Genomes and Genes
Arsenic co-carcinogenesis with UVR: nitrosation and oxidation of target proteins
Principal Investigator: Ke Jian Liu
Abstract: DESCRIPTION (provided by applicant): Widespread human exposure to arsenic through drinking water at levels in excess of the Environmental Protection Agency and World Health Organization minimum contaminant level of 10 [unreadable]g/L is a national and international concern. It is becoming increasingly appreciated that low and non-cytotoxic concentrations of arsenic can amplify the DNA damaging and carcinogenic potential of other genotoxic agents such as ultraviolet radiation, at least in part, through inhibition of DNA repair processes. The mechanisms by which arsenic inhibits DNA repair target proteins is central to understanding the carcinogenic and co-carcinogenic potential of arsenic and to identify avenues to reverse or prevent the adverse effects of arsenic exposure in human populations. The current project will test the hypothesis that arsenic-generated reactive oxygen and nitrogen species inhibits the activity of zinc finger DNA repair proteins through reaction with redox-sensitive cysteine residues of the zinc finger domains. In Aim 1 we will investigate the impact of arsenic-mediated iNOS and NADPH oxidase (NOX) induction and subsequent nitric oxide and superoxide generation on the activity of two DNA repair proteins (XPA and PARP-1), DNA repair and genotoxicity in keratinocytes. Genetic and pharmacologic disruption of iNOS and NOX will define which pathway(s) are involved in arsenic-mediated inhibition of DNA repair. Aim 2 will investigate the interaction of arsenic-generated reactive oxygen and nitrogen species with the zinc fingers of XPA and PARP-1 and apply analytical techniques to define specific modifications of the zinc finger domain and consequences with regard to zinc binding. Data generated by our laboratories and others indicate selectivity for arsenic binding to zinc finger structures and we find that arsenic- bound, but not zinc bound, zinc finger peptide is highly vulnerable to oxidation We will test whether arsenic binding to a zinc finger translates to targeted oxidative and nitrosative modification and loss of zinc finger protein function. In Aim 3, we will test the iNOS and NOX dependence for the reported synergism between arsenic and ultraviolet radiation in DNA damage and skin tumorigenesis in vivo using genetic models. Thus, this project rigorously tests mechanisms of arsenic inhibition of key DNA repair target proteins using a multi- faceted approach. The outcomes from these studies will improve our understanding of mechanisms underlying arsenic disruption of zinc finger DNA repair protein function and may have significant impact on treatments or preventative interventions for arsenic exposed populations. Additionally, these studies may lead to testable hypotheses regarding potential arsenic targets in cancer and other arsenic-associated diseases.
Funding Period: 2012-09-01 - 2017-05-31
more information: NIH RePORT
- Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly(ADP-ribose) polymerase-1Feng Wang
Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131, USA Department of Nutrition and Food Hygiene, Fourth Military Medical University, Xi an, Shaanxi, 710032, China
Free Radic Biol Med 61:249-56. 2013..These results strongly suggest that cellular generation of ROS/RNS plays an important role in arsenite inhibition of PARP-1 activity, leading to the loss of PARP-1 DNA-binding ability and enzymatic activity. ..
- Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repairXi Sun
Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Toxicol Appl Pharmacol 274:313-8. 2014....
- Arsenic methylation and lung and bladder cancer in a case-control study in northern ChileDawit Melak
Global Health Sciences, University of California, San Francisco, San Francisco, CA, USA
Toxicol Appl Pharmacol 274:225-31. 2014....
- Differential binding of monomethylarsonous acid compared to arsenite and arsenic trioxide with zinc finger peptides and proteinsXixi Zhou
Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, United States
Chem Res Toxicol 27:690-8. 2014..These findings provide insights on the molecular mechanisms underlying the differential effects of inorganic versus methylated arsenicals, as well as the role of in vivo arsenic methylation in arsenic toxicity and carcinogenesis...
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