The goal of this research project is to investigate the role of the circadian clock in melanocyte biology and solar ultraviolet radiation (UVR)-induced melanomagenesis. The malignant transformation of melanocytes, pigment producing cells, leads to the development of melanoma. Cutaneous melanoma is the deadliest form of skin cancer and one of the fastest growing cancers in the U.S. Among the contributing environmental factors, exposure to solar UV radiation is a major risk factor for melanoma development, acting as an initiator, causing mutations in important melanoma oncogenes/tumor-suppressors, and UVR also acts as a promoter, through immune system modulation such as sunburn-mediated inflammation and immunosuppression. In human and placental animals, nucleotide excision repair (NER) removes genetic damage caused by UVR which causes melanoma and non-melanoma skin cancer. The circadian clock is the molecular time-keeping system that underlies daily rhythms in multiple physiological and biochemical processes in concert with the 24 h day-night cycle. Recently, I found that the level of the XPA protein, a key component of the NER pathway, and the rate of NER, both oscillate with a circadian rhythm in mouse skin. Importantly, I found that mice irradiated with UVR in the morning, when the repair rate was low, were more susceptible to development of squamous cell carcinoma than mice irradiated in the evening. However, effects of the circadian clock on melanocyte biology and UVR-induced melanoma have not been explored. Such studies are needed because NER, which is a defense mechanism that prevents UVR-induced melanoma, is controlled by the circadian clock. Therefore, this project will use genetically modified murine models and primary melanocytes derived from those models to understand the role of the circadian clock in melanocyte biology (Aim 1, K99 phase), identify the circadian clock function in UVR-induced melanocyte proliferation and sunburn/inflammatory processes (Aim 2, K99 and R00 phases), and identify DNA damage response signaling pathways and environmental melanomagenesis as a function of the circadian clock (Aim 3, R00 phase). The information obtained will be used to test whether circadian effects on melanocyte biology can be exploited to prevent UVR-induced melanomagenesis.
Solar ultraviolet radiation is the major etiological factor responsible for both melanoma and non- melanoma skin cancers in humans. The outcome of the proposed work will lead to new strategies for prevention of melanoma, the deadliest form of skin cancer. These strategies will be based on modulating the activity of the circadian clock regulated pathway(s) by mechanisms that will be elucidated during the course of this grant proposal.
|Kemp, Michael G; Gaddameedhi, Shobhan; Choi, Jun-Hyuk et al. (2014) DNA repair synthesis and ligation affect the processing of excised oligonucleotides generated by human nucleotide excision repair. J Biol Chem 289:26574-83|