The Impact of the Circadian Clock on Skin Physiology and Cancer Development

Abstract

Skin cancers are growing in incidence worldwide and are primarily caused by exposures to ultraviolet (UV) wavelengths of sunlight. UV radiation induces the formation of photoproducts and other lesions in DNA that if not removed by DNA repair may lead to mutagenesis and carcinogenesis. Though the factors that cause skin carcinogenesis are reasonably well understood, studies over the past 10-15 years have linked the timing of UV exposure to DNA repair and skin carcinogenesis and implicate a role for the body's circadian clock in UV response and disease risk. Here we review what is known about the skin circadian clock, how it affects various aspects of skin physiology, and the factors that affect circadian rhythms in the skin. Furthermore, the molecular understanding of the circadian clock has led to the development of small molecules that target clock proteins; thus, we discuss the potential use of such compounds for manipulating circadian clock-controlled processes in the skin to modulate responses to UV radiation and mitigate cancer risk.

Keywords: DNA repair; UV radiation; cell cycle; circadian clock; genotoxicity; skin biology; skin cancer.

Figure 1

Multiple factors influence skin cancer development. Though exposure to UV radiation is a major contributor to skin carcinogenesis, other factors, including age, genetics, skin pigmentation, immunosuppression, viruses, and other carcinogens are also known to influence the likelihood of developing skin cancer.

Figure 2

Central and peripheral circadian clocks. The body’s central or “master” clock is found in the suprachiasmatic nucleus (SCN) in the brain, which receives input from photosensitive, melanopsin-containing retinal ganglion cells via the retinohypothalamic tract. Through neuronal and hormonal signaling, the SCN then sends signals to peripheral organs to synchronize these peripheral clocks with the master clock in the brain.

Figure 3

Molecular architecture of the circadian clock transcription machinery. The CLOCK-BMAL1 complex binds to E-box elements in the promoter region of clock-control genes (CCGs). These CCGs include the period (PER) and cryptochrome (CRY) gene products that feed back to inhibit CLOCK-BMAL1 activity. A secondary loop encompassing the retinoic acid-related orphan receptor (ROR) and REV–ERB gene products bind competitively to retinoic acid-related orphan receptor response elements (ROREs) in the BMAL1 promoter to regulate BMAL1 expression.

Figure 4

Regulators and targets of the circadian clock in the skin. Multiple factors influence circadian rhythmicity in the skin. The clock subsequently regulates many aspects of skin physiology.

Figure 5

UV radiation causes the formation of lesions in DNA that are targeted for removal by DNA repair. UVA and UVB wavelengths of sunlight induce the formation of oxidative lesions in DNA, such as 8-oxoguanine (8-oxoG). These small-base lesions are targeted for removal by base excision repair (BER). UV radiation also induces the formation of photoproducts between adjacent pyrimidines in DNA (T<>T) that can only be removed by the nucleotide excision repair (NER) system. Research has shown that the expression or activity of both the BER protein OGG1 and (8-oxoguanine DNA glycosylase) and NER protein XPA (xeroderma pigmentosum group A) are controlled by the circadian clock in various organ systems.

Figure 6

DNA replication and nucleotide excision repair in the skin display circadian rhythmicity. Studies in mice showed that XPA expression, UV photoproduct removal by NER, and DNA synthesis display circadian rhythmicity. Thus, XPA protein levels and NER are low in the early morning hours (AM) when DNA replication is high. In the afternoon and evening (PM), XPA expression and NER are high and rates of DNA replication are low. Thus, unrepaired UV photoproducts are more problematic in the early morning hours and lead to increased mutagenesis, carcinogenesis, apoptosis, and erythema. The phases of these rhythmic processes are expected to display the opposite phase in humans. Indeed, DNA synthesis has been shown to display circadian rhythmicity in human skin epidermis, such that DNA replication peaks in the mid-afternoon.

Figure 7

Pharmacological modulation of the skin circadian clock. Several small-molecule compounds that target circadian clock proteins have been discovered in the past few years. The application of these compounds onto human skin could potentially be used to transiently alter the amplitude or phase of CCG expression to prevent or treat skin diseases.