title: The circadian clock controls sunburn apoptosis and erythema in mouse skin.
abstract: Epidemiological studies of humans and experimental studies with mouse models suggest that sunburn resulting from exposure to excessive UV light and damage to DNA confers an increased risk for melanoma and non-melanoma skin cancer. Previous reports have shown that both nucleotide excision repair, which is the sole pathway in humans for removing UV photoproducts, and DNA replication are regulated by the circadian clock in mouse skin. Furthermore, the timing of UV exposure during the circadian cycle has been shown to affect skin carcinogenesis in mice. Because sunburn and skin cancer are causally related, we investigated UV-induced sunburn apoptosis and erythema in mouse skin as a function of circadian time. Interestingly, we observed that sunburn apoptosis, inflammatory cytokine induction, and erythema were maximal following an acute early-morning exposure to UV and minimal following an afternoon exposure. Early-morning exposure to UV also produced maximal activation of ataxia telangiectasia mutated and Rad3-related (Atr)-mediated DNA damage checkpoint signaling, including activation of the tumor suppressor p53, which is known to control the process of sunburn apoptosis. These data provide early evidence that the circadian clock has an important role in the erythemal response in UV-irradiated skin. The early morning is when DNA repair is at a minimum, and thus the acute responses likely are associated with unrepaired DNA damage. The prior report that mice are more susceptible to skin cancer induction following chronic irradiation in the AM, when p53 levels are maximally induced, is discussed in terms of the mutational inactivation of p53 during chronic irradiation.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington, USA.. Electronic address: shobhan.gaddameedhi@wsu.edu.
authors.forename: Shobhan
authors.initials: S
authors.lastname: Gaddameedhi
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Selby
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kemp
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Ye
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. Electronic address: Aziz_Sancar@med.unc.edu.
authors.forename: Aziz
authors.initials: A
authors.lastname: Sancar
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D057906:Circadian Clocks; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004890:Erythema / Q000209:etiology*; D007150:Immunohistochemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012867:Skin / Q000378:metabolism / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000378:metabolism; D013471:Sunburn; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: D016207:Cytokines; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins