Poly(ADP-ribose) polymerase-1 activity modulates mitochondrial function following UVB irradiation
Csaba Hegedűs1, Gábor Boros2, Eszter Anna Janka1, Marianna Lovászi1, Katalin Karikó2, Tamás Juhász3, Gréta Kis Nikoletta3, Gabriella Emri1, Péter Bai4, Éva Remenyik1
1. Department of Dermatology, University of Debrecen, Debrecen, Hungary
2. RNA pharmaceuticals, BioNTech AG, Mainz, Germany
3. Department of Anatomy, Histology and Embryology, University of Debrecen, Debrecen, Hungary 
4. Department of Medical Chemistry, University of Debrecen, Debrecen, Hungary

Ultraviolet B radiation (UVB) induces diverse cellular events that involve the formation of photolesions and the activation of the Poly (ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a zinc finger protein with well-documented role in regulating several cellular processes. In this study, we investigated how PARP-1 inhibition by ABT-888 (Veliparib) treatment modulates the mitochondrial response of HaCaT keratinocytes following a single dose of 20 mJ/cm2 and 40 mJ/cm2 of UVB.
Chemical inhibition of PARP-1 induced cell cycle arrest, resulted in the retention of cyclobutane pyrimidine dimers and DNA strand breaks with higher level of cell death following UVB exposure. UVB triggered mitochondrial fragmentation, disintegration of the internal membrane structure and caused a decrease in total mitochondrial area, mass and copy number, whereas PARP-1 inhibition provided partial protection against the UVB-mediated mitochondrial changes. Regarding the functionality of mitochondria, ABT-888 treatment increased total cellular ATP content which was proved to be dependent on oxidative phosphorylation. PARP inhibition also induced mitochondrial membrane depolarization, late increase in ROS production and mRNA changes in the antioxidant response genes. Finally, PARP inhibition preserved the availability of NAD+, and induced mRNA upregulation of mitochondrial regulator proteins. 
Here we demonstrated that the elevated NAD+ level and the upregulation of key mitochondrial regulators by PARP inhibition can be the underlying mechanism in the modulation of mitochondrial functionality. Our results suggest that PARP-1 is an essential player not only in UVB induced cell death and DNA repair but also in mitochondrial activity of HaCaT keratinocytes.