Impact of the Circadian Clock on UV-Induced DNA Damage Response and Photocarcinogenesis

Abstract

The skin is in constant exposure to various external environmental stressors, including solar ultraviolet (UV) radiation. Various wavelengths of UV light are absorbed by the DNA and other molecules in the skin to cause DNA damage and induce oxidative stress. The exposure to excessive ultraviolet (UV) radiation and/or accumulation of damage over time can lead to photocarcinogenesis and photoaging. The nucleotide excision repair (NER) system is the sole mechanism for removing UV photoproduct damage from DNA, and genetic disruption of this repair pathway leads to the photosensitive disorder xeroderma pigmentosum (XP). Interestingly, recent work has shown that NER is controlled by the circadian clock, the body’s natural time keeping mechanism, through regulation of the rate-limiting repair factor xeroderma pigmentosum group A (XPA). Studies have shown reduced UV-induced skin cancer after UV exposure in the evening compared to the morning, which corresponds with times of high and low repair capacities, respectively. However, most studies of the circadian clock-NER connection have utilized murine models, and it is therefore important to translate these findings to humans to improve skin cancer prevention and chronotherapy.

Graphical Abstract

Exposure of the skin to sunlight causes DNA damage. As a result, the body responds to this environmental insult through various defensive mechanisms including the nucleotide excision repair, which is regulated by the circadian clock. Hence, the time-of-the-day is important in determining the mutagenic and carcinogenic potential of UVR insult to the skin.

INTRODUCTION

Cancer is a disease that results from complex events within cells that enable normal cells to become tumorigenic and eventually malignant (1). Skin cancer is one of the most common types of cancers in the United States. There are several different types of skin cancers, with the most common being non-melanoma and melanoma skin cancers. The American Cancer Society reports that there are over 3.3 million new cases of non-melanoma skin cancers each year, and there will be an estimated 76,000 new cases of melanoma skin cancer in the United States in 2016. Non-melanoma skin cancers, which account for 98% of skin cancers, primarily affect the squamous and basal cells of the skin, and are typically non-lethal when treated properly. On the other hand, melanoma accounts for only 2% of all skin cancers but is associated with more than 80% of skin cancer-related deaths due to its predilection to early metastasis and is often associated with a poor prognosis due to resistance to therapy (2, 3).

Skin cancer results from the accumulation of mutations in genomic DNA that are generated primarily by UV radiation. If this damage is not efficiently repaired by the nucleotide excision repair (NER) system, or if the damaged cell is not properly redirected to apoptosis, the damaged bases can be replicated by error-prone mechanisms to give rise to mutations that drive the formation of cancer (4). For instance, there is a 1000-fold increase in melanoma risk in patients with the disease xeroderma pigmentosum (XP), which is characterized by defects in NER (5). In addition to carcinogenesis, photoaging is another result of the accumulation of oxidative stress and inflammation. Due to solar exposure, photoaging is characterized by deep wrinkling, loss of elasticity, rough-textured appearance, telangiectasia, and pigmentation disorders, and further affects cellular functionality processes such as cell proliferation and DNA damage repair (6, 7). Consequently, the body has various mechanisms in place to monitor the cell cycle process and ensure high genome integrity. This monitoring system is regulated by several factors which, when understood, can be optimized to improve its efficacy and reduce the risk of cancer formation and progression. This review will address the advancements made in understanding the role of a major endogenous factor, the circadian clock, in regulating the repair of DNA damage and skin carcinogenesis in response to UV radiation.

CIRCADIAN CLOCK AND THE SKIN

The skin is the largest organ of the body and is in constant exposure to the external environment. Different times of the day present unique environmental stimuli to which the skin is exposed. As such, the skin primarily functions in a protective role for the body against exposures to pathogens, toxins, physical injuries, and UV radiation (6). Besides external exposure, the skin is equally in constant exposure to biological signals from within the body (8). The anatomy of the skin is divided into the epidermal, dermal, and adipose layers, each possessing specialized cells and structures which enable the skin to carry out its functions of protection, as well as homeostasis and osmoregulation. The epidermal layer is composed of keratinocytes, which is the most abundant cell type, and by melanocytes, Langerhans cells, and Merkel cells (9). The melanocytes, via regulation by the microphthalmia-associated transcription factor (MITF), secrete the pigment melanin that gives color to the skin and hair, and offers protection against environmental stress agents such as UV radiation (10–13). The dermal layer consists of fibroblasts, hair follicles, sebaceous glands, macrophages, and collagen for tensile strength, while the adipose layer is comprised of mainly fat tissue and adipocytes (14). While the skin is a protective organ, it is equally important that its own integrity is protected. The skin ensures its integrity through various mechanisms, especially via regulation of the cell cycle, given the high proliferation rates of skin cells. The activities of the DNA repair, checkpoint, and apoptotic systems highlight the role of caretakers, which ensure the integrity of genomic information in the skin (15, 16).

The term circadian is derived from the Latin words circa and dies, which translates to “about a day”. The circadian phenomenon refers to the daily rhythmicity in the biochemistry, physiology, and behavior of living organisms, and is controlled by a molecular time-keeping system called the circadian clock (17). At the anatomical level in mammals, the suprachiasmatic nucleus (SCN), which is the master clock, is located in the anterior hypothalamus of the brain. The master clock receives external light cues from the environment via the optic nerve and synchronizes the independent peripheral clocks in other organs of the body such as the liver, kidney, lungs, heart, and skin via systemic signaling (18). At the molecular level, the mechanism driving this process is a cell-autonomous and self-sustained transcriptional-translational feedback loop (TTFL) (17). The four genes that constitute the core clock are circadian locomotor output cycles kaput (Clock), brain and muscle ARNT-like 1 (Bmal1), cryptochromes (Cry1, Cry2), and periods (Per1, Per2, Per3) genes. The CLOCK-BMAL1 proteins heterodimerize and transcriptionally activate certain E-box sequences in the promoter region of target genes, including Cry and Per. The resulting CRY and PER proteins translocate from the nucleus and accumulate in the cytoplasm. After a time delay, the PER and CRY proteins translocate back into the nucleus to bind and transcriptionally inhibit CLOCK-BMAL1 activity. Hence, a negative feedback loop is formed (19–22). The negative feedback loop interlocks with another positive feedback loop to regulate the circadian clock by the activation or repression of Bmal1 transcription via Ror/Rev-Erb elements (23). In addition to the clock genes, there are numerous other clock-controlled genes (CCGs) that are subject to this mechanism (20). Using mouse models, it was recently reported that 43% of protein-coding genes showed circadian rhythmicity at transcriptional levels somewhere in the body mostly in a tissue-specific manner (24). Even more interestingly, recent evidence suggests almost all aspects of circadian systems are post-transcriptionally regulated to enable enhanced robustness and adaptiveness of clocks (25, 20). Consequently, circadian rhythmicity plays a significant role in influencing various biochemical and physiological processes such as body temperature, hormonal levels, metabolism, cell cycle and proliferation, sleep-wake cycles, and other behavioral patterns, in a dynamic manner. All these events take place with a periodicity of approximately 24 hours (18).

The skin has been long implicated in circadian clock studies. Given the environmental elements that the skin is exposed to on a daily basis, including temperature changes, humidity, and UVR, it is important that the skin is able to adjust and properly function in these various conditions and to ensure adequate regulation of cellular differentiation and proliferation (8). While the SCN (the master clock) influences systemic biochemical operations, including those within the skin, the skin itself also possesses an intrinsic and robust peripheral clock (26). The complex anatomy of the skin with its several layers and thousands of mini-organ structures suggests that the peripheral skin clock could be a complex network. Thus, considering the skin as a single entity may be misleading (14). However, studies have been conducted to functionally define the role of the skin’s peripheral clock, and in particular keratinocytes, fibroblasts, and hair follicles have all been shown in mice to contain robust autonomous clocks (26, 27, 8). Several physiological traits of the skin, such as temperature, capillary blood flow, sebum production, keratinocyte proliferation rates, moisture level, and surface pH have been shown to follow a periodic pattern in mouse skin (8). In humans, studies using oral mucosa, hair follicles, and epidermal suction blister samples have shown circadian expression of genes that are involved in the core clock regulation, proliferation, and pigmentation (28–31). Hair follicle samples have proven to be dependable clock-related experimental models by showing rhythmical clock gene expression (32). Hair follicles are part of the skin’s network and regenerate hair over an entire life span. This regeneration process is driven by repetitive consecutive cycles of growth (anagen), involution (catagen), and quiescence (telogen), which are supported mainly by the bulge stem cell population (33, 14) and are optimized by the cell autonomous circadian clock (32). The skin is believed to possess stem cells that regenerate tissue in a similar manner as hair follicles, even though the roles of the stem cells, especially related to the circadian clock, are not fully defined due to the complex nature of the skin (34, 35). However, though the circadian clock has been shown to influence changes in skin cell proliferation and pigmentation, the mechanisms remain to be fully elucidated. Nevertheless, the current evidence strongly suggests that both the skin and hair follicles have active and robust autonomous peripheral clocks that regulate the optimal functioning of these tissues.

UV IMPACT ON SKIN: DNA DAMAGE

Ultraviolet (UV) radiation from the sun is categorized into three main groups based on their wavelengths along the electromagnetic spectrum. The UVA band spans from 320–400 nm, the UVB band ranges from 280–320 nm, and the UVC band is from 200–280 nm. As the wavelengths of these radiation categories decrease, photon energies increase proportionally, making the UVC band the most threatening of the three categories to the stability of organic molecules that are crucial to the existence of living organisms on earth. The stratospheric ozone layer of the atmosphere protects us from dangerous high energy radiation by absorbing it, especially UVC. Although most of the UVB radiation is absorbed by the ozone layer, a small fraction of UVB (1–10%), in its longer wavelength region, and 90–99% of UVA radiation reaches the earth’s surface and is absorbed by the skin (36–38). Both UVB and, to a lesser extent, UVA are responsible for sunlight-induced skin carcinogenesis (36). Photocarcinogenesis is a complex disease process as a result of DNA damage, initiated by both UVB and UVA, which have been demonstrated to be complete carcinogens. It is a process that involves many simultaneous biochemical and signaling events such as initiation, promotion, and progression of sunlight exposed epidermal cells which results in melanoma and non-melanoma skin cancers (38, 36).

UVB radiation causes direct DNA damage to the skin and has consequently been identified to be 1,000–10,000 times more carcinogenic than UVA (39). High energy UV radiation (both UVC and UVB) is absorbed by DNA, which causes the formation of two main photoproducts: cyclobutane-type pyrimidine dimers (CPDs) and (6–4) pyrimidine photoproducts ((6–4) PPs) (4, 37, 38). The formation of both of these photoproducts is characterized by similar covalent interactions on the same polynucleotide chain. The CPD is a 4-membered cyclobutyl ring formed between carbon 5 and 6 (C5 and C6) of adjacent pyrimidines and comprises of 70–80% of the total photoproducts formed. On the other hand, (6–4) photoproduct is formed between carbon 4 and 6 (C4 and C6) and constitutes a 20–30% abundance of total photoproducts (40, 4, 41). UVB radiation causes C→T and CC→TT transitions at the dipyrimidine sites, which are unique to UVB radiation, and have notably become reliable signature markers for the identification of UV-induced carcinogenesis (42). Such mutations have been shown to occur in the ras oncogene and within the the p53 and PTCH tumor suppressor genes to drive the process of cellular transformation by simultaneously triggering limitless proliferation and evading growth suppression (43). UVA, on the other hand, is able to penetrate the deep layers of the skin and cause a less severe damaging effect. The UVA interacts with endogenous photosensitizers in the mitochondria, such as porphyrins and NADH, to yield highly reactive oxygen species (ROS) such as singlet oxygens, superoxide anions, hydrogen peroxides, and hydroxyl radicals (37, 6). The products of these radiations cause DNA lesions and are mutagenic (38).

DNA damage response and photocarcinogenesis

Given that epidermal skin cells proliferate at a high rate, the skin utilizes the DNA damage response and repair mechanisms extensively to ensure the propriety of cellular proliferation (Figure 1). When there is UV-induced DNA damage, several signaling cascades and proteins involved in cell cycle, apoptosis, DNA repair and other related functions are triggered (4). The UV damage is sensed by the phosphoinositide-3-kinase (PI3K) family member ataxia telangiectasia and Rad3-related protein kinase (ATR), which has overlapping functions and crosstalk with ataxia telangiectasia-mutated (ATM) which is another kinase of PI3K family. The Rad9 and claspin proteins are recruited to mediate the signal to phosphorylate checkpoint kinase 1 (Chk1). The activated Chk1 further transduces the signals and phosphorylates the Cdc25C phosphatase, which degrades Cdc25C and inactivates the cell cycle-driving cyclin B/Cdk2 complex. This chain of events results in cell cycle arrest at the G2/M checkpoint. While the cell is in arrest mode, p53 is activated to coordinate a sustained arrest, DNA damage repair, and apoptosis (44). Nucleotide excision repair (NER) functions in the repair of various bulky DNA lesions and is the sole pathway for the repair of CPDs and (6–4) PPs in mice and humans (16). There are essentially four steps involved in the process of NER, including the recognition of damage by sensors, the excision of 24–32 nucleotides encapsulating the region of damage, synthesis and filling of the gap by DNA polymerases δ or ε, and sealing of repair by DNA ligase. The excision step involves six core factors, including XPA, XPC, XPG, XPF-ERCC1, RPA and TFIIH (45, 46). Studies in various human cell types have shown different rates of repair by the NER system in the removal of CPDs versus (6–4)PPs (47). CPDs have a slower repair rate in human skin, with a half-life of 33.3 hours, compared to (6–4)PPs which have a half-life of only 2.3 hours (48). Similar results were also obtained in monkey skin (49).

Figure 1.

Representation of the mechanisms of UV-induced cellular response in skin: 1) UV-radiation is absorbed by the genomic DNA and causes direct DNA damage through the formation of CPDs and (6–4) PPs. The formation of these photoproducts further triggers the ATR signaling pathway to activate Chk1 and p53. Activated p53 further initiates cell cycle arrest, DNA repair and/or apoptosis. In the case where repair and tumor suppressor functions are compromised, mutations occur that eventually lead to skin cancer. 2) Molecules in the mitochondria such as porphyrins absorb UV radiation to generate reactive oxygen species (ROS). These ROS can either cause DNA damage, or activate the MAPK pathway through ERK1/2, JNK or p38 MAPK, which in turn activates transcription factors AP-1 and NF-κB. These pathways regulate inflammation, cellular proliferation, and apoptosis, and the presence of ROS destabilizes these processes and induce cellular stress.

In addition to UVB, UVA contributes significantly, but less severely, to skin damage via generation of ROS to induce oxidative stress (36). The generation of ROS can either drive the production of specific products, such as 4-hydroxy-2-nonenal, which can denature proteins and alter immune pathways, or activate the mitogen-activated protein kinase (MAPK) pathway through either the extracellular signal-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), or the p38 MAPK signaling cascades. ERK and JNK signaling drive the transcription of AP-1 which further regulates cellular proliferation and apoptosis. The p38 MAPK is involved in the activation of NF-κB which regulates inflammation (iNOS, COX2) and cell cycle progression, as well as cellular proliferation and apoptosis (Cyclin D1, p21, p53, Bcl-2, Bcl-x, IAP, etc). However, the mechanisms explaining how ROS can activate these kinases are yet to be fully elucidated (50, 51). Furthermore, ROS can cause other types of DNA damage including the generation of 8-oxo-7,8-dihydroxyguanine (8-oxoG) and 5,6-dihydroxy-5,6-dihydrothymine (thymine glycol), which can cause site-specific mutagenesis (52), and are repaired by the base excision repair (BER) system (53, 54). These species form a miscoding lesion on any of the nucleic acid bases, even though the most prominent ones are G→T and G→A transversions (37). In addition to BER, the body copes with the deleterious effects of ROS by producing anti-oxidant molecules such as gluthathione peroxidases (GPxs), superoxide dismutases (SODs), Vitamin C and E, among others, to minimize or eliminate their effects (51, 6).

Both in vitro and in vivo studies have demonstrated that UV-induced DNA damage responses and repair are facilitated by p53 (42, 44). Therefore, p53 mutation provides an enabling environment for cancer progression. All forms of UV radiation induce high levels of p53 in normal human skin, unlike the low expression levels seen in normally dividing cells. The up-regulation of p53 induces responses from a myriad of pathways involved in cell cycle arrest, DNA repair, and apoptosis. The mutation of p53 impedes cell cycle arrest and apoptosis, thereby favoring continuous cell division of mutant cells (38). In addition to p53, mutations in the genes involved in the NER pathway also contribute to continuous cell division because repair cannot be carried out. One of such proteins is the Xeroderma pigmentosum (XP) family of proteins, which are mutated in the rare genetic disorder XP. The XP proteins are evolutionarily conserved among eukaryotes and have been studied in a wide variety of species. NER-deficient models have shown reduced DNA repair and cell survival and increased mutability (43). Mice with mutations in Xpa, Xpc and p53 genes have a significant predisposition to skin cancer, with more severe effects in p53 knockout mice (55, 56). In the skin of XP patients, there was a higher frequency in C→T and CC→TT tandem mutations of oncogenes and tumor suppressor genes, including ras and p53, compared to the skin of normal patients, indicating that the accumulation of unstable photoproducts can lead to more mutations (57–59). An alteration in the damage response and repair capacity of skin cells lead to favorable tumor environments.

The circadian clock controls DNA damage response and photocarcinogenesis

The remarkable work by Sancar and colleagues has shown that the circadian clock regulates various cellular responses to DNA damage including NER, checkpoint activity, and apoptosis (16, 60–62, 17, 63). The first report established that there is a circadian oscillation of the NER activity in mouse brain and liver (61, 64). This repair activity was in-phase with one of the repair factors, Xeroderma pigmentosum complementation group A (XPA), a rate-limiting factor in the NER (64, 65). Gaddameedhi et al. took these findings a step further and applied them to the study of skin carcinogenesis. Mice kept under light/dark (LD) 12:12 conditions showed a daily rhythmicity of XPA protein levels in skin tissues, which peaked at early evening hours (~5:00 PM) and troughed at early morning hours (~5:00 AM). Alternatively, Cry1 protein levels exhibited an opposite phase to the XPA levels. This relationship was expected because Cry1 is a primary repressor of the transcription-translational feedback loop and as such, low levels of Cry1 would enable more expression of other clock-controlled genes such as XPA. These observations were consistent across different mouse strains tested using various techniques. With a solid foundation laid, mice were exposed to UVB radiation for DNA damage to occur through the formation of CPDs and (6–4) PPs, and for the NER to repair the damage. The repair activity was significantly higher in the group irradiated in the evening in comparison to the group irradiated in the morning. Additionally, mice with a disruption in the circadian clock (Cry1^−/−Cry2^−/−) showed a loss in the rhythmicity in repair. Furthermore, acute responses to unrepaired DNA damage, such as sunburn apoptosis, inflammatory cytokine induction, and erythema, were observed to be high in mice exposed to UV in the early morning, compared to afternoon exposure (60). Collectively, these findings indicate that the circadian clock impacts the skin protection against UVB and has important implications for skin carcinogenesis. In contrast to DNA repair, cell proliferation, as a contributing factor to carcinogenesis, was tested and it was observed that high repair activity corresponded with low cellular replication, and vice versa. These observations led to the proposed clock-regulated photocarcinogenesis model shown in Figure 2. The hypothesis proposed that UVB-induced DNA damage can trigger mutagenesis and eventually lead to the formation of skin cancer, with higher susceptibility at the time when DNA damage repair is less efficient. Further tumorigenic experiments revealed that the mice receiving chronic UVB radiation treatment in the morning group had an early onset of cancer and a five-fold higher number of invasive squamous cell carcinomas compared to the evening-treated group. Therefore, UVB radiation, consequent upon replication and DNA damage repair factors, is more carcinogenic at different times of the day in mice (16, 41, 60). These findings could have significant clinical impact in humans as it relates to the circadian rhythm, especially regarding skin cancer development and photoaging (Figure 2).

Figure 2.

The hypothetical model proposes that time-of-the-day is important in the onset and progression of skin cancer in mice and humans. In case of mice, UVB-induced DNA damage in the morning (AM), when DNA repair is low and replication is high, will have more mutagenic and carcinogenic potential than UVB-induced DNA damage in the evening (PM), when replication is low and DNA damage is high. Given that mice are nocturnal and humans are diurnal, this model proposes that these outcomes will be opposite-phased between both species. This image was adapted and modified from Gaddameedhi et al. (16).

In addition to NER, oxidative stress has been shown to be clock-regulated (66). A number of factors involved cell cycle/checkpoint response, in addition to XPA, are encoded by clock-controlled genes (CCGs). In an indirect manner, the p21 and wee1 proteins, and c-Myc transcription factor have been shown to be involved in cell cycle and cellular proliferation respectively, and consequently, these functions are gated by the clock (64, 67, 68). Alternatively, a more direct mechanism involves Timeless (Tim), an accessory clock protein, coupling with Cry protein to regulate the ATR-Chk1 signaling pathway in damage response (69). In addition to cell cycle, NER and checkpoint signaling, the circadian clock also regulates extrinsic and intrinsic apoptotic pathways through TNFα by regulating the NF-κB signaling and p73 expression, respectively (62, 70). UVR-induced ROS were also shown to be dependent on the time of the day (66), and as such research has looked at the role of the clock on anti-oxidants in order to lessen the effects of oxidative stress. Melatonin is one of the major candidates for this anti-oxidant role. Melatonin is a strong clock-regulated hormone and has been shown to scavenge ROS and exhibit tumoristatic properties (71, 6). The working hypothesis proposes that a disruption in the synthesis of melatonin can lead to deleterious carcinogenic effects (71). Other elements being researched upon in the clock-control response to oxidative stress include retinoids, and 8-oxoguanine DNA Glycosylase, among others (72, 73).

UV IMPACT ON SKIN: PHOTOAGING

Photoaging is defined as a premature aging process of the skin that accumulates oxidative damage over a period of time as a result of chronic exposure to UV radiation from the sun (74). Photoaging is the environmental contributor to the aging process; the other being the genetic contributor, and concerns telomere length shortening (75). The progression of UV-induced aging involves numerous simultaneous processes as is the case with chronological aging (74). The functions of different cell types of the skin have been shown to decrease with chronological aging (74, 75). In photoaging, oxidative stress triggers mechanisms that lead to decline in cell growth and proliferation, alterations of dermal extracellular matrix proteins, increased DNA damage, decreased DNA repair capacity, and increased senescence (14, 76). Research into photoaging has made significant findings with collagen, which is one of the main structural proteins in various connective tissues. The loss of skin collagen has been widely regarded as a major factor driving aging. This loss occurs primarily through two methods: the inhibition of the synthesis of collagen and the degradation of existing skin collagen (74). UV radiation induces increased levels of matrix metalloproteinases (MMP)-1,-3, and -9, which cleave types I and III collagen in the skin for subsequent degradation (74). In addition to the induction of MMPs, UV exposure stimulates the expression levels of transcription factors AP1 and NF-κB (77). The transcription factor AP-1 has also been shown to inhibit type I and type III collagen synthesis by blocking the effects of transforming growth factor β (TGF-β), a profibrotic cytokine, and interfering with TGF-β dependent type-1 procollagen gene expression (74). Further findings helped to clarify that the MAPK pathways were involved, through the epidermal growth factor (EGF) receptors, p21 Ras, ERK, JNK and p38 MAPK signaling pathways (77). ROS were subsequently shown to augment the production of MMP-1 and other inflammatory mediators (78), thus making them second messengers in the process. In vivo studies have also successfully shown that collagen, which already has a low turnover rate in normal skin, is even more decreased in severe UV-radiated skin with the loss of type 1 procollagen expression (76). Collectively, the phenotypic expressions of the cellular and biochemical alterations include loss of recoil capacity, decreased tensile strength, wrinkle formation, and impaired wound healing of the skin, which are all indicative of photoaging (76). A recent mechanistic study proposes stem cell exhaustion and dysfunction as underlying mechanisms driving the aging process, and this could have a connection with the circadian clock (14). In addition, better understanding of the clock’s role in the generation and response to reactive oxygen species will provide valuable insights to the area of study.

THERAPEUTIC IMPLICATIONS

Radiation and chemotherapies, and recently immunotherapy, have been widely used in clinical practice for the treatment of tumors, including skin tumors. Such approaches, however, have limitations by causing considerable negative side-effects on patients’ health. Consequently, the emerging field of chronotherapy proposes the administration of treatment by time-of-the-day with the goal of maximizing efficacy and minimizing toxicity (79). Given the recent understanding of the clock-regulated functions of the skin, current or novel cancer treatments can be modulated for better outcomes by harnessing this knowledge. The mode of action for the currently available therapies is clearly defined. Radiation therapy and most chemotherapeutic agents, such as 5-flurouracil and cisplatin, damage DNA and stop replication in tumor cells, as well as normal cells such as proliferating epidermal keratinocytes and hair follicles, hence the side-effects to healthy skin. More recently, efforts are being directed towards targeting of the specific elements in the DNA repair pathways, such as PARP inhibitors in BRCA-mutant tumors in a concept known as synthetic lethality (80, 81). Interestingly, the circadian clock elements can be a target as it was demonstrated that the loss of Cry1 and Cry2 core clock genes sensitizes p53-deficienttumor cells through p73 mediated intrinsic apoptosis against genotoxic stress (70). Also, further understanding of the role of the circadian clock in UVA and UVB radiation effects on humans could offer a more preventive approach considering the varying levels and kinds of radiation exposures that different occupations are associated with. The works discussed in this paper could pave a path for strategically optimizing these therapies, individually or in combination, in the future.

CONCLUSION

All mammals and a good number of classes of living organisms exposed to UV radiation from the sun have a circadian clock. The connection between these two phenomena has recently garnered attention because of its potential to be a skin disease prevention and management tool. Today’s modern world is introducing the concept of circadian disruption as a new twist to these phenomena. Understanding the implications of circadian disruption on human health is important especially with a focus on diseases. From the onset of cancer, to its progression, and finally therapy, the circadian rhythm is proving to be a potentially significant piece of the puzzle. The future of circadian studies is promising and its implications in a vast array of human situations provide an additionally flexible tool to better manage diseases.