1128 Role of nucleotide excision repair pathway in insulin-like growth factor-1-mediated keratinocyte photoresponses

Skin forms a critical barrier against detrimental environmental agents including ultraviolet radiation (UVR). Keratinocytes are extremely vulnerable to the damaging effects of UV-BR. Previously, the role of IGF-1 in protection of keratinocytes against UV-BR through its effects on basic cellular processes has been described. However, the explicit signalling cascades underlying IGF-1-mediated cellular responses to UVR have not yet been elucidated. Thus, we intend to further explore these pathways and identify whether IGF-1 is directly linked to damage prevention or associated with enhanced activation of repair pathways. Using specific pathway inhibitors, implicated UV-damage/repair pathways were blocked and downstream responses were analysed in 2-D and 3-D photobiology cell culture-based skin models. Subsequently, targeted knockdown of key signalling mediators and consequent effects on photoresponses will validate the pathway. Our preliminary findings delineate the ability of IGF-1 to rescue keratinocytes post-UV-BR exposure, suggesting the probable elimination of photodamage through the activation of repair mechanisms. Using 2-D and 3-D skin models, we have shown that IGF-1 post-UV-BR promotes cell survival, reduces UV-B-induced DNA damage and prevents apoptosis. Further, abrogated IGF-1 effect, using a specific pathway inhibitor, TDRL-505, which targets replication protein A (RPA-1) within the NER, validated the reparative role for IGF-1 rather than a preventative role. IGF-1 post-irradiation may activate repair pathways such as NER pathway, thus minimizing UV-BR damage in keratinocytes. A better understanding of the signalling mechanisms will be instrumental in developing effective remedial strategies against photodamage.