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8 pool of inactive transcription factor. Inactivation of WCC requires the continuous activity of FRQ, since FRQ-dependent phosphorylation is antag- onized by PP2A-dependent dephosphorylation and reactivation of WCC. Fig. 3: The activity of the WCC is regulated by phosphorylation. Hyperphosphorylated WCC is inactive. It is activated by PP2A-dependent dephosphorylation. Dephosphorylated WCC binds to the frq promoter and activates transcription. When FRQ protein is synthesized, it recruits CK1a and inactivates the WCC by promoting its phosphorylation. Fig. 4: Molecular model of FRQ-dependent modulation of WCC activity and stability. Michael Brunner In the course of a circadian period FRQ is progressively hyperphosphorylated by a number of kinases, including CK1a. Progressive phosphorylation of FRQ supports its accumulation in the cytosol. Cytosolic FRQ promotes, in the same way as nuclear FRQ, CK1a-dependent phosphorylation of the shuttling WCC. The phosphorylated WCC is less active but more stable than the unphosphorylated transcription factor. Thus, in the presence of FRQ, newly assembled WCC is phosphorylated and stabilized. Accordingly, levels of WCC rise, reflecting the positive limb of the interconnected feedback loops. Since the accu- mulating WCC is phosphorylated, FRQ supports accumulation of high levels of its inactive transcription factor. Hyperphosphorylation of FRQ is progressing throughout the circadian period and triggers eventually its degradation during the subjective night. When FRQ levels decrease, PP2A- dependent dephosphorylation of the WCC kineti- cally dominates over FRQ-dependent phosphorylation. The pool of WCC becomes progressively
activated and frq transcription sets in shortly be- fore subjective dawn and a new circadian cycle begins. As a result of the interconnected negative and positive feedback loops, frq RNA abundance os- cillates in circadian fashion. The resulting circadian accumulation of FRQ drives a robust daily rhythm of WCC activity. WCC activates directly or indirectly circadian transcription and expression of a large number of ccg’s. Genes directly controlled by WCC are expected to be light-activated and expressed in phase with frq. In addition, oth- er ccg’s are not directly controlled by the WCC and expressed in different phases. In particular, genes involved in conidiation are expressed with a peak in the evening/night. Selected Publications 2004 - 2007 Brunner, M. and Schafmeier, T. (2006) Transcriptional and posttranscriptional regulation of the circadian clock of cyanobacteria and Neurospora. Genes & Dev. 20, 1061-1074 (Review). Schafmeier, T., Káldi, K., Diernfellner, A., Mohr, C.A. and Brunner, M. (2006) Phosphorylation dependent maturation of Neurospora circadian clock protein from a nuclear repressor towards a cytoplasmic activator. Genes & Dev. 20, 297-306. Káldi, K., Herreros González, B. and Brunner, M. (2006) A positive feedback loop of the Neurospora circadian clock gene wc-1 modulates the phase of circadian output. EMBO reports 7, 199-204. Diernfellner, A.C.R., Schafmeier, T., Merrow, M.W. and Brunner, M. (2005). Molecular mechanism of temperature sensing by the circadian clock of Neurospora crassa. Genes & Dev. 19, 1968-1973. Schafmeier, T., Haase, A., Káldi, K., Scholz, J. , Fuchs, M. and Brunner, M. (2005). Transcriptional feedback of Neurospora circadian clock gene by phosphorylation-dependent inactivation of its transcription factor. Cell 122, 235-246. Michael Brunner Biochemie-Zentrum der Universität Heidelberg (BZH) Im Neuenheimer Feld 328 D-69120 Heidelberg Phone Office: +49 (0)6221-54 4207 Phone Lab: +49 (0)6221-54 4245 Fax: +49 (0)6221-54 4769 E-mail: michael.brunner@bzh.uni-heidelberg.de Michael Brunner 9
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