Editing Circadian rhythm (section)

==In ''Drosophila''==
{{Main|Drosophila circadian rhythm}}
[[File:Drosophila brains and the circadian system.jpg|thumb|Key centers of the mammalian and ''Drosophila'' brains (A) and the circadian system in ''Drosophila'' (B)]]
The molecular mechanism of circadian rhythm and light perception are best understood in ''Drosophila''. Clock genes are discovered from ''Drosophila'', and they act together with the clock neurones. There are two unique rhythms, one during the process of hatching (called [[eclosion]]) from the pupa, and the other during mating.<ref>{{cite journal | vauthors = Veleri S, Wülbeck C | title = Unique self-sustaining circadian oscillators within the brain of Drosophila melanogaster | journal = Chronobiology International | volume = 21 | issue = 3 | pages = 329–342 | date = May 2004 | pmid = 15332440 | doi = 10.1081/CBI-120038597 | s2cid = 15099796 }}</ref> The clock neurones are located in distinct clusters in the central brain. The best-understood clock neurones are the large and small lateral ventral neurons (l-LNvs and s-LNvs) of the [[Optic lobe (arthropods)|optic lobe]]. These neurones produce pigment dispersing factor (PDF), a neuropeptide that acts as a circadian neuromodulator between different clock neurones.<ref name=yoshi>{{cite journal | vauthors = Yoshii T, Hermann-Luibl C, Helfrich-Förster C | title = Circadian light-input pathways in Drosophila | journal = Communicative & Integrative Biology | volume = 9 | issue = 1 | pages = e1102805 | date = 2015 | pmid = 27066180 | pmc = 4802797 | doi = 10.1080/19420889.2015.1102805 }}</ref>

[[File:Drosophila circadian rhythm.jpg|thumb|Molecular interactions of clock genes and proteins during ''Drosophila'' circadian rhythm]]
''Drosophila'' circadian rhythm is through a transcription-translation feedback loop. The core clock mechanism consists of two interdependent feedback loops, namely the PER/TIM loop and the CLK/CYC loop.<ref>{{cite journal | vauthors = Boothroyd CE, Young MW | title = The in(put)s and out(put)s of the Drosophila circadian clock | journal = Annals of the New York Academy of Sciences | volume = 1129 | issue = 1 | pages = 350–357 | date = 2008 | pmid = 18591494 | doi = 10.1196/annals.1417.006 | s2cid = 2639040 | bibcode = 2008NYASA1129..350B }}</ref> The CLK/CYC loop occurs during the day and initiates the transcription of the ''per'' and ''tim'' genes. But their proteins levels remain low until dusk, because during daylight also activates the ''doubletime'' (''dbt'') gene. DBT protein causes phosphorylation and turnover of monomeric PER proteins.<ref>{{cite journal | vauthors = Grima B, Lamouroux A, Chélot E, Papin C, Limbourg-Bouchon B, Rouyer F | title = The F-box protein slimb controls the levels of clock proteins period and timeless | journal = Nature | volume = 420 | issue = 6912 | pages = 178–182 | date = November 2002 | pmid = 12432393 | doi = 10.1038/nature01122 | s2cid = 4428779 | bibcode = 2002Natur.420..178G }}</ref><ref>{{cite journal | vauthors = Ko HW, Jiang J, Edery I | title = Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime | journal = Nature | volume = 420 | issue = 6916 | pages = 673–678 | date = December 2002 | pmid = 12442174 | doi = 10.1038/nature01272 | s2cid = 4414176 | bibcode = 2002Natur.420..673K }}</ref> TIM is also phosphorylated by shaggy until sunset. After sunset, DBT disappears, so that PER molecules stably bind to TIM. PER/TIM dimer enters the nucleus several at night, and binds to CLK/CYC dimers. Bound PER completely stops the transcriptional activity of CLK and CYC.<ref name=helfrich05>{{cite journal | vauthors = Helfrich-Förster C | title = Neurobiology of the fruit fly's circadian clock | journal = Genes, Brain and Behavior | volume = 4 | issue = 2 | pages = 65–76 | date = March 2005 | pmid = 15720403 | doi = 10.1111/j.1601-183X.2004.00092.x | s2cid = 26099539 | doi-access = free }}</ref>

In the early morning, light activates the ''cry'' gene and its protein CRY causes the breakdown of TIM. Thus PER/TIM dimer dissociates, and the unbound PER becomes unstable. PER undergoes progressive phosphorylation and ultimately degradation. Absence of PER and TIM allows activation of ''clk'' and ''cyc'' genes. Thus, the clock is reset to start the next circadian cycle.<ref name="lalch">{{cite journal| vauthors = Lalchhandama K |title=The path to the 2017 Nobel Prize in Physiology or Medicine|journal=Science Vision|date=2017|volume=3|issue=Suppl|pages=1–13|url=https://www.researchgate.net/publication/321533113}}</ref>

===PER-TIM model===
This protein model was developed based on the oscillations of the PER and TIM proteins in the ''Drosophila''.<ref name="leloup">{{cite journal | vauthors = Leloup JC, Goldbeter A | title = A model for circadian rhythms in Drosophila incorporating the formation of a complex between the PER and TIM proteins | journal = Journal of Biological Rhythms | volume = 13 | issue = 1 | pages = 70–87 | date = February 1998 | pmid = 9486845 | doi = 10.1177/074873098128999934 | s2cid = 17944849 }}</ref> It is based on its predecessor, the PER model where it was explained how the PER gene and its protein influence the biological clock.<ref name="gold1995">{{cite journal | vauthors = Goldbeter A | title = A model for circadian oscillations in the Drosophila period protein (PER) | journal = Proceedings. Biological Sciences | volume = 261 | issue = 1362 | pages = 319–324 | date = September 1995 | pmid = 8587874 | doi = 10.1098/rspb.1995.0153 | s2cid = 7024361 | bibcode = 1995RSPSB.261..319G }}</ref> The model includes the formation of a nuclear PER-TIM complex which influences the transcription of the PER and the TIM genes (by providing negative feedback) and the multiple phosphorylation of these two proteins. The circadian oscillations of these two proteins seem to synchronise with the light-dark cycle even if they are not necessarily dependent on it.<ref name="gold2002">{{cite journal | vauthors = Goldbeter A | title = Computational approaches to cellular rhythms | journal = Nature | volume = 420 | issue = 6912 | pages = 238–245 | date = November 2002 | pmid = 12432409 | doi = 10.1038/nature01259 | s2cid = 452149 | bibcode = 2002Natur.420..238G }}</ref><ref name="leloup"/> Both PER and TIM proteins are phosphorylated and after they form the PER-TIM nuclear complex they return inside the nucleus to stop the expression of the PER and TIM mRNA. This inhibition lasts as long as the protein, or the mRNA is not degraded.<ref name="leloup"/> When this happens, the complex releases the inhibition. Here can also be mentioned that the degradation of the TIM protein is sped up by light.<ref name="gold2002"/>