title: S-nitrosation on zinc finger motif of PARP-1 as a mechanism of DNA repair inhibition by arsenite.
abstract: Arsenic, a widely distributed carcinogen, is known to significantly amplify the impact of other carcinogens through inhibition of DNA repair. Our recent work suggests that reactive oxygen/nitrogen species (ROS/RNS) induced by arsenite (AsIII) play an important role in the inhibition of the DNA repair protein Poly(ADP-ribose) polymerase 1 (PARP-1). AsIII-induced ROS lead to oxidation of cysteine residues within the PARP-1 zinc finger DNA binding domain. However, the mechanism underlying RNS-mediated PARP inhibition by arsenic remains unknown. In this work, we demonstrate that AsIII treatment of normal human keratinocyte (HEKn) cells induced S-nitrosation on cysteine residues of PARP-1 protein, in a similar manner to a nitric oxide donor. S-nitrosation of PARP-1 could be reduced by 1400W (inducible nitric oxide synthase inhibitor) or c-PTIO (a nitric oxide scavenger). Furthermore, AsIII treatment of HEKn cells leads to zinc loss and inhibition of PARP-1 enzymatic activity. AsIII and 1400W/c-PTIO co-treatment demonstrate that these effects occur in an iNOS- and NO-dependent manner. Importantly, we confirmed S-nitrosation on the zinc finger DNA binding domain of PARP-1 protein. Taken together, AsIII induces S-nitrosation on PARP-1 zinc finger DNA binding domain by generating NO through iNOS activation, leading to zinc loss and inhibition of PARP-1 activity, thereby increasing retention of damaged DNA. These findings identify S-nitrosation as an important component of the molecular mechanism underlying AsIII inhibition of DNA repair, which may benefit the development of preventive and intervention strategies against AsIII co-carcinogenesis.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Xixi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Cooper
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Juliana
authors.initials: J
authors.lastname: Huestis
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Burchiel
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003545:Cysteine; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D015538:Nitrosation; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000633:toxicity*; D011499:Protein Processing, Post-Translational; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors; D014466:Ultraviolet Rays; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D018053:Arsenites; D016166:Free Radical Scavengers; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017670:Sodium Compounds; D009569:Nitric Oxide; C017947:sodium arsenite; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D015032:Zinc; D003545:Cysteine
keywords: DNA repair; PARP-1; arsenic; reactive nitrogen species; zinc finger