Circadian clocks regulate molecular oscillations that manifest into physiological and behavioral rhythms. In all systems investigated, clocks are controlled through interlocked transcriptional feedback loops, which regulate the daily oscillations of clock mRNAs. These mRNA oscillations are precisely translated to daily cycles of clock protein levels via regulation and fine-tuning by posttranslational mechanisms. A conserved feature of animal clocks is that PERIOD (PER) proteins undergo daily oscillations in levels and phosphorylation states that are regulated by DOUBLETIME (DBT in Drosophila) [casein kinase 1e (CK1e in mammals)]. In Drosophila, our lab recently showed that hyperphosphorylated PER proteins are eventually targeted to the 26S proteasome for degradation by the F-box protein Slimb (a homolog of beta-TrCP in mammals). The overall goal of this proposal is to better understand the role of posttranslational regulation in clock function by focusing on PER phosphorylation and its intersection with the ubiquitin/proteasome pathway. I will integrate in vitro assays, tissue culture based systems, and whole animal approaches. The use of Drosophila melanogaster as the model animal provides a powerful system for genetic manipulations.
| Ko, Hyuk Wan; Kim, Eun Young; Chiu, Joanna et al. (2010) A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3beta/SGG in circadian clocks. J Neurosci 30:12664-75 |
| Chiu, Joanna C; Vanselow, Jens T; Kramer, Achim et al. (2008) The phospho-occupancy of an atypical SLIMB-binding site on PERIOD that is phosphorylated by DOUBLETIME controls the pace of the clock. Genes Dev 22:1758-72 |
