title: Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly(ADP-ribose) polymerase-1.
abstract: Arsenic enhances the genotoxicity of other carcinogenic agents such as ultraviolet radiation and benzo[a]pyrene. Recent reports suggest that inhibition of DNA repair is an important aspect of arsenic cocarcinogenesis, and DNA repair proteins such as poly(ADP ribose) polymerase (PARP)-1 are direct molecular targets of arsenic. Although arsenic has been shown to generate reactive oxygen/nitrogen species (ROS/RNS), little is known about the role of arsenic-induced ROS/RNS in the mechanism underlying arsenic inhibition of DNA repair. We report herein that arsenite-generated ROS/RNS inhibits PARP-1 activity in cells. Cellular exposure to arsenite, as well as hydrogen peroxide and NONOate (nitric oxide donor), decreased PARP-1 zinc content, enzymatic activity, and PARP-1 DNA binding. Furthermore, the effects of arsenite on PARP-1 activity, DNA binding, and zinc content were partially reversed by the antioxidant ascorbic acid, catalase, and the NOS inhibitor, aminoguanidine. Most importantly, arsenite incubation with purified PARP-1 protein in vitro did not alter PARP-1 activity or DNA-binding ability, whereas hydrogen peroxide or NONOate retained PARP-1 inhibitory activity. These results strongly suggest that cellular generation of ROS/RNS plays an important role in arsenite inhibition of PARP-1 activity, leading to the loss of PARP-1 DNA-binding ability and enzymatic activity.
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA; Department of Nutrition and Food Hygiene, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Xixi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: lhudson@salud.unm.edu.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: kliu@salud.unm.edu.
authors.forename: Ke
authors.initials: K
authors.lastname: Jian Liu
mesh_terms: D018053:Arsenites / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D018053:Arsenites; D006146:Guanidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D004247:DNA; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D015032:Zinc; C015001:arsenite; D001205:Ascorbic Acid; C004479:pimagedine
keywords: Arsenic; PARP-1; RNS; ROS