Arsenic co-carcinogenesis with UVR: nitrosation and oxidation of target proteins

Summary

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

Top Publications

  1. ncbi Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly(ADP-ribose) polymerase-1
    Feng 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
  2. pmc Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair
    Xi 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
  3. ncbi Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile
    Dawit Melak
    Global Health Sciences, University of California, San Francisco, San Francisco, CA, USA
    Toxicol Appl Pharmacol 274:225-31. 2014
  4. pmc Differential binding of monomethylarsonous acid compared to arsenite and arsenic trioxide with zinc finger peptides and proteins
    Xixi 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

Research Grants

  1. EPIDEMIOLOGY OF ALCOHOL PROBLEMS
    Thomas K Greenfield; Fiscal Year: 2013
  2. Synergistic Immunosuppression by PAHs and Arsenite
    SCOTT WILLIAM BURCHIEL; Fiscal Year: 2013
  3. Mitochondrial Proteins in Parkinson's Disease
    J Timothy Greenamyre; Fiscal Year: 2013
  4. Genomics of Kidney Transplantation Admin
    Arthur J Matas; Fiscal Year: 2013
  5. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
  6. Metal inhibition of the base excision repair enzymes
    Anton Guliaev; Fiscal Year: 2013
  7. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
  8. Predicting Novel Arsenic Targets in DNA Repair Pathways
    Laurie G Hudson; Fiscal Year: 2013
  9. The influence of DNA repair on inflammation associated carcinogenesis
    Leona D Samson; Fiscal Year: 2013
  10. Regulation of Nucleotide Excision Repair by Proteolysis
    Pengbo Zhou; Fiscal Year: 2013

Detail Information

Publications4

  1. ncbi Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly(ADP-ribose) polymerase-1
    Feng 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. ..
  2. pmc Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair
    Xi 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
    ....
  3. ncbi Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile
    Dawit Melak
    Global Health Sciences, University of California, San Francisco, San Francisco, CA, USA
    Toxicol Appl Pharmacol 274:225-31. 2014
    ....
  4. pmc Differential binding of monomethylarsonous acid compared to arsenite and arsenic trioxide with zinc finger peptides and proteins
    Xixi 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...

Research Grants30

  1. EPIDEMIOLOGY OF ALCOHOL PROBLEMS
    Thomas K Greenfield; Fiscal Year: 2013
    ..We plan to build research capacity in the Center and other organizations, enhance careers of new investigators, and make key findings accessible to researchers, policy makers, practitioners, and the public. ..
  2. Synergistic Immunosuppression by PAHs and Arsenite
    SCOTT WILLIAM BURCHIEL; Fiscal Year: 2013
    ..The results of these studies will make an important contribution to understanding environmental agents that modulate the human immune system and perhaps provide an approach to intervention for As+3 drinking water exposures. ..
  3. Mitochondrial Proteins in Parkinson's Disease
    J Timothy Greenamyre; Fiscal Year: 2013
    ....
  4. Genomics of Kidney Transplantation Admin
    Arthur J Matas; Fiscal Year: 2013
    ..The Administrative Core will also facilitate interaction between Sites, Cores, and Projects. ..
  5. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  6. Metal inhibition of the base excision repair enzymes
    Anton Guliaev; Fiscal Year: 2013
    ..Understanding the mechanisms, by which toxic metals interfere with DNA repair, is relevant to developing fundamental knowledge that will aid in cancer prevention and treatment. ..
  7. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  8. Predicting Novel Arsenic Targets in DNA Repair Pathways
    Laurie G Hudson; Fiscal Year: 2013
    ..These results will inform testable hypotheses regarding additional potential arsenic targets in cancer and other arsenic-associated diseases. ..
  9. The influence of DNA repair on inflammation associated carcinogenesis
    Leona D Samson; Fiscal Year: 2013
    ..Understanding how DNA repair contributes to carcinogenesis will provide insights into the mechanism by which chronic inflammation increases the chance of cancer as well as identify possible approaches to decrease cancer risk. ..
  10. Regulation of Nucleotide Excision Repair by Proteolysis
    Pengbo Zhou; Fiscal Year: 2013
    ..abstract_text> ..
  11. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  12. Puerto Rico Testsite for Exploring Contamination Threats (PRoTECT)
    Akram N Alshawabkeh; Fiscal Year: 2013
    ..The cross-disciplinary approach will employ the data-rich centralized data repository and integrated modeling/analysis capabilities to better understand complex interrelationships between multiple risk factors. ..
  13. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  14. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  15. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  16. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..