A number of genes in Drosophila are turned on when the animal is exposed to light:
  • effector genes whose products mediate the animal's responses (e.g. hatching or molting)
  • clock genes whose products regulate the circadian clock. Two key members of this group are:
    • period (per)
    • timeless (tim)
Activation of all of these genes requires that their promoters are bound by the protein transcription factors
  • CLOCK encoded by the gene clock (clk) and
  • CYCLE encoded by the gene cycle (cyc)
(The names of proteins will be designated with capitalized Roman letters; the genes that encode them indicated in lower case italics.)

The Mechanism
  • The PER and TIM proteins (synthesized on ribosomes in the cytoplasm) form dimers.
  • When the concentration of these gets high enough (early evening), they dissociate and are transported into the nucleus.
  • Here PER
    • binds to the CLK/CYC transcription factors, removing them from the promoters of the genes they activate; thus shutting off transcription. Because these genes include per and tim, the result is a negative feedback loop; that is, the product of the per gene inhibit its own synthesis (as well as that of tim). Just as the heat of a furnace turns — through the thermostat — its own production off, so a rising level of PER/TIM dimers turns off further synthesis of them. As the level then falls, this inhibition is lifted and PER/TIM activity begins anew.
    • turns on clock gene expression.
  • The time required for the different effects results in the levels of PER/TIM and CLOCK oscillating in opposite phases with a circadian (~24 hr) rhythm (figure).

Setting the Clock

Even without any external cues (e.g., alternating light and dark), the cycles persist although they tend to drift away from environmental time.
  • Under natural conditions, the clocks are precise.
  • This is because they are "set" (synchronized) by environmental cues, of which light is one of the most important.
In Drosophila, it works like this.
  • Light (blue) is absorbed by the protein cryptochrome (CRY).
  • This causes an allosteric change in its conformation enabling it to
  • bind to TIM and PER.
  • This causes TIM and PER to break down (in proteasomes) ending their inhibition of gene transcription.
    • If this happens when PER/TIM levels are rising (late in the "day"), it sets the clock back.
    • If it happens when PER/TIM levels are declining (late in the "night"), it sets the clock ahead.