Figure 2.

Schematic diagram of the intracellular suprachiasmatic nucleus (SCN) clockwork with points of regulation by mutations and drugs. The canonical clockwork involves a transcription–translational negative feedback loop in which PER–CRY dimers inhibit their own transcription by repressing the actions of CLOCK–BMAL1 dimers on E-box elements in clock genes. Beyond this, mRNA maturation and posttranslational regulation of clock gene products including phosphorylation by AMPK and CK1, ubiquitinylation by FBXL3, FBXL21, and βTrCP, and translational regulation by eIF4E and mRNA methylation contribute to oscillation and determine circadian period. Deletions of Cry1 or Cry2, circadian mutations (gray) in PER genes (Edo and FASP), CK1ɛ (Tau), Fbxl3 (Afterhours, Overtime), and CLOCK (Δ19) as well as drug manipulations (purple, Leptomycin B and PF-670462) highlight key points of regulatory control of the molecular clock.