page_title: Transcription translation feedback loop
section_title: Drosophila melanogaster
hierarchical_section_title: Transcription translation feedback loop / Prominent Models / Drosophila melanogaster
caption_attribution_description: English: An overview of the most important genes and proteins in the biological clock of Drosophila melanogaster. The DNA molecule is modified from DNA Overview by Michael Ströck, released under GFDL and published on Commons. PER=Period, TIM=Timeless, CLK=Clock, CYC=Cycle, VRI=Vrille, PDP1=PAR Domain Protein 1ε, DBT=Doubletime, CRY=Cryptochrome Svenska: En översikt av de viktigaste komponenterna i bananflugans biologiska klocka. DNA-spiralen som används är modifierad från DNA Overview, av Michael Ströck, publicerad under GFDL på Commons. PER=Period, TIM=Timeless, CLK=Clock, CYC=Cycle, VRI=Vrille, PDP1=PAR Domain Protein 1ε, DBT=Doubletime, CRY=Cryptochrome
context_page_description: Transcription-translation feedback loop, is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.
context_section_description: The TTFL was first discovered in Drosophila, and the system shares several components with the mammalian TTFL. Transcription of the clock genes, Period  (per) and Timeless (tim), is initiated when positive elements Cycle (dCYC) and Clock (dCLK) form a heterodimer and bind E-box promoters, initiating transcription. During the day TIM is degraded; light exposure facilitates CRY binging to TIM, which leads to TIM's ubiquitination and eventual degradation. During the night, TIM and PER are able to form heterodimers and accumulate slowly in the cytoplasm, where PER is phosphorylated by the kinase DOUBLETIME (DBT). The post-transcriptional modification of multiple phosphate groups both targets the complex for degradation and facilitates nuclear localization. In the nucleus, the PER-TIM dimer binds to the CYC-CLK dimer, which makes the CYC-CLK dimer release from the E-boxes and inhibits transcription. Once PER and TIM degrade, CYC-CLK dimers are able to bind the E-boxes again to initiate transcription, closing the negative feedback loop.
  Secondary feedback loops interact with this primary feedback loop. CLOCKWORK ORANGE (CWO) binds the E-boxes to act as a direct competitor of CYC-CLK, therefore inhibiting transcription. PAR-DOMAIN PROTEIN 1 ε (PDP1ε) is a feedback activator and VRILLE (VRI) is a feedback inhibitor of the Clk promoter, and their expression is activated by dCLK-dCYC. Ecdysone-induced protein 75 (E75) inhibits clk expression and tim-dependently activates per transcription. All of these secondary loops act to reinforce the primary TTFL.
  Cryptochrome in Drosophila is a blue-light photoreceptor that triggers degradation of TIM, indirectly leading to the clock phase being reset and the renewed promotion of per expression.
caption: Figure shows  the Drosophila melanogaster TTFL and their general interactions between the main players. In this case we can see how CLK and CYC are the positive regulators (yellow and green) and PER and TIM are the negative (red and blue) regulators that each play a role in the circadian clock.
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