In mammals, the homolog of DBT is casein kinase I epsilon, which has a similar role in regulating the circadian rhythm.
[2] The doubletime gene (DBT) was first discovered and characterized in 1998 by Michael Young and his team at Rockefeller University.
[3] Young's research group, headed by Jeffrey Price, published their findings in a paper which characterized three alleles of DBT in fruit flies.
[4] It was reported that two mutant alleles, named short and long (DBTs and DBTl, respectively), were able to disrupt the normal cycling of the genes Period (per) and Timeless (TIM).
[4] Young's team also identified a third allele, DBTP, which is lethal to pupae while ablating any per or TIM products in larvae.
[5] In Drosophila, a molecularly-driven clock mechanism works to regulate circadian rhythms such as locomotor activity and eclosion by oscillating the levels of the proteins PER and TIM via positive and negative feedback loops.
[7] The DBTL mutation causes the period of PER and TIM oscillations and animal behavioral activity to lengthen to about 27 hours.
This extended rhythm is caused by a decreased rate of phosphorylation of PER due to lower DBT kinase activity levels.
[7] Clock gene mutations, including those in Drosophila's DBT, alter the sensitization of drug-induced locomotor activity after repeated exposure to psychostimulants.
Drosophila with mutant alleles of DBT failed to display locomotor sensitization in response to repeated cocaine exposure.
[5] The DBT protein may play a noncatalytic role in attracting kinases that phosphorylate CLOCK (CLK), an activator of transcription.
The DBT protein is noncatalytic in recruiting additional kinases that indirectly phosphorylate CLK, which downregulates transcription.
[16] Since DBT is a member of this family, it has prompted questions regarding the roles of these related genes in other model systems.
The tau mutation in the Syrian golden hamster was the first to show a heritable abnormality of circadian rhythms in mammals.
[16] Because of previous research investigating the role of DBT in establishing periods, the tau mutation was found to be at the same locus as the CKIε gene.
It was found that the point mutation resulting in the tau mutant decreased the activity of the CKIε kinase in vitro.
[18] CKIε also plays a role in humans concerning Familial Advanced Sleep Phase Syndrome, where individuals exhibit a significantly shorter circadian period compared to the general population.
Traditionally, the transcription-translation negative feedback loop has been recognized as the source of oscillations and rhythms in biological clocks.
However, in vitro experiments showcasing the phosphorylation of the cyanobacterial protein KaiC demonstrated that rhythmic oscillations could persist even in the absence of transcription or translation processes.