title: Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair.
abstract: Inhibition of DNA repair is a recognized mechanism for arsenic enhancement of ultraviolet radiation-induced DNA damage and carcinogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding. Since cellular poly(ADP-ribosyl)ation capacity has been positively correlated with zinc status in cells, we hypothesize that arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. To test this hypothesis, we compared the effects of arsenite exposure with zinc deficiency, created by using the membrane-permeable zinc chelator TPEN, on 8-OHdG formation, PARP-1 activity and zinc binding to PARP-1 in HaCat cells. Our results show that arsenite exposure and zinc deficiency had similar effects on PARP-1 protein, whereas supplemental zinc reversed these effects. To investigate the molecular mechanism of zinc loss induced by arsenite, ICP-AES, near UV spectroscopy, fluorescence, and circular dichroism spectroscopy were utilized to examine arsenite binding and occupation of a peptide representing the first zinc finger of PARP-1. We found that arsenite binding as well as zinc loss altered the conformation of zinc finger structure which functionally leads to PARP-1 inhibition. These findings suggest that arsenite binding to PARP-1 protein created similar adverse biological effects as zinc deficiency, which establishes the molecular mechanism for zinc supplementation as a potentially effective treatment to reverse the detrimental outcomes of arsenic exposure.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Sun
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: Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
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. Electronic address: kliu@salud.unm.edu.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D002614:Chelating Agents / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005029:Ethylenediamines / Q000378:metabolism; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D015032:Zinc / Q000172:deficiency* / Q000494:pharmacology; D016335:Zinc Fingers
chemical_list: D018053:Arsenites; D002614:Chelating Agents; D005029:Ethylenediamines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000080242:8-Hydroxy-2'-Deoxyguanosine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D003849:Deoxyguanosine; D015032:Zinc; C015001:arsenite; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: 4-(2-Pyridylazo)-resorcinol monosodium salt; 8-OHdG; 8-hydroxyl-2′-deoxyguanine; Arsenite; CD spectrum; DNA damage repair; ICP/AES; N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine; PAR; PARP-1; PMSF; TECP; TPEN; Tris (2-carboxyethyl) phosphine; UVR; Zinc deficiency; Zinc finger; circular dichroism spectrum; inductively coupled plasma atomic emission spectroscopy; phenylmethylsulfonyl fluoride; poly(ADP-ribose) polymerase-1; ultraviolet radiation; zf; zinc finger