| per | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Organism | D. melanogaster | ||||||
| Symbol | per | ||||||
| Entrez | 31251 | ||||||
| RefSeq (mRNA) | NM_080317 | ||||||
| RefSeq (Prot) | NP_525056 | ||||||
| UniProt | P07663 | ||||||
| Other data | |||||||
| Chromosome | X: 2.58 - 2.59 Mb | ||||||
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Period (per) is a gene located on the X chromosome ofDrosophila melanogaster.Oscillations in levels of bothper transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of theDrosophila biological clock drivingcircadian rhythms ineclosion and locomotor activity.[1][2] Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.[1]
The period gene and three mutants (perS,perL, andper0) were isolated in anEMSmutagenesis screen byRonald Konopka andSeymour Benzer in 1971.[3] TheperS,perL, andper0 mutations were found to not complement each other, so it was concluded that the three phenotypes were due to mutations in the same gene.[3] The discovery of mutants that altered the period of circadian rhythms in eclosion and locomotor activity (perS andperL) indicated the role of the per gene in the clock itself and not an output pathway. The period gene was first sequenced in 1984 byMichael Rosbash and colleagues.[4] In 1998, it was discovered thatper produces two transcripts (differing only by the alternative splicing of a single untranslated intron) which both encode the PER protein.[5]
InDrosophila,per mRNA levels oscillate with a period of approximately 24 hours, peaking during the early subjective night.[1] Theper product PER also oscillates with a nearly 24-hour period, peaking about six hours afterper mRNA levels during the middle subjective night.[6][citation needed] When PER levels increase, the inhibition ofper transcription increases, lowering the protein levels. However, because PER protein cannot directly bind to DNA, it does not directly influence its own transcription; alternatively, it inhibits its own activators.[7] After PER is produced from per mRNA, it dimerizes withTimeless (TIM) and the complex goes into the nucleus and inhibits the transcription factors ofper andtim, theCLOCK/CYCLE heterodimer.[7] This CLOCK/CYCLE complex acts as a transcriptional activator forper andtim by binding to specific enhancers (calledE-boxes) of their promoters.[7][8] Therefore, inhibition of CLK/CYC lowersper andtim mRNA levels, which in turn lower the levels of PER and TIM.[7] Now, cryptochrome (CRY) is a light sensitive protein which inhibits TIM in the presence of light.[9] When TIM is not complexed with PER, another protein,doubletime, or DBT, phosphorylates PER, targeting it for degradation.[10]
In mammals, an analogoustranscription-translation negative feedback loop is observed.[11] Translated from the three mammalian homologs of drosophila-per, one of three PER proteins (PER1, PER2, and PER3) dimerizes via itsPAS domain with one of twocryptochrome proteins (CRY1 and CRY2) to form a negative element of the clock.[11] This PER/CRY complex moves into the nucleus upon phosphorylation by CK1-epsilon (casein kinase 1 epsilon) and inhibits the CLK/BMAL1 heterodimer, the transcription factor that is bound to the E-boxes of the three per and two cry promoters bybasic helix-loop-helix (BHLH) DNA-binding domains.[11]
The mammalian period 1 and period 2 genes play key roles in photoentrainment of the circadian clock to light pulses.[12][13] This was first seen in 1999 when Akiyama et al. showed that mPer1 is necessary for phase shifts induced by light or glutamate release.[12] Two years later, Albrecht et al. found genetic evidence to support this result when they discovered that mPer1 mutants are not able to advance the clock in response to a late-night light pulse (ZT22) and that mPer2 mutants are not able to delay the clock in response to an early night light pulse (ZT14).[13] Thus, mPer1 and mPer2 are necessary for the daily resetting of the circadian clock to normal environmental light cues.[13]
per has also been implicated in the regulation of several output processes of the biological clock, including mating activity[14] andoxidative stress response,[15] throughper mutation and knockout experiments.
Drosophila melanogaster has naturally occurring variation in Thr-Gly repeats, occurring along a latitude cline. Flies with 17 Thr-Gly repeats are found more commonly in Southern Europe and 20 Thr-Gly repeats are found more commonly in Northern Europe.[16]
In addition to its circadian functions,per has also been implicated in a variety of other non-circadian processes.
The mammalian period 2 gene plays a key role in tumor growth in mice; mice with an mPer2 knockout show a significant increase in tumor development and a significant decrease in apoptosis.[17] This is thought to be caused by mPer2 circadian deregulation of common tumor suppression and cell cycle regulation genes, such asCyclin D1,Cyclin A,Mdm-2, andGadd45α, as well as the transcription factorc-myc, which is directly controlled by circadian regulators through E box-mediated reactions.[17] In addition, mPer2 knockout mice show increased sensitivity togamma radiation and tumor development, further implicating mPer2 in cancer development through its regulation of DNA damage-responsive pathways.[17] Thus, circadian control of clock controlled genes that function in cell growth control and DNA damage response may affect the development of cancerin vivo.[17]
per has been shown to be necessary and sufficient forlong-term memory (LTM) formation inDrosophila melanogaster.per mutants show deficiencies in LTM formation that can be rescued with the insertion of apertransgene and enhanced withoverexpression of theper gene.[18] This response is absent in mutations of other clock genes (timeless,dClock, andcycle).[18] Research suggests thatsynaptic transmission throughper-expressing cells is necessary for LTM retrieval.[18]
per has also been shown to extend the lifespan of the fruit fly, suggesting a role in aging.[19] This result, however, is still controversial, as the experiments have not been successfully repeated by another research group.
In mice it has been shown that there is a link between per2 and preferred alcohol intake.[20] Alcohol consumption has also been linked to shortening the free running period.[21] The effect of alcoholism on per1 and per2 genes have also linked to the depression associated with alcohol as well as an individual's disposition to relapse into alcoholism.[21]
In mammals, there are three known PER family genes:PER1,PER2, andPER3. The mammalian molecular clock hashomologs to the proteins found inDrosophila. A homolog ofCLOCK plays the same role in the human clock, and CYC is replaced byBMAL1.[7]CRY has two human homologs,CRY1 andCRY2, which was discovered by Edmund A. Griffin, Jr., David Staknis andCharles J. Weitz to encompass light-independent interactions with CLOCK and BMAL1.[22] A computational model for model has been developed by Jean-Christophe Leloup andAlbert Goldbeter to simulate the feedback loop created by the interactions between these proteins and genes, including theper gene and PER protein.[23]
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The human homologs show sequence and amino acid similarity to Drosophila Per and also contain the PAS domain andnuclear localization sequences that the Drosophila Per have. The human proteins are expressed rhythmically in thesuprachiasmatic nucleus as well as areas outside the SCN. Additionally, while Drosophila PER moves between the cytoplasm and the nucleus, mammalian PER is more compartmentalized: mPer1 primarily localizes to the nucleus and mPer2 to the cytoplasm.[24]
Familial advanced sleep-phase syndrome known to be associated with mutations in the mammalian Per2 gene. People suffering from the disorder have a shorter period and advanced phase where they go to sleep in the early evening (around 7pm) and wake up before sunrise (around 4am). In 2006, a lab in Germany identified particular phosphorylated residues of PER2 that are mutated in people suffering of FASPS.[25] Chronotherapy is sometimes used as a treatment, as an attempt to alter the phase of the individual's clock using cycles of bright light.