Sankar Mitra1 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1079
C
ircadian clocks are time tracking systems for all organisms, including mammals, to adjust to the day/night cycle in regard to physiological behaviors. Usually, a 24-h periodicity is observed in the rhythms of mammals related to feeding, sleep and other behaviors. However, the cycle can also be reset by light or other external signals. Circadian regulation involves a central clock in the hypothalamus and peripheral clocks located in most mammalian tissues (1). Circadian regulation has been observed in a vast array of genes involved in cell cycle and growth, metabolism, survival, and DNA damage responses. In mammals, circadian oscillation of specific genes has been observed in most but not all organs. Sancar and coworkers showed that UV damage repair in mammals via the nucleotide excision repair (NER) pathway is regulated by circadian rhythm (2). The UV part of the solar spectrum is relatively small but has profound impact on human health, primarily because of the damage UV photons cause to the genome (3). UV causes multiple damages in DNA bases, the predominant among which are pyrimidine photoproducts (PPs) including cyclobutane pyrimidine dimers (CPDs) and (64) PPs (4). These lesions in the genome block replication (and transcription) and are highly toxic. Several specialized DNA translesion synthesis polymerases replicate these photoproducts (5) without using normal base pairing and often induce mutations at the photoproduct sites. Such mutations in tumor suppressor genes such as p53 and PTEN could lead to melanoma and nonmelanoma skin cancers (6, 7). The UV photoproducts are repaired in the mammals in an error-free fashion via the NER pathway, in which xeroderma pigmentosum group A (XPA) plays a key role (8). Subsequent steps in repair involve assembly of the repair complex, which excises an approximately 30 nt-containing single-strand segment spanning the damage site to leave a single-stranded gap which is then filled in by DNA polymerase by using the undamaged, intact strand as the template. Thus, NER is essential for preventing UV-induced skin cancer by repairing the mutagenic photoproducts. In PNAS (9), Gaddameedhi et al. show that XPA exhibits circadian rhythmicity in mouse skin. Because XPA is limiting in NER (10), repair of CPDs and (6-4) PPs in UV-irradiated mouse skin was also found to follow the same circadian periwww.pnas.org/cgi/doi/10.1073/pnas.1116516108
Fig 1. Effect of the circadian clock on skin carcinogenesis. Repair and replication of DNA in mouse skin are controlled by the circadian clock: repair is at its maximum in the afternoon/evening hours and at its minimum in the early morning. In contrast, DNA replication in epidermal keratinocytes is high in the mornings and low in the afternoon. As a consequence, UV-induced DNA damage is more likely to cause mutation and skin cancer in mice in the morning hours than the same UV damage inflicted in the afternoon/ evening hours. The human circadian clock is very similar to that of the mouse, but has the opposite phase. Therefore, it is predicted that UV radiation would be less carcinogenic to humans in the mornings than in the afternoon/evening hours. (Image courtesy of Aziz Sancar.)
odicity when the mice were kept in a 12 h/12 h light/dark cycle. Thus, mouse skin has the lowest level of XPA at 4:00 AM and the highest at 4:00 PM, and repair of CPDs and (6-4) PPs corresponded with the XPA level. Interestingly, DNA replication in mouse also showed circadian periodicity but with antiphase to XPA, showing higher rate of synthesis in the AM group than in PM group. This may imply “double jeopardy” for risk of skin mutation/carcinogenesis when replication of unrepaired UV photoproducts increases the likelihood of mutation fixation. The authors (9) finally document the consequence of circadian variation in UV photoproducts’ repair by examining time dependence of UV irradiation on skin carcinogenesis. Both invasive and noninvasive tumor yield and size were higher in the morning irradiation group compared with the afternoon group. Circadian regulation is quite complex, involving multiple negative feedback loops, and controls activity at transcription
and protein stability levels. Peripheral clocks in tissues such as epidermis maintain periodicity of tissue-specific gene expression by modulating transcription factors’ activity. The central players activating clock-controlled gene transcription are CLOCK and BML1, which activate genes by binding to the E-boxes in their promoters (1). Among these genes are the cryptochromes CRY1 and 2 (and PER 1–3), which are key negative regulators. After nuclear translocation, these inhibit CLOCK/BMAL1-mediated transcription of genes, including their own (11). CRY 1and 2 proteins have short half-lives, which is necessary for reactivating the next cycle of transcription, and are degraded via polyubiquitylation (12, 13). XPA also has a short life as expected, and is degraded via polyubiquitylation mediated by HERC2 ubiquitin ligase (14). An interesting question is about how prokaryotes and other eukaryotes repair UV photoproducts, which should be linked to their solar exposure. The cellular processes for the repair of UV photoproducts have evolved in all organisms. During early evolution, the prokaryotes expressed DNA photolyases for repairing CPDs and (6-4) PPs, which are absent in mammals (15). On the contrary, cryptochromes were discovered initially in Arabidopsis plant and later identified in organisms (16). The cryptochromes and photolyases, both photosensory receptors for blue and long-wavelength UV light, are evolutionarily connected in a large superfamily (15). Cryptochromes lack photolyase activity but share significant sequence homology and structural similarity with DNA photolyases (15, 16). Gehring and Rosbash (17) postulated that cryptochromes, originally evolved for photorepair of UV damage, lost the photolyase activity but acquired the function of signaling to the internal clock. Thus, NER, the sole mechanism for UV damage repair in mammals, still involves photolyase family, although indirectly (14). Finally, there is the public health issue about exposure to sun, which causes more than 1 million new cases of skin cancer each year in the United States. Author contributions: S.M. wrote the paper. The author declares no conflict of interest. See companion article on page 18790 of issue 46 in volume 108. 1
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PNAS | November 22, 2011 | vol. 108 | no. 47 | 18857–18858
COMMENTARY
Does evening sun increase the risk of skin cancer?
The study of Gaddameedhi et al. (9) may suggest that people should reduce their sun exposure in the morning, when UV damage repair is minimal in mouse skin. However, as the authors have pointed out, circadian regulation may not be the
same for humans as for the mouse. In fact, the circadian clock in human skin is antiphase to that in the mouse (18), predicting that evening sun exposure would be more harmful to us than morning sun exposure. However, a note of caution is
warranted about a definitive conclusion because many other parameters, some of which are also clock-regulated and individually variable, may affect carcinogenic outcome of exposure to sun in humans.
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Mitra
