title: Inhibition of poly(ADP-ribose) polymerase-1 by arsenite interferes with repair of oxidative DNA damage.
abstract: Arsenic enhances skin tumor formation when combined with other carcinogens, including UV radiation (UVR). In this study we report that low micromolar concentrations of arsenite synergistically increases UVR-induced oxidative DNA damage in human keratinocytes as detected by 8-hydroxyl-2'-deoxyguanine (8-OHdG) formation. Poly(ADP-ribose) polymerase-1 (PARP-1) is involved in base excision repair, a process that repairs 8-OHdG lesions. Arsenite suppresses UVR-induced PARP-1 activation in a concentration-dependent manner. Inhibition of PARP-1 activity by 3-aminobenzamide or small interfering RNA silencing of PARP-1 expression significantly increases UVR-induced 8-OHdG formation, suggesting that inhibition of PARP-1 activity by arsenite contributes to oxidative DNA damage. PARP-1 is a zinc finger protein, and mass spectrometry analysis reveals that arsenite can occupy a synthetic apopeptide representing the first zinc finger of PARP-1 (PARPzf). When the PARPzf peptide is preincubated with Zn(II) followed by incubation with increasing concentrations of arsenite, the ZnPARPzf signal is decreased while the AsPARPzf signal intensity is increased as a function of arsenite dose, suggesting a competition between zinc and arsenite for the same binding site. Addition of Zn(II) abolished arsenite enhancement of UVR-stimulated 8-OHdG generation and restored PARP-1 activity. Our findings demonstrate that arsenite inhibits oxidative DNA damage repair and suggest that interaction of arsenite with the PARP-1 zinc finger domain contributes to the inhibition of PARP-1 activity by arsenite. Arsenite inhibition of poly(ADP-ribosyl)ation is one likely mechanism for the reported co-carcinogenic activities of arsenic in UVR-induced skin carcinogenesis.
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico 87131-0704, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.forename: Karen L
authors.initials: KL
authors.lastname: Cooper
authors.forename: Xu-Jun
authors.initials: XJ
authors.lastname: Qin
authors.forename: Patrícia L
authors.initials: PL
authors.lastname: de Souza Bergo
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
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 / Q000528:radiation effects*; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects*; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects / Q000528:radiation effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013723:Teratogens / Q000633:toxicity*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D016335:Zinc Fingers
chemical_list: D018053:Arsenites; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D013723:Teratogens; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C015001:arsenite