Period (gene)
Encyclopedia
Period 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 (per01) the period of the circadian rhythm.
screen by Ronald Konopka
and Seymour Benzer
in 1971. The perS, perL, and per01 mutations were found to 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.
(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-box
es) 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, the three PER proteins (PER1, PER2, and PER3) dimerize via their PAS domain
s with 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-box
s 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.
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 Gadd45
α, 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.
per has been shown to be necessary and sufficient for long-term memory
(LTM) formation in Drosophila melanogaster
. per mutants show deficiencies in LTM formation that can be rescued with the insertion of a per transgene
and enhanced with overexpression of the per gene. This response is absent in mutations of other clock genes (timeless
, dClock, and cycle). Research suggests that synaptic transmission through per-expressing cells is necessary for LTM retrieval.
per has also been shown to extend the lifespan of the fruit fly, suggesting a role in aging. 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. Alcohol consumption has also been linked to shortening the free running period. 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.
, PER2
, and PER3
. The mammalian molecular clock has homologs
to the proteins found in Drosophila. A homolog of CLOCK
plays the same role in the human clock, and CYC is replaced by BMAL1. CRY
has two human homologs, CRY1 and CRY2. A computational model for model has been developed by Jean-Christophe Leloup and Adam Goldbeter to simulate the feedback loop created by the interactions between these proteins and genes, including the per gene and PER protein.
The human homologs show sequence and amino acid similarity to Drosophila Per and also contain the PAS domain and nuclear localization
sequences that the Drosophila Per have. The human proteins are expressed rhythmically in the suprachiasmatic 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.
known to be associated with mutations in the mammalian Per2 gene. People suffering of 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. Chronotherapy is sometimes used as a treatment, as an attempt to alter the phase of the individual's clock using cycles of bright light.
http://flybase.org/reports/FBgn0003068.html
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
. 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 (per01) the period of the circadian rhythm.
Discovery
The period gene and three mutants (perS, perL, and per01) were isolated in an EMS mutagenesisMutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...
screen by Ronald Konopka
Ron Konopka
Ronald J. Konopka is a former American geneticist who studied chronobiology. He made his most notable contribution to the field while working with Drosophila in the lab of Seymour Benzer at the California Institute of Technology...
and Seymour Benzer
Seymour Benzer
Seymour Benzer was an American physicist, molecular biologist and behavioral geneticist. His career began during the molecular biology revolution of the 1950s, and he eventually rose to prominence in the fields of molecular and behavioral genetics. He led a productive genetics research lab both at...
in 1971. The perS, perL, and per01 mutations were found to 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.
Circadian clock
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 TimelessTimeless (gene)
Timeless is a gene in Drosophila which encodes TIM, an essential protein that regulates circadian rhythms. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation [negative feedback] loop involving the period gene and its protein.-Discovery:Timeless was...
(TIM) and the complex goes into the nucleus and inhibits the transcription factors of per and tim, the CLOCK
CLOCK
Clock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...
/CYCLE heterodimer. This CLOCK/CYCLE complex acts as a transcriptional activator for per and tim by binding to specific enhancers (called E-box
E-box
An E-box is a DNA sequence which usually lies upstream of a gene in a promoter region. It is a transcription factor binding site where the specific sequence of DNA, CANNTG, is recognized by proteins that can bind to it to help initiate its transcription. Once transcription factors bind to...
es) 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
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
is observed. Translated from the three mammalian homologs of drosophila-per, the three PER proteins (PER1, PER2, and PER3) dimerize via their PAS domain
PAS domain
The PAS domain is a protein domain contained in many signaling proteins where it functions as a signal sensor. PAS domains are found in a large number of organisms from bacteria to humans...
s with two cryptochrome
Cryptochrome
Cryptochromes are a class of blue light-sensitive flavoproteins found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and in the sensing of magnetic fields in a number of species...
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
Casein kinase 1
The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types...
) and inhibits the CLK/BMAL1 heterodimer, the transcription factor that is bound to the E-box
E-box
An E-box is a DNA sequence which usually lies upstream of a gene in a promoter region. It is a transcription factor binding site where the specific sequence of DNA, CANNTG, is recognized by proteins that can bind to it to help initiate its transcription. Once transcription factors bind to...
s 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.
Non-circadian
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 D
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition...
, Cyclin A
Cyclin A
Cyclin A is a member of the cyclin family.Cyclin A binds to S phase Cdk2 and is required for the cell to progress through the S phase. Cyclin A/ Cdk2 is inhibited by the complex p21CIP.-External links:*...
, Mdm-2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
, and Gadd45
Gadd45
The Growth Arrest and DNA Damage or gadd45 genes, including , and , are implicated as stress sensors that modulate the response of mammalian cells to genotoxic/physiological stress, and modulate tumor formation...
α, 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.
per has been shown to be necessary and sufficient for long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...
(LTM) formation in Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
. per mutants show deficiencies in LTM formation that can be rescued with the insertion of a per transgene
Transgene
A transgene is a gene or genetic material that has been transferred naturally or by any of a number of genetic engineering techniques from one organism to another....
and enhanced with overexpression of the per gene. This response is absent in mutations of other clock genes (timeless
Timeless (gene)
Timeless is a gene in Drosophila which encodes TIM, an essential protein that regulates circadian rhythms. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation [negative feedback] loop involving the period gene and its protein.-Discovery:Timeless was...
, dClock, and cycle). Research suggests that synaptic transmission through per-expressing cells is necessary for LTM retrieval.
per has also been shown to extend the lifespan of the fruit fly, suggesting a role in aging. 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. Alcohol consumption has also been linked to shortening the free running period. 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.
Mammalian homologs of per
In mammals, there are three known PER family genes: PER1PER1
Period circadian protein homolog 1 is a protein that in humans is encoded by the PER1 gene....
, PER2
PER2
Period circadian protein homolog 2 is a protein that in humans is encoded by the PER2 gene.PER2 contains glucocorticoid response elements and a GRE within the core clock gene Per2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo...
, and PER3
PER3
Period circadian protein homolog 3 is a protein that in humans is encoded by the PER3 gene....
. The mammalian molecular clock has homologs
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
to the proteins found in Drosophila. A homolog of CLOCK
CLOCK
Clock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...
plays the same role in the human clock, and CYC is replaced by BMAL1. CRY
Cryptochrome
Cryptochromes are a class of blue light-sensitive flavoproteins found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and in the sensing of magnetic fields in a number of species...
has two human homologs, CRY1 and CRY2. A computational model for model has been developed by Jean-Christophe Leloup and Adam Goldbeter to simulate the feedback loop created by the interactions between these proteins and genes, including the per gene and PER protein.
The human homologs show sequence and amino acid similarity to Drosophila Per and also contain the PAS domain and nuclear localization
Nuclear localization signal
A nuclear localization signal or sequence is an amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different...
sequences that the Drosophila Per have. The human proteins are expressed rhythmically in the suprachiasmatic nucleus
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
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.
Associated Diseases
Familial advanced sleep-phase syndromeAdvanced sleep phase syndrome
Advanced sleep phase syndrome , also known as the advanced sleep-phase type of circadian rhythm sleep disorder, is a condition in which patients feel very sleepy and go to bed early in the evening and wake up very early in the morning Advanced sleep phase syndrome (ASPS), also known as the...
known to be associated with mutations in the mammalian Per2 gene. People suffering of 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. Chronotherapy is sometimes used as a treatment, as an attempt to alter the phase of the individual's clock using cycles of bright light.
External References
http://www.sdbonline.org/fly/neural/period.htmhttp://flybase.org/reports/FBgn0003068.html
See also
- Clock geneCLOCKClock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...
- Suprachiasmatic nucleusSuprachiasmatic nucleusThe suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
- Timeless (gene)Timeless (gene)Timeless is a gene in Drosophila which encodes TIM, an essential protein that regulates circadian rhythms. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation [negative feedback] loop involving the period gene and its protein.-Discovery:Timeless was...
- Oscillating geneOscillating geneIn molecular biology, an oscillating gene or clock gene is a gene that is expressed in an oscillating pattern, often circadian....
- PDFPigment dispersing factorPigment dispersing factor is a gene that encodes for the protein PDF, which is part of a large family of neuropeptides. The analogous hormone, pigment dispersing hormone was named for the diurnal pigment movement effect it has in crustacean retinal cells, and was initially discovered in the...