Enhanced Repair of UV-Induced DNA Damage by 1,25-Dihydroxyvitamin D3 in Skin Is Linked to Pathways that Control Cellular Energy

Abstract

Inadequately repaired post-UV DNA damage results in skin cancers. DNA repair requires energy but skin cells have limited capacity to produce energy after UV insult. We examined whether energy supply is important for DNA repair after UV exposure, in the presence of 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), which reduces UV-induced DNA damage and photocarcinogenesis in a variety of models. After UV exposure of primary human keratinocytes, the addition of 1,25(OH)₂D₃ increased unscheduled DNA synthesis, a measure of DNA repair. Oxidative phosphorylation was depleted in UV-irradiated keratinocytes to undetectable levels within an hour of UV irradiation. Treatment with 1,25(OH)₂D₃ but not vehicle increased glycolysis after UV. 2-Deoxyglucose-dependent inhibition of glycolysis abolished the reduction in cyclobutane pyrimidine dimers by 1,25(OH)₂D₃, whereas inhibition of oxidative phosphorylation had no effect. 1,25(OH)₂D₃ increased autophagy and modulated PINK1/Parkin consistent with enhanced mitophagy. These data confirm that energy availability is limited in keratinocytes after exposure to UV. In the presence of 1,25(OH)₂D₃, glycolysis is enhanced along with energy-conserving processes such as autophagy and mitophagy, resulting in increased repair of cyclobutane pyrimidine dimers and decreased oxidative DNA damage. Increased energy availability in the presence of 1,25(OH)₂D₃ is an important contributor to DNA repair in skin after UV exposure.