A Mutant Drosophila Homolog of Mammalian Clock Disrupts Circadian Rhythms and Transcription of period and timeless

Abstract

We report the identification, characterization, and cloning of a novel Drosophila circadian rhythm gene, dClock. The mutant, initially called Jrk, manifests dominant effects: heterozygous flies have a period alteration and half are arrhythmic, while homozygous flies are uniformly arrhythmic. Furthermore, these flies express low levels of the two clock proteins, PERIOD (PER) and TIMELESS (TIM), due to low per and tim transcription. Mapping and cloning of the Jrk gene indicates that it encodes the Drosophila homolog of mouse Clock. The mutant phenotype results from a premature stop codon that eliminates much of the putative activation domain of this bHLH-PAS transcription factor, thus explaining the dominant features of Jrk. The remarkable sequence conservation strongly supports common clock components present in the common ancestor of Drosophila and mammals.

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

“…It includes four core clock proteins: TIMELESS (TIM), CLOCK (CLK), CYCLE (CYC), and PERIOD (PER). The CLK/CYC heterodimer activates the transcription of hundreds of genes, including tim and per (6,7). TIM and PER then enter the nucleus to suppress the activity of the CLK/ CYC dimer, resulting in a decrease in their own levels (8).…”

Clk post-transcriptional control denoises circadian transcription both temporally and spatially

“…Circadian clocks appear to function on a cellautonomous basis and are generated by interconnected complex transcriptional and post-translational feedback loops 1 . In Drosophila, the master genes Clock (Clk) and cycle (cyc) activate the circadian system by promoting rhythmic transcription of a number of key genes [2][3][4] . Three of these target gene products, PERIOD (PER) 5 , TIMELESS (TIM) 6 and CLOCKWORK ORANGE (CWO) [7][8][9] , repress CLK-CYC-mediated transcription on a daily basis.…”

Modelling of circadian rhythms in Drosophila incorporating the interlocked PER/TIM and VRI/PDP1 feedback loops

“…In clk Jrk flies, experimental data have shown low levels of per, tim, vri and pdp1 mRNAs (Allada, White et al 1998;Cyran, Buchsbaum et al 2003), and a high level of clk mRNA which is near the WT peak (Glossop, Lyons et al 1999). The simulated data ( Figure 8B) agree in terms of the low levels of per, tim, vri and pdp1 mRNAs, but show a disparity in the low level of clk mRNA.…”

“…In previous models, transcriptional regulation was modelled by Hill functions without explicit descriptions of binding and unbinding processes of transcription factors to E-boxes elements in promoters (Allada, White et al 1998;Leloup and Goldbeter 1998;Glossop, Lyons et al 1999;Ueda, Hagiwara et al 2001;Smolen, Hardin et al 2004). Hill cooperativity coefficient may correspond to the number of binding sites of genes (Hill 1910;Segel 1993).…”

“…Transcriptional regulation underlying the circadian clock in Drosophila includes two interacting feedback loops, as shown in Figure 1 (Glossop, Lyons et al 1999;Cyran, Buchsbaum et al 2003;Hardin 2005 (Allada, 1998). After initial activation of per and tim expression, there is a 4 h -6 h delay between the peak concentrations of per and tim mRNAs and that of PER and TIM proteins (Zerr, Hall et al 1990;Zeng, Qian et al 1996).…”