Control of skin cancer by the circadian rhythm

Abstract

Skin cancer is the most common form of cancer in the United States. The main cause of this cancer is DNA damage induced by the UV component of sunlight. In humans and mice, UV damage is removed by the nucleotide excision repair system. Here, we report that a rate-limiting subunit of excision repair, the xeroderma pigmentosum group A (XPA) protein, and the excision repair rate exhibit daily rhythmicity in mouse skin, with a minimum in the morning and a maximum in the afternoon/evening. In parallel with the rhythmicity of repair rate, we find that mice exposed to UV radiation (UVR) at 4:00 AM display a decreased latency and about a fivefold increased multiplicity of skin cancer (invasive squamous cell carcinoma) than mice exposed to UVR at 4:00 PM. We conclude that time of day of exposure to UVR is a contributing factor to its carcinogenicity in mice, and possibly in humans.circadian clock | cryptochrome | sunbathing | tanning salons S kin cancer is the most common form of cancer in the United States. With over 1.3 million new cases each year, it constitutes nearly 40% of all diagnosed cancers (1). Moreover, because of changes in lifestyle and the environment, the incidence of skin cancer is steadily increasing (2). The main causative agent of skin cancer is the UV component of sunlight. UV radiation (UVR) produces two major lesions in DNA, the cyclobutane pyrimidine dimer (CPD) and the (6-4) photoproduct [(6-4) PP], both of which are mutagenic and carcinogenic in animal model systems and are thought to be the primary cause of skin cancer in humans (3-7).In mice and humans, nucleotide excision repair is the sole repair system for removing CPDs and (6-4) PPs from DNA. As a consequence, humans with hereditary mutations in excision repair genes suffer from xeroderma pigmentosum, a syndrome characterized by a nearly 5,000-fold increase in skin cancer in sunlight-exposed areas of the afflicted individuals (8). Excision repair involves photoproduct removal by dual incisions bracketing the lesion, removal of the damage in the form of a 24-to 32-nt-long oligomer, filling in the resulting single-stranded gap, and sealing by ligase (9). The dual incision is carried out by six excision repair factors: RPA, xeroderma pigmentosum group A (XPA), XPC, TFIIH, XPG, and XPF-ERCC1 (10). Recently, in a study that analyzed liver and brain tissues from mice, it was found that XPA, a critical protein involved in damage recognition and a rate-limiting factor in excision repair, is controlled by the core molecular circadian clock (11, 12). As a consequence, excision repair activity exhibited circadian rhythmicity in these organs, increasing during the day to reach a maximum at 4-6:00 PM and decreasing during the night to a minimum at 4-6:00 AM.Here we analyzed the expression pattern of XPA and excision repair activity in mouse skin. We found that protein and repair activity exhibit a circadian rhythm similar to that found in the liver and brain. To determine whether this rhythmicity affected UV-induced skin cancer development we exposed a...

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

“…Consistently, we show that oxidative phosphorylation is one of the most significant categories among genes up-regulated in the skin of Bmal1 −/− mice at ZT22 (4:00 AM). The regulation of circadian epidermal proliferation likely involves canonical clock mechanisms rather than clock-independent function of BMAL1, because circadian S-phase also is obliterated in Cry1 −/− ;Cry2 −/− mice (13). In contrast to our findings, another study reported reduced proliferation in Bmal1 −/− epidermis (12).…”

“…The mammalian epidermis is now emerging as a prime model to study the role of the circadian clock in cell proliferation and cancer susceptibility (8,12,13). Previous studies have established circadian variation in proliferation in several tissues, including mouse epidermis (21).…”

“…5 A and B). We speculate that this lack of difference between the two genotypes could be a result of the constitutively higher rate of excision repair in Bmal1 −/− skin, as was found in Cry1 −/− /Cry2 −/− mouse skin (13). To quantify time-dependent double-strand DNA breaks after UVB exposure, we treated mice with UVB at ZT20 (2:00 AM) and ZT8 (2:00 PM).…”

“…Our previous work demonstrating that global mutations in core clock genes Clock and Bmal1 cause a delay in early anagen progression in mice (7) suggests a role for the circadian system in hair cycling, a process linked to seasonal control in many species. Other recent studies have identified a clock role in DNA repair and skin cancer susceptibility and in determining the activation status of hair follicle stem cells (12,13).…”

“…Our previous work demonstrating that global mutations in core clock genes Clock and Bmal1 cause a delay in early anagen progression in mice (7) suggests a role for the circadian system in hair cycling, a process linked to seasonal control in many species. Other recent studies have identified a clock role in DNA repair and skin cancer susceptibility and in determining the activation status of hair follicle stem cells (12,13).To gain insights into the role of the circadian clock in skin, we defined the circadian transcriptome of skin during telogen (resting stage of hair follicles) and anagen (growing stage of hair follicles). Among enriched functional categories represented by circadian genes in telogen skin are cell-cycle regulation and metabolism.…”