Drosophila melanogaster

Clk–Cyc heterodimers bind to E-boxes and activate transcription of Per and Tim. As Per is produced it is phosphorylatedDrosophila feedback loop 1 by Dbt and CK2, which leads to its degradation. Tim binds to, and stabilizes, phosphorylated Per, which remains bound to Dbt. Per is also stabilized by PP2a, which removes phosphates that were added to Per. The Tim–Per–Dbt complexes are phosphorylated by Sgg which, in concert with phosphorylation by CK2, promotes their transport into the nucleus. Tim–Per–Dbt complexes then bind to Clk–Cyc, thereby removing Clk–Cyc from the E-box and inhibiting Per and Tim transcription. Per and Clk are then destabilized, via Dbt phosphorylation, and degraded, whereas Tim degradation (at least in response to light) is triggered by tyrosine phosphorylation. The accumulation of non-phosphorylated (or hypophosphorylated) Clk leads to heterodimerization with Cyc and another cycle of Per and Tim transcription. Solid lines with arrow, sequential steps in the feedback loop; blocked line, inhibitory interaction; wavy line, Per and Tim mRNA; double arrow line, reversible phosphorylation; dashed lines, proteasomal degradation; black X, degraded proteins; P, protein phosphorylation; double line, nuclear membrane.

Clk–Cyc heterodimers bind to E-boxes and activate Vri and Pdp1ε transcription. Vri accumulates in parallel with its mRNA, binds to V/P boxes and inhibits Clk transcription. PDP1ε accumulates in a delayed fashion and supplants Vri from V/P boDrosophila feedback loop 2xes to derepress Clk transcription. A clock independent activator (Act) constitutively activates Clk transcription in the absence of Vri, which would explain the high levels of Clk mRNA in the absence of Clk or Cyc. Accumulation of non-phosphorylated (or hypophosphorylated) Clk leads to heterodimerization with Cyc and another cycle of Vri and Pdp1ε transcription. Solid lines with arrow, sequential steps in the feedback loop; wavy lines, Vri and Pdp1ε or Clk mRNA; double line, nuclear membrane.

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Hardin P. (2005) The Circadian Timekeeping System of Drosophila. Curr Biol. 15:R714-R722.

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