Cyclin dependent kinase 5 (CDK5) regulates the circadian clock

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. We observed that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine 394 (S394) in a diurnal fashion. This facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the circadian cycle. Therefore, CDK5 is critically involved in the regulation of the circadian clock.

昼夜节律振荡源自转录与翻译后反馈环路。产生节律性的关键步骤之一是时钟蛋白组分向细胞核的转位，该过程在多数情况下由激酶调控。在哺乳动物中，介导核心时钟蛋白组分周期蛋白2（PER2）核输入的激酶至今尚未明确。本研究发现，细胞周期蛋白依赖性激酶5（CDK5）可通过磷酸化PER2调控哺乳动物生物钟。在哺乳动物昼夜节律系统的主要调控中枢视交叉上核（SCN）中敲低Cdk5，会缩短小鼠的自由运行周期。CDK5以昼夜节律依赖的方式在丝氨酸394（S394）位点磷酸化PER2。这一修饰促进了PER2与隐花色素1（CRY1）的相互作用，并加速了PER2-CRY1复合物的核输入过程。综上，本研究证实CDK5可介导PER2的核输入，这对于建立合适的昼夜节律周期至关重要。因此，CDK5在生物钟调控中发挥关键作用。