PER2 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
in mammals encoded by the ''PER2''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. ''PER2'' is noted for its major role in circadian rhythms.
Discovery
The ''per ''gene'' ''was first discovered using forward genetics in ''
Drosophilla melanogaster'' in 1971.
Mammalian
Mammals () are a group of vertebrate animals constituting the class (biology), class Mammalia (), characterized by the presence of mammary glands which in Female#Mammalian female, females produce milk for feeding (nursing) their young, a ...
Per2 was discovered by in 1997 through a search for homologous
cDNA
In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...
sequences to
PER1
The PER1 gene encodes the period circadian protein homolog 1 protein in humans.
Function
The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. This gene is a memb ...
. It is more similar to Drosophila ''
per
Per is a Latin preposition which means "through" or "for each", as in per capita.
Per or PER may also refer to:
Places
* IOC country code for Peru
* Pér, a village in Hungary
* Chapman code for Perthshire, historic county in Scotland
Math ...
'' than its
paralogs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
. Later experiments in also identified ''Per2 ''in humans.
Function
''PER2'' is a member of the Period family of genes and is expressed in a
circadian
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
pattern in the
suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...
, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the
circadian
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...
clock, which regulates the daily rhythms of locomotor activity, metabolism, and behavior. Circadian expression of these genes and their encoded proteins in the
suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...
. Human PER2 is involved in human sleep disorder and cancer formation.
Lowered ''PER2'' expression is common in many tumors cells within the body, suggesting PER2 is integral for proper function and decreased levels promotes tumor progression.
''PER2'' contains
glucocorticoid response elements Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes.
Under conditions of stress, a transcription activator protein binds ...
(GREs) and a GRE within the core clock gene ''PER2'' is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo. Mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. PER2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.
PER2 expression in mice is increased by exposure to 13000 lumens of intense daylight such as
Sunshine
Sunlight is a portion of the electromagnetic radiation given off by the Sun, in particular infrared, visible, and ultraviolet light. On Earth, sunlight is scattered and filtered through Earth's atmosphere, and is obvious as daylight when th ...
while decreasing
Troponin
image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL
Troponin, ...
levels in equal opposite amounts. PER2 in turn enhances oxygen-efficient
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
and hence provides cardioprotection from
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
. Therefore, it is speculated that strong light may reduce the risk of heart attacks and decrease the damage after experiencing one.
[
*] Moreover, PER2 has protective functions in liver diseases, as it antagonizes hepatitis C viral replication.
''Per2'' knockout mice experience a free-running period of around 21.8 hours, compared to the normal mouse free-running period of 23.3 hours. Some of the ''Per2'' knockout mice can also become arrhythmic under constant light conditions. PER2 has also been shown to be possibly important in the development of cancer. PER2 expression is significantly lower in human patients with lymphoma and acute myeloid leukemia.
The PER2 protein seems to be important for the proliferation of
osteoblasts
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
, which aid in adding density to the bone through a pathway utilizing
Myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
and
Ccnd1
Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene.
Gene expression
The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
. Certain PER2 mutations have shown that they can increase the tolerance to the amount of alcohol that a mouse can intake through reduced uptake of glutamate.
Main interactions
In mammals, mPER2 forms a heterodimer with
mPER1,
mCRY1, and
mCRY2 by binding to
PAS domains. The heterodimer acts to inhibit their own transcription by suppressing the
CLOCK
A clock or a timepiece is a device used to measure and indicate time. The clock is one of the oldest human inventions, meeting the need to measure intervals of time shorter than the natural units such as the day, the lunar month and the ...
/
BMAL1
Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...
complex resulting in a negative feedback loop.
This negative feedback loop is essential for maintaining a functioning circadian clock. A disruption of either both mPER1 and mPER2 genes together or both mCRY genes causes behavioural arrhythmicity when the double-knockout animals are placed in constant conditions. A third PER gene,
''mPer3'', does not have a critical role in the maintenance of the core clock feedback loops. Molecular and behavioural rhythms are preserved in mice lacking m''Per3''.
Interactions with CK1e
PER2 has been shown to interact with a kinase called
CK1e. CK1e phosphorylates PER2 in mammals. In Syrian hamster, a mutation called tau has been discovered in the CK1e, which increases phosphorylation of homologous PER2 leading to a faster degradation and a shortened period. Mutations in hPER2 can cause FASPS because of a lack of phosphorylation site in the mutated hPER2 protein.
Interaction table
Clinical significance
A genetic test from a cheek swab can use PER2 expression levels to tell whether a person is an early morning person or a "night owl".
Familial Advanced Sleep Phase
Familial advanced sleep phase (FASP) is characterized as a short period (e.g. 23.3 vs 24.3hr for population) in humans. A mutation in hPER2 decreases its phosphorylation by CK1d, which causes the phenotype seen in some FASP. The primary cause of these FASP is a mutation that changes amino acid 662 from serine to glycine (S662G) in PER2. The S662G mutation makes PER2 mutant protein a stronger repressor than normal PER2, decreasing cellular PER2 levels and therefore causing this form of FASP. The mutation also seems to cause an increase in the turnover rate of PER2 in the nucleus.
Gene
The ''PER2'' gene is located on the long (q) arm of chromosome 2 at position 37.3 and has 25 exons.
Predicted human PER2 protein created from the ''PER2'' gene shares 44% identity with human ''PER1'' and 77% identity with mouse ''Per2''. Northern blots analysis revealed that ''PER2'' was expressed as a 7-kb mRNA in all tissues examined. An additional 1.8-kb transcript was also detected in some tissues.
''PER2'' mRNA has been shown to peak at ZT 6 in the SCN.
See also
*
PER1
The PER1 gene encodes the period circadian protein homolog 1 protein in humans.
Function
The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. This gene is a memb ...
*
PER3
The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associate with delayed sleep phase syndrome in humans.
History
The Per3 gene was independently ...
*
Familial sleep traits
Familial sleep traits are heritable variations in sleep patterns, resulting in abnormal sleep-wake times and/or abnormal sleep length.
Circadian rhythms are coordinated physiological and biological changes that oscillate on an approximately 24-h ...
References
Further reading
*
External links
*
*
*
{{Transcription factors, g1
Transcription factors
PAS-domain-containing proteins