，从而影响 DYRK2 的定位和活性。在细胞周期进程和对 DNA 损伤的反应中，观察到 DYRK2 和 CDC25A 蛋白量之间存在负相关，其中 CDC25A 的积累响应于任一生理情况下 DYRK2 水平或活性的操纵。功能数据表明，CDC25A 的促生存活性和 DYRK2 的促凋亡活性可以部分解释为两种蛋白之间的相互调节。此外，DYRK2 对 CDC25A 表达和/或活性的调节有助于 DYRK2 在细胞周期调节中的作用。总而言之，我们提供的证据表明 DYRK2 和 CDC25A 通过反馈调节环路相互控制其活性和稳定性，对基因毒性应激途径、细胞凋亡和细胞周期调节具有相关影响。