Regulation of DNA damage signaling and circadian rhythms by the casein kinase 1 family of proteins

The CK1 family of protein kinases is a group of ubiquitously expressed serine/threonine kinases found in all eukaryotic organisms from protozoa to man. Research on these kinases has revealed important roles in the regulation of diverse cellular processes such as membrane transport, cell division, DNA repair and circadian rhythms. We now further delineate the biochemical roles of CK1 and find heretofore unidentified roles in transcriptional control and regulation of protein stability. The cyclic AMP-response element-binding protein (CREB) is a bZIP family transcription factor implicated as an oncoprotein and neuron survival factor. We previously demonstrated that the interaction between CREB and its coactivator CBP (CREB-binding protein) is inhibited by DNA damaging stimuli through a mechanism whereby CREB is phosphorylated by the ataxiatelangiectasia-mutated (ATM) protein kinase. We now show that CK1 is a critical mediator of DNA damage-dependent CREB phosphorylation and regulation and outline a complex phosphorylation cascade where CKI-mediated phosphorylation events license CREB for ATM-dependent phosphorylation. We also identify the CREB family member Activating transcription factor 1 (ATF1) as a target of the DNA damage response and identify overlapping and distinct modes of CREB/ATF1 regulation by CK1-dependent phosphorylation. Our studies identify coregulated ATM and CK phosphorylation sites as amplifiers of ATM mediated phosphorylation of CREB/ATF1 and they may constitute a signaling motif that is common to other DNA damage-regulated substrates. In other studies, we implicate CK1 family members, CK1S and CK1c in regulating the stability of mammalian circadian clock component PERIOD2 (PER2). PER2 plays a critical role in circadian rhythm entrainment and mutations in the gene have recently been identified in patients suffering from the rare sleep disorder, Familial advanced sleep phase syndrome (FASPS). Patients with FASPS display abnormal sleep-wake patterns characterized by a life-long pattern of sleep onset in the early evening and offset in the early morning. Using phospho-specific antibodies we identify one of the mutated sites in FASPS as a CK1 phosphorylation target that enhances PER2 protein stability. Our combined findings provide new insights into PER2 regulation and the biochemical basis of FASPS.