Detailseite
Projekt
The functional significance of SUMOylierung in biological timing
Antragsteller
Dr. Frank Weber (†)
Fachliche Zuordnung
Zellbiologie
Förderung
Förderung von 2008 bis 2009
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 72353738
Most organisms on earth synchronize their physiological and behavioral activities with the environ-mental cycles of day and night. Such synchronization is achieved by a molecular circadian clock that is constituted by transcription factors, which form interlocked transcriptional/translational feedback loops. The center of the homologous circadian clock of Drosophila and mammals is formed by the complex of transcription factors CLOCK (CLK) and CYCLE (CYC), which control genome-wide tran-scription of key regulatory factors from a large array of vital activities including metabolism, immune-response, cell proliferation and neuronal activity. Increasing evidence has shown that posttranslational regulation of CLK is crucial for circadian clock function and timing of circadian transcription. We re-cently found a regulation of CLK/CYC activity by cyclic nucleotides/PKA, calcium/CaMK II and Ras/MAPK, which involves direct phosphorylation of CLK by CaMK II and MAPK. Also casein kinase I was shown to phosphorylate CLK. We identified specific phosphorylation sites that control CLK nuclear localization and activity. In addition, we characterized functional nuclear localization and export signals that demonstrated a nucleo-cytoplasmic shuttling of CLK. Interestingly, we found com-partment specific phosphorylation states in addition to SUMOylation of CLK. We also identified a SUMOylation site that is crucial for nuclear retention and localization of CLK in nuclear foci. Our data indicate a sequence of posttranlational modifications that target CLK through its life-cycle. In this proposal we aim to investigate this sequence of modifications, particularly SUMOylation and ubiquitination, in order to understand on the molecular level how the temporal regulation of CLK accumulation, nuclear import/export, activation and inactivation, and finally degradation is controlled. These studies will provide important insights into the role of ubiquitin like proteins for post-translational regulation of transcription factors in general and for biological timing of circadian transcription in particular.
DFG-Verfahren
Schwerpunktprogramme
