Regulating protein translation to protect from UV-induced damage

Skin is the barrier that protects our body against the external environment, but chronic exposure to ultraviolet (UV) light causes skin inflammation, aging and cancer. The maintenance of the skin epidermis is tightly balanced and controlled by stem cells that continuously maintain their population (self-renewal) while generating progeny (differentiation). Skin stem cells are established during development and are retained in adulthood allowing the body to replace, restore and regenerate dead, damaged or diseased epidermal cells. Our research plan is designed to (i) analyze the specific contribution of epidermal stem cell to regenerate UV-exposed skin and (ii) identify novel intrinsic key factors that promote cell survival in response to UV-damage. Our research will improve our current understanding of how a healthy skin is maintained and will lead to novel discoveries with important implications for regenerative medicine in particular for skin repair, aging and cancer.

Post-transcriptional regulation of gene expression ultimately determines the rate of protein translation and is therefore crucial for virtually all cellular processes. Global reduction of protein synthesis is a well-known early response to UV-stress, yet the intrinsic selective mechanisms that subsequently determine cell death or survival are largely unknown. We propose to decipher the functional roles of protein synthesis in regulating epidermal stem cell fate by determining the global and specific protein translation rates in response to UV-exposure in vivo. We will then evaluate the importance of post-transcriptional methylation pathways in mediating cell survival under UV-stress. Using a combination of system-wide approaches, mouse models and in vitro differentiation assays, we propose to (1) measure protein production in distinct UV-radiated epidermal stem cell populations; (2) profile the translational landscape of UV-radiated epidermal stem cell populations; (3) identify cytosine-5 RNA methylation as regulatory mechanism to promote cell survival in response to UV-stress. Our comprehensive approach will answer how protein synthesis contributes to the UV-stress response and might lead to the discovery of novel therapeutic strategies for skin diseases, aging and cancer.

The potential beneficiaries of the proposed research grant are (1) the broad scientific community, (2) the public, and (3) patients affected by skin regenerative diseases and cancer.

Exposure to environmental hazards such as ultraviolet radiation (UV) affects every human being: Intense exposure to UV-radiation is the primary cause of skin cancer and less intense but chronic exposure to UV-light is thought to be main cause of skin aging. The identification of novel pathways and key regulators that promote skin regeneration in response to UV can potential contribute the nations health and enhance the quality of live. For instance, we will identify novel protein candidates and test whether they promote cell survival and skin regeneration in response to UV-stress. Because we will focus on protein candidates, for which small inhibitors are already available, we may well identify novel therapeutic strategies for skin regeneration over the course of this grant.