Deciphering the Genome Protection Roles of Autophagy in Primary Human Dermal Fibroblasts (HDFs) against Ultraviolet-(B) –Induced Skin Photodamage

Abstract

AbstractUltraviolet-B (UV-B) exposure to skin causes photo-damage and acts as the primary etiological agent in photo-carcinogenesis. UV-B exposure induces photodamage in epidermal cells and is the major factor that challenges skin homeostasis. Autophagy allows fundamental adaptation of cells to metabolic needs and stresses. Cellular dysfunction is observed in aged tissues and in toxic insults to cells that undergo through stress. Conversely, promising anti-aging strategies aimed at inhibiting the mTOR pathway has been found to significantly improve the aging related disorders. Recently, autophagy has been found to positively regulate skin homeostasis by enhancing DNA damage recognition. Here we investigated the Geno-protective roles of autophagy in UV-B exposed primary HDFs. We found that improving autophagy levels in HDFs regulates UV-B mediated cellular stress by decreasing the formation of DNA photo adducts, alleviates oxidative and ER stress response and by regulating the expression levels of cell cycle regulatory proteins P21 and P27. Autophagy also prevents HDFs from UV-B -induced nuclear damage as is evident from Tunnel assay and Acridine Orange/Ethidium Bromide co-staining. Salubrinal, (an eIf2α inhibitor) significantly decreases the DNA damage response in HDFs. P62 silenced HDFs show enhanced DNA damage response and disturbs the tumor suppressor axis PTEN/pAKT towards damage whereas ATG7 silenced HDFs reveal an unexpected consequence by decreasing the UV-B -induced DNA damage compared to UV-B treated HDFs. Together, our results suggest that autophagy is essential in protecting skin cells from UV-B radiation -induced photo-damage and holds great promise in devising it as a suitable therapeutic strategy against skin photo-damage.HighlightsAutophagy is an immediate molecular event induced following exposure of primary HDFs to UV-B –irradiationAutophagy offers pro-survival capacity to HDFs under UV-B induced genotoxic stressAutophagy regulates DNA Damage Response via regulation of oxidative and ER stress in UV-B exposed HDFsRelieving ER stress response offers significant protection to primary HDFs from UV-B by decreasing the DNA damageAutophagy deprivation to HDFs via P62 silencing potentiates UV-B -induced DNA damage responseATG7 silencing in UV-B exposed HDFs unexpectedly alleviates the DNA Damage Response in primary HDFs