User:Jetlag2015/sandbox

Jetlag (gene) Jetlag, also known as jet, CG8873, Dmel\CG8873, and FBXL15, is a gene first discovered in Drosophila melanogaster that encodes for an F-box protein with leucine-rich repeats. Mutations in this gene make the circadian clock of Drosophila less sensitive to light. The fruit fly circadian clock synchronizes to daily cycles of light and dark through the light entrainment pathway, in which TIM (Timeless protein) and CRY (circadian photopigment Cryptochrome) are degraded by the same proteasomal pathway in response to light, a process mediated by JET, the jetlag protein, which is part of the Skp1/Cullin/F-box (SCF) E3 ubiquitin ligase complex. The gene is 1,579 bases long and located on the left arm of the second chromosome of the fly genome. A similarly structured gene has been identified in humans, but the gene's role in human circadian rhythms is not clear.

History and discovery
In 2006, Dr. Kyunghee Koh, a postdoctoral fellow in the lab of Dr. Amita Sehgal at the Perelman School of Medicine discovered a mutant strain of Drosophila that maintained free-running rhythms in constant 24 hour-per day exposure to light. Wild-type Drosophila show a random behavioral pattern throughout a 24-hour period of constant light, so identifying behavioral rhythmicity in constant light is a common method to screen for mutations in the fly clock's light input pathway. These mutant flies can synchronize to a typical day:night cycle, but experience jet lag, or take longer than the wild-type flies to adjust to new schedules, hence the name jetlag for the gene. The researchers mapped the jetlag mutation using meiotic recombination, and found the gene to be near tim on the second chromosome.

Gene characteristics
Drosophila jet is a protein coding gene that is 1,579 base pairs long, consisting of 2 exons and 1 intron. It is located on the left arm of chromosome 2 in Drosophila melanogaster. Two of the defining aspects of the structure of jet is the F-box and leucine rich protein repeats, which are important for degrading TIM. This gene is conserved, showing orthologs in the F-box and leucine rich repeat proteins of humans (FBXL3), chimpanzees, rhesus monkeys, dogs, mice, cats, chickens, zebrafish, mosquitoes, worms, sea urchins, rats, water fleas, silkmoths, frogs, yeast, and other flies. There is no known paralog in D. melanogaster.

Mutants
Eight total alleles are reported for the jetlag gene. The three most common mutants are jetr (rare) and jetc (common), and jetset. Flies with the jetc mutation are the result of a phenylalanine to isoleucine substitution within the leucine-rich-repeat region of the protein. Strains with the jetr mutation, are the result of a serine to leucine substitution in a region next to the leucine-rich repeat region. Behaviorally, both jetr and jetc flies are identical to wild-type flies in consistent light-dark cycles and in constant darkness, but maintain rhythmicity in constant light when wild-type flies normally become arrythmic. These mutant phenotypes also demonstrate decreased phase shifts in response to light pulses and decreased light-induced degradation of TIM and take longer to entrain to new light-dark cycles. Jetset mutants showed loss of function and arrhythmic phenotypes. This mutation was caused by the mutagen ethyl methanesulfonate.

Circadian functions
JETLAG protein has a N-terminal F-box domain and seven leucine-rich repeats (LRR). The LRR domain serves as the protein-protein interaction domain. JET is part of the Skp1/Cullin/F-box (SCF) E3 ubiquitin ligase complex. JET interacts with CRY and TIM through the LRR domain. Jetlag (jet) is instrumental in resetting the circadian clock in Drosophila. Jetlag promotes degradation of Timeless and Cryptochrome under light conditions. Upon light exposure, CRY protein undergoes a conformational change, which allows it to bind to TIM protein. This targets TIM for phosphorylation. TIM posttranslational phosphorylation is essential for JET to target TIM for ubiquitination and degradation. The reduced levels of TIM are essential to shift the circadian clock’s phase. The degradation activity of JET is blocked by a proteasome inhibitor. JET’s degradation activity is light-dependent and requires coexpression of CRY. JET also binds and degrades CRY and regulates Cry turnover in vitro. However, JET has a much higher affinity for light-activated TIM and will preferentially associate with TIM over CRY.

Current research
Recent studies have attempted to clarify the degradation pathways of circadian clock proteins in both light and dark, especially that of Drosophila CRY. Additional genes have been found to play a part in the pathway along with JET, including the protein SLIMB and the COP9 signalosome, which works downstream of JET to degrade TIM, and possibly CRY as well. SLIMB was found to be important in mediating light-independent (i.e. dark) degradation of TIM, while BRWD3 was found to be involved in the light-dependent degradation of TIM together with JET.