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Title: Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity

Abstract

Epidemiological studies have associated arsenic exposure with many types of human cancers. Arsenic has also been shown to act as a co-carcinogen even at low concentrations. However, the precise mechanism of its co-carcinogenic action is unknown. Recent studies indicate that arsenic can interfere with DNA-repair processes. Poly(ADP-ribose) polymerase (PARP)-1 is a zinc-finger DNA-repair protein, which can promptly sense DNA strand breaks and initiate DNA-repair pathways. In the present study, we tested the hypothesis that low concentrations of arsenic could inhibit PAPR-1 activity and so exacerbate levels of ultraviolet radiation (UVR)-induced DNA strand breaks. HaCat cells were treated with arsenite and/or UVR, and then DNA strand breaks were assessed by comet assay. Low concentrations of arsenite ({<=} 2 {mu}M) alone did not induce significant DNA strand breaks, but greatly enhanced the DNA strand breaks induced by UVR. Further studies showed that 2 {mu}M arsenite effectively inhibited PARP-1 activity. Zinc supplementation of arsenite-treated cells restored PARP-1 activity and significantly diminished the exacerbating effect of arsenite on UVR-induced DNA strand breaks. Importantly, neither arsenite treatment, nor zinc supplementation changed UVR-triggered reactive oxygen species (ROS) formation, suggesting that their effects upon UVR-induced DNA strand breaks are not through a direct free radical mechanism. Combinationmore » treatments of arsenite with PARP-1 inhibitor 3-aminobenzamide or PARP-1 siRNA demonstrate that PARP-1 is the target of arsenite. Together, these findings show that arsenite at low concentration exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity, which may represent an important mechanism underlying the co-carcinogenicity of arsenic.« less

Authors:
 [1]; ; ;  [1]
  1. Program of Toxicology, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131-0001 (United States)
Publication Date:
OSTI Identifier:
21144119
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 232; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2008.05.019; PII: S0041-008X(08)00237-8; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADP; ALBUMINS; ARSENIC; CARCINOGENESIS; CARCINOGENS; CATTLE; DNA; EXCISION REPAIR; HYDROXIDES; LEAD SULFIDES; NEOPLASMS; PHOSPHATES; POLYMERASES; RIBOSE; RNA; STRAND BREAKS; ZINC CHLORIDES

Citation Formats

Xujun, Qin, Department of Toxicology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, Hudson, Laurie G, Wenlan, Liu, Timmins, Graham S, and Liu Kejian. Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity. United States: N. p., 2008. Web.
Xujun, Qin, Department of Toxicology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, Hudson, Laurie G, Wenlan, Liu, Timmins, Graham S, & Liu Kejian. Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity. United States.
Xujun, Qin, Department of Toxicology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, Hudson, Laurie G, Wenlan, Liu, Timmins, Graham S, and Liu Kejian. 2008. "Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity". United States.
@article{osti_21144119,
title = {Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity},
author = {Xujun, Qin and Department of Toxicology, Fourth Military Medical University, Xi'an, Shaanxi, 710032 and Hudson, Laurie G and Wenlan, Liu and Timmins, Graham S and Liu Kejian},
abstractNote = {Epidemiological studies have associated arsenic exposure with many types of human cancers. Arsenic has also been shown to act as a co-carcinogen even at low concentrations. However, the precise mechanism of its co-carcinogenic action is unknown. Recent studies indicate that arsenic can interfere with DNA-repair processes. Poly(ADP-ribose) polymerase (PARP)-1 is a zinc-finger DNA-repair protein, which can promptly sense DNA strand breaks and initiate DNA-repair pathways. In the present study, we tested the hypothesis that low concentrations of arsenic could inhibit PAPR-1 activity and so exacerbate levels of ultraviolet radiation (UVR)-induced DNA strand breaks. HaCat cells were treated with arsenite and/or UVR, and then DNA strand breaks were assessed by comet assay. Low concentrations of arsenite ({<=} 2 {mu}M) alone did not induce significant DNA strand breaks, but greatly enhanced the DNA strand breaks induced by UVR. Further studies showed that 2 {mu}M arsenite effectively inhibited PARP-1 activity. Zinc supplementation of arsenite-treated cells restored PARP-1 activity and significantly diminished the exacerbating effect of arsenite on UVR-induced DNA strand breaks. Importantly, neither arsenite treatment, nor zinc supplementation changed UVR-triggered reactive oxygen species (ROS) formation, suggesting that their effects upon UVR-induced DNA strand breaks are not through a direct free radical mechanism. Combination treatments of arsenite with PARP-1 inhibitor 3-aminobenzamide or PARP-1 siRNA demonstrate that PARP-1 is the target of arsenite. Together, these findings show that arsenite at low concentration exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity, which may represent an important mechanism underlying the co-carcinogenicity of arsenic.},
doi = {},
url = {https://www.osti.gov/biblio/21144119}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 232,
place = {United States},
year = {Wed Oct 01 00:00:00 EDT 2008},
month = {Wed Oct 01 00:00:00 EDT 2008}
}