Protection from Ultraviolet Damage and Photocarcinogenesis by Vitamin D Compounds 12 Warusavithana Gunawardena Manori De Silva, Myriam Abboud, Chen Yang, Katie M. Dixon, Mark S. Rybchyn, and Rebecca S. Mason Abstract Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitro- gen species also cause local and systemic sup- pression of the adaptive immune system. Together, these changes underpin the develop- ment of skin tumours. The hormone derived from vitamin D, calcitriol (1,25- dihydroxyvitamin D 3 ) and other related compounds, working via the vitamin D recep- tor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reac- tive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehi- cle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after top- ical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduc- tion in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds. Keywords 1,25(OH) 2 D 3 · DNA damage · Ultraviolet radiation · Photoprotection · Photocarcinogenesis · Photo-immune suppression · Energy · Vitamin D receptor · ERp57 · CYP11A1 · Lumisterol derivatives · ROS/RNS W. G. M. De Silva · C. Yang · M. S. Rybchyn · R. S. Mason (*) Department of Physiology, School of Medical Sciences and Bosch Institute, Faculty of Medicine & Health, University of Sydney, Sydney, Australia e-mail: rebecca.mason@sydney.edu.au M. Abboud Zayed University, Dubai, United Arab Emirates K. M. Dixon Department of Anatomy and Histology, School of Medical Sciences and Bosch Institute, Faculty of Medicine & Health, University of Sydney, Sydney, Australia # Springer Nature Switzerland AG 2020 J. Reichrath (ed.), Sunlight, Vitamin D and Skin Cancer, Advances in Experimental Medicine and Biology 1268, https://doi.org/10.1007/978-3-030-46227-7_12 227