Per2: A Potential Drug Target and Biomarker for Circadian Clock Protein PERIOD 2

Target Name: PER2

NCBI ID: G8864

PER2

Per2: A Potential Drug Target and Biomarker for Circadian Clock Protein PERIOD 2

Abstract:
Per2, a non-coding RNA molecule belonging to the PERIOD 2 subfamily of the PERIOD gene family, is a key regulator of the circadian clock in various organisms. Disruptions in Per2 function have been implicated in various sleep disorders, including insomnia, obesity, and mood disorders. This article summarizes the current understanding of Per2 function, its potential as a drug target, and its potential as a biomarker for various sleep disorders.

Introduction:
The circadian clock plays a crucial role in regulating various physiological processes in the body, including sleep-wake cycles, hormone secretion, and metabolism. The PERIOD gene family, which encodes the clock proteins that make up the circadian clock, is the focus of much research in the field of circadian biology. One of the key proteins in this family is Per2, which is a non-coding RNA molecule that plays a critical role in regulating the circadian clock in various organisms.

Function and Implications of Per2:
Per2 is a key regulator of the circadian clock in various organisms, including humans. It is a key component of the clock that regulates the expression of clock genes, including PER2 itself, and is involved in the timing of various physiological processes that are synchronized with the circadian rhythm.

Per2 function is critical for the regulation of the circadian clock, as disruptions in Per2 can cause various physiological disorders, including insomnia, obesity, and mood disorders. For example, studies have shown that Per2 dysfunction is associated with increased risk of obesity and decreased sleep quality in humans. Additionally, Per2 mutations have been implicated in the development of certain inherited sleep disorders, such as the Stickelberger syndrome.

Potential as a Drug Target:
Per2's unique structure and function make it an attractive target for drug development. The research suggests that Per2 functions as a negative regulator of the circadian clock, and that inhibition of its activity could be a useful treatment for various sleep disorders.

Studies have shown that Per2 inhibition can improve sleep quality in individuals with insomnia and obesity, as well as regulate body weight. Additionally, the Stickelberger syndrome, a rare inherited sleep disorder that is caused by a mutation in Per2, has been shown to be associated with decreased Per2 function.

Potential as a Biomarker:
Per2 function has also been suggested as a potential biomarker for various sleep disorders. The stickelberger syndrome, which is caused by a mutation in Per2, is a good example of a disorder that can be diagnosed by a single gene. The severity of symptoms is directly proportional to the level of Per2 function, which suggests that Per2 function may be a useful biomarker for this disorder.

Conclusion:
In conclusion, Per2 is a non-coding RNA molecule that plays a critical role in regulating the circadian clock in various organisms. Disruptions in Per2 function have been implicated in various physiological disorders, including insomnia, obesity, and mood disorders. As a result, Per2 has emerged as a promising target for drug development and a potential biomarker for various sleep disorders. Further research is needed to fully understand the role of Per2 in the circadian clock and its potential as a drug and biomarker.

Protein Name: Period Circadian Regulator 2

Functions: Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndrome and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like BMAL1 or G6PC1. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of ca

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