page_title: Timeless (gene)
section_title: Drosophila homolog
hierarchical_section_title: Timeless (gene) / Timeless homologs / Drosophila homolog
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: Timeless is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period gene and its protein.
context_section_description: The timeless gene is an essential component of the molecular circadian clock in Drosophila. It acts as part of an autoregulatory feedback loop in conjunction with the period (per) gene product as noted in collaborative studies performed by the labs of Michael W. Young and Amita Sehgal.  Further studies by the labs of Young, Sehgal, Charles Weitz, and Michael Rosbash indicated that timeless protein (TIM) and period protein (PER) form a heterodimer that exhibits circadian rhythms in wild type Drosophila. Researchers in Rosbash's lab also showed that tim mRNA levels and TIM protein levels have circadian rhythms that are similar to those of the period (per) mRNA and its product.  Experiments done jointly by the Weitz, Young, and Sehgal labs using yeast 2-hybrid proved that TIM directly binds with PER. During the early evening, PER and TIM dimerize and accumulate. Late at night, the dimer travels into the nucleus to inhibit per and tim transcription. In 1996, the teams of Sehgal, Edery, and Young found that exposure to light leads to the degradation of TIM and subsequently PER.
  The PER/TIM heterodimer negatively regulates transcription of  period (per) and timeless (tim) genes.  Within this negative feedback loop, first the PER/TIM heterodimers form in the cytoplasm, accumulate, and then translocate to the nucleus.   The complex then blocks the positive transcription factors clock (CLK) and cycle (CYC), thereby repressing the transcription of per.
  
  As part of the circadian clock, timeless is essential for entrainment to light-dark (LD) cycles.  The typical period length of free-running Drosophila is 23.9 hours, requiring adaptations to the 24-hour environmental cycle. Adaptation first begins with exposure to light. This process leads to the rapid degradation of the TIM protein, allowing organisms to entrain at dawn to environmental cycles. 
    In light-dark cycles, TIM protein level decreases rapidly in late night/early morning, followed by the similar but more gradual changes in PER protein level. TIM degradation is independent of per and its protein, and releases PER from the PER/TIM complex.  In some cell types, the photoreceptor protein cryptochrome (CRY) physically associates with TIM and helps regulate light-dependent degradation. CRY is activated by blue light, which binds to TIM and tags it for degradation. This ends the PER/TIM repression of the CLK/CYC-mediated transcription of per and tim genes, allowing per and tim mRNA to be produced to restart the cycle.
  This mechanism allows entrainment of flies to environmental light cues.  When Drosophila receive light inputs in the early subjective night, light-induced TIM degradation causes a delay in TIM accumulation, which creates a phase delay.  When light inputs are received in the late subjective night, a light pulse causes TIM degradation to occur earlier than under normal conditions, leading to a phase advance.
  In Drosophila, the negative regulator PER, from the PER/TIM complex, is eventually degraded by a casein kinase-mediated phosphorylation cycle, allowing fluctuations in gene expression according to environmental cues. These proteins mediate the oscillating expression of the transcription factor VRILLE (VRI), which is required for behavioral rhythmicity, per and tim expression, and accumulation of PDF (pigment-dispersing factor).
caption: Circadian clock of drosophila
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