Period circadian protein homolog 1

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.^[5]

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 member of the

Functional conservation of the PER gene is shown in a study by Shigeyoshi et al. 2002. In this study, mouse mPer1 and mPer2 genes were driven by Drosophila timeless promoter in Drosophila melanogaster. They found that both mPer constructs could restore rhythm to arrhythmic flies (per01 flies). Thus mPer1 and mPer2 can function as clock components in flies and may have implications concerning the homology of per genes.[11]

Role in chronobiology

The PER1 gene, also called rigui, is a characteristic circadian oscillator. PER1 is rhythmically transcribed in the SCN, keeping a period of approximately 24 hours. This rhythm is sustained in constant darkness, and can also be entrained to changing light cycles.^[5] PER1 is involved in generating circadian rhythms in the SCN, and also has an effect on other oscillations throughout the body. For example, PER1 knockouts affect food entrainable oscillators and methamphetamine-sensitive circadian oscillators, whose periods are altered in the absence of PER1.^[12] In addition, mice with knockouts in both the PER1 and PER2 genes show no circadian rhythmicity.^[13] Phase shifts in PER1 neurons can be induced by a strong, brief light stimulus to the SCN of rats. This light exposure causes increases in PER1 mRNA, suggesting that the PER1 gene plays an important role in entrainment of the mammalian biological clock to the light-dark cycle.^[14]

Feedback mechanism

The PER1 mRNA is expressed in all cells, acting as a part of a transcription-translation negative feedback mechanism, which creates a cell autonomous molecular clock. PER1 transcription is regulated by protein interactions with its five E-box and one D-box elements in its promoter region. Heterodimer

PER interacts with other PER proteins as well as the E-box regulated, clock controlled proteins CRY1 and CRY2 to create a heterodimer which translocates into the nucleus. There it inhibits CLOCK-BMAL activation.[19] PER1 is not necessary for the creation circadian rhythms, but homozygous PER1 mutants display a shortened period of mRNA expression.^[13] While PER1 must be mutated in conjunction with PER2 to result in arhythmiticity, the two translated PER proteins have been shown to have slightly different roles, as PER1 acts preferentially through interaction with other clock proteins.^[20]

Clinical significance

PER1 expression may have significant effects on the cell cycle. Cancer is often a result of unregulated cell growth and division, which can be controlled by circadian mechanisms. Therefore, a cell's circadian clock may play a large role in its likelihood of developing into a cancer cell. PER1 is a gene that plays an important role in such a circadian mechanism. Its overexpression, in particular, causes DNA-damage induced apoptosis. In addition, down-regulation of PER1 can enhance tumor growth in mammals.

The following is a list of some orthologs of the PER1 gene in other species:^[24]

Paralogs

• PER2
• PER3

Location

The human PER1 gene is located on chromosome 17 at the following location:^[25]

• Start: 8,140,470
• Finish: 8,156,405
• Length: 15,936
• Exons: 24

PER1 has 19 transcripts (splice variants).

Discovery

The PER1