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.

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.

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).