RPA facilitates rescue of keratinocytes from UVB radiation damage through insulin-like growth factor-I signalling.

UVBR-induced photolesions in genomic DNA of keratinocytes impair cellular functions and potentially determine the cell fate post-irradiation. The ability of insulin-like growth factor-I (IGF-I) to rescue epidermal keratinocytes after photodamage via apoptosis prevention and photolesion removal was recently demonstrated using in vitro 2D and 3D skin models. Given the limited knowledge of specific signalling cascades contributing to post-UVBR IGF-I effects, we used inhibitors to investigate the impact of blockade of various signalling mediators on IGF-I photoprotection. IGF-I treatment, in the presence of signalling inhibitors particularly, TDRL-505 which targets replication protein A (RPA), impaired activation of IGF-1R downstream signalling, diminished CPD removal, arrested growth, reduced cell survival, and increased apoptosis. Further, the transient partial knockdown of RPA was found to abrogate IGF-I-mediated responses in keratinocytes, ultimately affecting photoprotection and thereby, establishing that RPA is required for IGF-I function. Our findings thus, elucidated the importance of RPA in linking the damage response activation, cell cycle regulation, repair and survival pathways, separately initiated by IGF-I upon UVBR-induced damage, information that is potentially imperative for the development of effective sunburn and photodamage repair strategies.