The role of vitamin D in ameliorating various health outcomes other than bone-related metabolism is controversial. A recent Institute of Medicine report identified as a major research need studies that address whether the sub-erythemal doses sufficient for vitamin D photosynthesis in the skin are associated with an additional risk of skin cancer. Due to the lengthy latency of skin cancers in normal humans, it is unlikely that clinical trials can address this issue in the near future. However, it is feasible to ask whether compensatory biological mechanisms exist that might couple vitamin D photosynthesis to the DNA repair pathways relevant for ultraviolet radiation (UV). The hypothesis of this research proposal is that, following doses of UV exposure associated with vitamin D photosynthesis, vitamin D receptor (VDR) independent of canonical vitamin D signaling is upregulated to mediate cellular responses that limit the collateral DNA damage incurred, thus minimizing skin cancer risk. In support of the hypothesis, we have observed that VDR is a UV- inducible gene, and that VDR knockout mouse epidermis is significantly impaired in the repair of the major UV photoproducts. These and other preliminary studies suggest that VDR, likely acting in a vitamin D-independent manner, is photoprotective. In Aim 1, we will identify the determinants of VDR activity in DNA repair following UV. Using mouse epidermal sheets as well as cultured human and mouse keratinocytes in which VDR is deficient, we will determine if VDR induction is a general response to multiple forms of DNA damage, or if it is UV-specific. The dependence of UV-induced VDR expression on the p53 family and on biologically active vitamin D will be measured. In Aim 2, we will assess VDR's role in both global genomic and transcription-coupled nucleotide excision repair by assaying DNA repair activity and levels of key DNA damage recognition proteins in mouse epidermal sheets and cultured mouse and human keratinocytes lacking VDR. We will also examine UV-induced tumor tissue from humans and mice to correlate VDR with levels of key DNA repair proteins as well as perform a mutational analysis on key tumor suppressor genes to test if VDR loss is associated with an abnormal mutator phenotype. At the conclusion of these studies, a systematic understanding should emerge of the role that VDR plays in the response to DNA damage incurred during vitamin D photosynthesis. These studies are relevant for understanding the physiological compensations required of skin in producing vitamin D and may inform future clinical studies and public health recommendations for sun exposure and protection.