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 zincmore »
- Authors:
-
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States)
- Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 (China)
- Publication Date:
- OSTI Identifier:
- 22285569
- Resource Type:
- Journal Article
- Journal Name:
- Toxicology and Applied Pharmacology
- Additional Journal Information:
- Journal Volume: 274; Journal Issue: 2; Other Information: Copyright (c) 2013 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; ARSENIC; CARCINOGENESIS; DNA; DNA DAMAGES; DNA REPAIR; EMISSION SPECTROSCOPY; FINGERS; MEMBRANES; PEPTIDES; RIBOSE; ULTRAVIOLET RADIATION; ZINC
Citation Formats
Sun, Xi, Zhou, Xixi, Du, Libo, Liu, Wenlan, Liu, Yang, Hudson, Laurie G., and Liu, Ke Jian, E-mail: kliu@salud.unm.edu. Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. United States: N. p., 2014.
Web. doi:10.1016/J.TAAP.2013.11.010.
Sun, Xi, Zhou, Xixi, Du, Libo, Liu, Wenlan, Liu, Yang, Hudson, Laurie G., & Liu, Ke Jian, E-mail: kliu@salud.unm.edu. Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. United States. https://doi.org/10.1016/J.TAAP.2013.11.010
Sun, Xi, Zhou, Xixi, Du, Libo, Liu, Wenlan, Liu, Yang, Hudson, Laurie G., and Liu, Ke Jian, E-mail: kliu@salud.unm.edu. 2014.
"Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair". United States. https://doi.org/10.1016/J.TAAP.2013.11.010.
@article{osti_22285569,
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},
author = {Sun, Xi and Zhou, Xixi and Du, Libo and Liu, Wenlan and Liu, Yang and Hudson, Laurie G. and Liu, Ke Jian, E-mail: kliu@salud.unm.edu},
abstractNote = {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. - Highlights: • Arsenite binding is equivalent to zinc deficiency in reducing PARP-1 function. • Zinc reverses arsenic inhibition of PARP-1 activity and enhancement of DNA damage. • Arsenite binding and zinc loss alter the conformation of zinc finger structure.},
doi = {10.1016/J.TAAP.2013.11.010},
url = {https://www.osti.gov/biblio/22285569},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 274,
place = {United States},
year = {Wed Jan 15 00:00:00 EST 2014},
month = {Wed Jan 15 00:00:00 EST 2014}
}