Period (gene)

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm. Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm. The period gene and three mutants (perS, perL, and per0) were isolated in an EMS mutagenesis screen by Ronald Konopka and Seymour Benzer in 1971. The perS, perL, and per0 mutations were found to not complement each other, so it was concluded that the three phenotypes were due to mutations in the same gene. The discovery of mutants that altered the period of circadian rhythms in eclosion and locomotor activity (perS and perL) indicated the role of the per gene in the clock itself and not an output pathway. The period gene was first sequenced in 1984 by Michael Rosbash and colleagues. In 1998, it was discovered that per produces two transcripts (differing only by the alternative splicing of a single untranslated intron) which both encode the PER protein. In Drosophila, per mRNA levels oscillate with a period of approximately 24 hours, peaking during the early subjective night. The per product PER also oscillates with a nearly 24-hour period, peaking about six hours after per mRNA levels during the middle subjective night. When PER levels increase, the inhibition of per 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. After PER is produced from per mRNA, it dimerizes with Timeless (TIM) and the complex goes into the nucleus and inhibits the transcription factors of per and tim, the CLOCK/CYCLE heterodimer. This CLOCK/CYCLE complex acts as a transcriptional activator for per and tim by binding to specific enhancers (called E-boxes) of their promoters. Therefore, inhibition of CLK/CYC lowers per and tim mRNA levels, which in turn lower the levels of PER and TIM. Now, cryptochrome (CRY) is a light sensitive protein which inhibits TIM in the presence of light. When TIM is not complexed with PER, another protein, doubletime, or DBT, phosphorylates PER, targeting it for degradation. In mammals, an analogous transcription-translation negative feedback loop is observed. Translated from the three mammalian homologs of drosophila-per, one of three PER proteins (PER1, PER2, and PER3) dimerizes via its PAS domain with one of two cryptochrome proteins (CRY1 and CRY2) to form a negative element of the clock. 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 by basic helix-loop-helix (BHLH) DNA-binding domains. The mammalian period 1 and period 2 genes play key roles in photoentrainment of the circadian clock to light pulses. This was first seen in 1999 when Akiyama et al. showed that mPer1 is necessary for phase shifts induced by light or glutamate release. 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). Thus, mPer1 and mPer2 are necessary for the daily resetting of the circadian clock to normal environmental light cues. per has also been implicated in the regulation of several output processes of the biological clock, including mating activity and oxidative stress response, through per mutation and knockout experiments. Drosphila 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. 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. This is thought to be caused by mPer2 circadian deregulation of common tumor suppression and cell cycle regulation genes, such as Cyclin D1, Cyclin A, Mdm-2, and Gadd45α, as well as the transcription factor c-myc, which is directly controlled by circadian regulators through E box-mediated reactions. In addition, mPer2 knockout mice show increased sensitivity to gamma radiation and tumor development, further implicating mPer2 in cancer development through its regulation of DNA damage-responsive pathways. Thus, circadian control of clock controlled genes that function in cell growth control and DNA damage response may affect the development of cancer in vivo.