Peroxynitrite contributes to arsenic-induced PARP-1 inhibition through ROS/RNS generation

Abstract

Arsenic, in the trivalent form (AsIII), is a human co-carcinogen reported to enhance mutagenesis effects of other carcinogens such as UV radiation by inhibiting DNA repair. The zinc finger DNA repair protein Poly (ADP-ribose) polymerase 1 (PARP-1) is a sensitive target of AsIII and both reactive oxygen and nitrogen species (ROS/RNS) generated by AsIII contribute to PARP-1 inhibition. However, the mechanisms of ROS/RNS-mediated PARP inhibition and how AsIII-generated ROS/RNS may be interconnected are still unclear. In this study, we found AsIII exposure of normal human keratinocyte (HEKn) cells generated peroxynitrite through superoxide and nitric oxide production in an AsIII concentration dependent manner. Peroxynitrite inhibited PARP-1 activity and caused zinc loss from PARP-1 protein while scavenging peroxynitrite was protective of the impacts on PARP-1. We identified peroxynitrite was responsible for S-nitrosation on cysteine residues resulting in PARP-1 zinc finger conformational changes. Taken together, the evidence indicates AsIII generates peroxynitrite through superoxide and nitric oxide production, induces S-nitrosation on PARP-1, leading to zinc loss and activity inhibition of PARP-1, thus enhancing DNA damage caused by UV radiation. These findings highlight a role for peroxynitrite as a key molecule of ROS/RNS mediated DNA repair inhibition by AsIII which should inform the development of prevention and intervention strategies against AsIII co-carcinogenesis.