Fig. 1

Circadian feedback regulatory loop in Drosophila melanogaster. In the per/tim loop, the CLK/CYC heterodimer binds to the E-box region of per and tim to activate their transcription. PER and TIM accumulate in the cytoplasm and form another complex at night. Phosphorylation of PER/TIM by kinases promotes their nuclear entry, which is counteracted by the dephosphorylation performed by phosphatases. The PER/TIM complex moves into the nucleus later in the night, and hyperphosphorylated PER/TIM represses CLK/CYC activity by promoting the phosphorylation of CLK. In the clk/cyc loop, CLK/CYC promotes the transcription of pdp1 and vri, which encode PDP1 and VRI transcription factors to activate and repress clk transcription, respectively. VRI inhibition precedes PDP1 activation in a way that causes clk mRNA to oscillate during the day. CLK—CLOCK, CYC—CYCLE, PER—PERIOD, TIM—TIMELESS, pdp1—PAR domain protein 1, VRI—VRILLE