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1
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Fan YG, Wu TY, Zhao LX, Jia RJ, Ren H, Hou WJ, Wang ZY. From zinc homeostasis to disease progression: Unveiling the neurodegenerative puzzle. Pharmacol Res 2024; 199:107039. [PMID: 38123108 DOI: 10.1016/j.phrs.2023.107039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/16/2023] [Accepted: 12/10/2023] [Indexed: 12/23/2023]
Abstract
Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Yong-Gang Fan
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China.
| | - Ting-Yao Wu
- First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China
| | - Ling-Xiao Zhao
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Rong-Jun Jia
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Hang Ren
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Wen-Jia Hou
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Zhan-You Wang
- Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China.
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2
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Speer RM, Nandi SP, Cooper KL, Zhou X, Yu H, Guo Y, Hudson LG, Alexandrov LB, Liu KJ. Arsenic is a potent co-mutagen of ultraviolet light. Commun Biol 2023; 6:1273. [PMID: 38104187 PMCID: PMC10725444 DOI: 10.1038/s42003-023-05659-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 12/01/2023] [Indexed: 12/19/2023] Open
Abstract
Arsenic enhances the carcinogenicity of ultraviolet radiation (UVR). However, the mechanisms of arsenic-driven oncogenesis are not well understood. Here, we utilize experimental systems to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR. In vitro and in vivo exposures indicate that, by itself, arsenic is not mutagenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis and to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, is observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13, to the best of our knowledge, the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing skin cancer genomics data reveals that only a subset of cancers harbor ID13 and these exhibit an elevated UVR mutagenesis. Our results report a unique mutational signature caused by a co-exposure to two environmental carcinogens and provide comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR.
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Affiliation(s)
- Rachel M Speer
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, 87106, USA
| | - Shuvro P Nandi
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, 92093, USA
- Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA
- Department of Bioengineering, UC San Diego, La Jolla, CA, 92093, USA
| | - Karen L Cooper
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, 87106, USA
| | - Xixi Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, 87106, USA
| | - Hui Yu
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, 33136, USA
| | - Yan Guo
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, 33136, USA
| | - Laurie G Hudson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, 87106, USA
| | - Ludmil B Alexandrov
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, 92093, USA.
- Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA.
- Department of Bioengineering, UC San Diego, La Jolla, CA, 92093, USA.
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, 87106, USA.
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, 11794, USA.
- Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY, 11794, USA.
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3
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Wysocki R, Rodrigues JI, Litwin I, Tamás MJ. Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony. Cell Mol Life Sci 2023; 80:342. [PMID: 37904059 PMCID: PMC10616229 DOI: 10.1007/s00018-023-04992-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/12/2023] [Accepted: 09/29/2023] [Indexed: 11/01/2023]
Abstract
Arsenic and antimony are metalloids with profound effects on biological systems and human health. Both elements are toxic to cells and organisms, and exposure is associated with several pathological conditions including cancer and neurodegenerative disorders. At the same time, arsenic- and antimony-containing compounds are used in the treatment of multiple diseases. Although these metalloids can both cause and cure disease, their modes of molecular action are incompletely understood. The past decades have seen major advances in our understanding of arsenic and antimony toxicity, emphasizing genotoxicity and proteotoxicity as key contributors to pathogenesis. In this review, we highlight mechanisms by which arsenic and antimony cause toxicity, focusing on their genotoxic and proteotoxic effects. The mechanisms used by cells to maintain proteostasis during metalloid exposure are also described. Furthermore, we address how metalloid-induced proteotoxicity may promote neurodegenerative disease and how genotoxicity and proteotoxicity may be interrelated and together contribute to proteinopathies. A deeper understanding of cellular toxicity and response mechanisms and their links to pathogenesis may promote the development of strategies for both disease prevention and treatment.
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Affiliation(s)
- Robert Wysocki
- Department of Genetics and Cell Physiology, Faculty of Biological Sciences, University of Wroclaw, 50-328, Wroclaw, Poland.
| | - Joana I Rodrigues
- Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, 405 30, Göteborg, Sweden
| | - Ireneusz Litwin
- Academic Excellence Hub - Research Centre for DNA Repair and Replication, Faculty of Biological Sciences, University of Wroclaw, 50-328, Wroclaw, Poland
| | - Markus J Tamás
- Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, 405 30, Göteborg, Sweden.
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4
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Qi Z, Zhou X, Dong W, Timmins GS, Pan R, Shi W, Yuan S, Zhao Y, Ji X, Liu KJ. Neuronal Zinc Transporter ZnT3 Modulates Cerebral Ischemia-Induced Blood-Brain Barrier Disruption. Aging Dis 2023; 15:2727-2741. [PMID: 37962463 PMCID: PMC11567248 DOI: 10.14336/ad.2023.1011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/11/2023] [Indexed: 11/15/2023] Open
Abstract
Zinc plays important roles in both physiological and pathological processes in the brain. Accumulation of free zinc in ischemic tissue is recognized to contribute to blood-brain barrier (BBB) disruption following cerebral ischemia, but little is known either about the source of free zinc in microvessels or the mechanism by which free zinc mediates ischemia-induced BBB damage. We utilized cellular and animal models of ischemic stroke to determine the source of high levels of free zinc and the mechanism of free zinc-mediated BBB damage after ischemia. We report that cerebral ischemia elevated the level of extracellular fluid (ECF-Zn) of ischemic brain, leading to exacerbated BBB damage in a rat stroke model. Specifically suppressing zinc release from neurons, utilizing neuronal-specific zinc transporter 3 (ZnT3) knockout mice, markedly reduced ECF-Zn and BBB permeability after ischemia. Intriguingly, the activity of zinc-dependent metalloproteinase-2 (MMP-2) was modulated by ECF-Zn levels. Elevated ECF-Zn during ischemia directly bound to MMP-2 in extracellular fluid, increased its zinc content and augmented MMP-2 activity, leading to the degradation of tight junction protein in cerebral microvessels and BBB disruption. These findings suggest the role of neuronal ZnT3 in modulating ischemia-induced BBB disruption and reveal a novel mechanism of MMP-2 activation in BBB disruption after stroke, demonstrating ZnT3 as an effective target for stroke treatment.
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Affiliation(s)
- Zhifeng Qi
- Department of Neurology, Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China.
| | - Xixi Zhou
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Wen Dong
- Department of Neurology, Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China.
| | - Graham S. Timmins
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Rong Pan
- Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Wenjuan Shi
- Department of Neurology, Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China.
| | - Shuhua Yuan
- Department of Neurology, Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China.
| | - Yongmei Zhao
- Department of Neurology, Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China.
| | - Xunming Ji
- Department of Neurology, Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China.
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
- Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
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5
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Chen J, Qu C, Lu M, Zhang M, Wu Y, Gao C, Huang Q, Cai P. Extracellular polymeric substances and mineral interfacial reactions control the simultaneous immobilization and reduction of arsenic (As(V)). JOURNAL OF HAZARDOUS MATERIALS 2023; 456:131651. [PMID: 37245361 DOI: 10.1016/j.jhazmat.2023.131651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/18/2023] [Accepted: 05/14/2023] [Indexed: 05/30/2023]
Abstract
Extracellular polymeric substances (EPS) play a crucial role in controlling the mobility and bioavailability of heavy metal(loid)s in water, soils, and sediments. The formation of EPS-mineral complex changes the reactivity of the end-member materials. However, little is known about the adsorption and redox mechanisms of arsenate (As(V)) in EPS and EPS-mineral complexes. Here we examined the reaction sites, valence state, thermodynamic parameters and distribution of As in the complexes using potentiometric titration, isothermal titration calorimetry (ITC), FTIR, XPS, and SEM-EDS. The results showed that ∼54% of As(V) was reduced to As(III) by EPS, potentially driven by an enthalpy change (ΔH) of - 24.95 kJ/mol. The EPS coating on minerals clearly affected the reactivity to As(V). The strong masking of functional sites between EPS and goethite inhibited both the adsorption and reduction of As. In contrast, the weak binding of EPS onto montmorillonite retained more reactive sites for the reaction with As. Meanwhile, montmorillonite facilitated the immobilization of As to EPS through the formation of As-organic bounds. Our findings deepen the understanding of EPS-mineral interfacial reactions in controlling the redox and mobility of As, and the knowledge is important for predicting the behavior of As in natural environments.
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Affiliation(s)
- Jinzhao Chen
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Hubei Key Laboratory of Soil Environment and Pollution Remediation, Huazhong Agricultural University, Wuhan 430070, China
| | - Chenchen Qu
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Hubei Key Laboratory of Soil Environment and Pollution Remediation, Huazhong Agricultural University, Wuhan 430070, China.
| | - Man Lu
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
| | - Ming Zhang
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Yichao Wu
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
| | - Chunhui Gao
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
| | - Qiaoyun Huang
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Hubei Key Laboratory of Soil Environment and Pollution Remediation, Huazhong Agricultural University, Wuhan 430070, China
| | - Peng Cai
- National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Hubei Key Laboratory of Soil Environment and Pollution Remediation, Huazhong Agricultural University, Wuhan 430070, China
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Li Z, Liu Y, Wei R, Yong VW, Xue M. The Important Role of Zinc in Neurological Diseases. Biomolecules 2022; 13:28. [PMID: 36671413 PMCID: PMC9855948 DOI: 10.3390/biom13010028] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/25/2022] Open
Abstract
Zinc is one of the most abundant metal ions in the central nervous system (CNS), where it plays a crucial role in both physiological and pathological brain functions. Zinc promotes antioxidant effects, neurogenesis, and immune system responses. From neonatal brain development to the preservation and control of adult brain function, zinc is a vital homeostatic component of the CNS. Molecularly, zinc regulates gene expression with transcription factors and activates dozens of enzymes involved in neuronal metabolism. During development and in adulthood, zinc acts as a regulator of synaptic activity and neuronal plasticity at the cellular level. There are several neurological diseases that may be affected by changes in zinc status, and these include stroke, neurodegenerative diseases, traumatic brain injuries, and depression. Accordingly, zinc deficiency may result in declines in cognition and learning and an increase in oxidative stress, while zinc accumulation may lead to neurotoxicity and neuronal cell death. In this review, we explore the mechanisms of brain zinc balance, the role of zinc in neurological diseases, and strategies affecting zinc for the prevention and treatment of these diseases.
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Affiliation(s)
- Zhe Li
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou 450001, China
| | - Yang Liu
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou 450001, China
| | - Ruixue Wei
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou 450001, China
| | - V. Wee Yong
- Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Mengzhou Xue
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou 450001, China
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7
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Banerjee M, Yaddanapudi K, States JC. Zinc supplementation prevents mitotic accumulation in human keratinocyte cell lines upon environmentally relevant arsenic exposure. Toxicol Appl Pharmacol 2022; 454:116255. [PMID: 36162444 PMCID: PMC9683715 DOI: 10.1016/j.taap.2022.116255] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/09/2022] [Accepted: 09/20/2022] [Indexed: 12/01/2022]
Abstract
Disrupted cell cycle progression underlies the molecular pathogenesis of multiple diseases. Chronic exposure to inorganic arsenic (iAs) is a global health issue leading to multi-organ cancerous and non-cancerous diseases. Exposure to supratherapeutic concentrations of iAs causes cellular accumulation in G2 or M phase of the cell cycle in multiple cell lines by inducing cyclin B1 expression. It is not clear if iAs exposure at doses corresponding to serum levels of chronically exposed populations (∼100 nM) has any effect on cell cycle distribution. In the present study we investigated if environmentally relevant iAs exposure induced cell cycle disruption and mechanisms thereof employing two human keratinocyte cell lines (HaCaT and Ker-CT), flow cytometry, immunoblots and quantitative real-time PCR (qRT-PCR). iAs exposure (100 nM; 24 h) led to mitotic accumulation of cells in both cell lines, along with the stabilization of ANAPC11 ubiquitination targets cyclin B1 and securin, without affecting their steady state mRNA levels. This result suggested that induction of cyclin B1 and securin is modulated at the level of protein degradation. Moreover, zinc supplementation successfully prevented iAs-induced mitotic accumulation and stabilization of cyclin B1 and securin without affecting their mRNA levels. Together, these data suggest that environmentally relevant iAs exposure leads to mitotic accumulation possibly by displacing zinc from the RING finger subunit of anaphase promoting complex/cyclosome (ANAPC11), the cell cycle regulating E3 ubiquitin ligase. This early cell cycle disruptive effect of environmentally relevant iAs concentration could underpin the molecular pathogenesis of multiple diseases associated with chronic iAs exposure.
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Affiliation(s)
- Mayukh Banerjee
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.
| | - Kavitha Yaddanapudi
- Immuno-Oncology Group, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA; Department of Microbiology/Immunology, University of Louisville, Louisville, KY, USA
| | - J Christopher States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
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8
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Speer RM, Zhou X, Volk LB, Liu KJ, Hudson LG. Arsenic and cancer: Evidence and mechanisms. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 96:151-202. [PMID: 36858772 PMCID: PMC10860672 DOI: 10.1016/bs.apha.2022.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Arsenic is a potent carcinogen and poses a significant health concern worldwide. Exposure occurs through ingestion of drinking water and contaminated foods and through inhalation due to pollution. Epidemiological evidence shows arsenic induces cancers of the skin, lung, liver, and bladder among other tissues. While studies in animal and cell culture models support arsenic as a carcinogen, the mechanisms of arsenic carcinogenesis are not fully understood. Arsenic carcinogenesis is a complex process due its ability to be metabolized and because of the many cellular pathways it targets in the cell. Arsenic metabolism and the multiple forms of arsenic play distinct roles in its toxicity and contribute differently to carcinogenic endpoints, and thus must be considered. Arsenic generates reactive oxygen species increasing oxidative stress and damaging DNA and other macromolecules. Concurrently, arsenic inhibits DNA repair, modifies epigenetic regulation of gene expression, and targets protein function due its ability to replace zinc in select proteins. While these mechanisms contribute to arsenic carcinogenesis, there remain significant gaps in understanding the complex nature of arsenic cancers. In the future improving models available for arsenic cancer research and the use of arsenic induced human tumors will bridge some of these gaps in understanding arsenic driven cancers.
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Affiliation(s)
- Rachel M Speer
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States
| | - Xixi Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States
| | - Lindsay B Volk
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States; Stony Brook Cancer Center, Renaissance School of Medicine, State University of New York Stony Brook, Stony Brook, NY, United States.
| | - Laurie G Hudson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States
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9
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Arsenic impairs the lineage commitment of hematopoietic progenitor cells through the attenuation of GATA-2 DNA binding activity. Toxicol Appl Pharmacol 2022; 452:116193. [PMID: 35961411 DOI: 10.1016/j.taap.2022.116193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 11/22/2022]
Abstract
Arsenic exposure produces significant hematotoxicity in vitro and in vivo. Our previous work shows that arsenic (in the form of arsenite, AsIII) interacts with the zinc finger domains of GATA-1, inhibiting the function of this critical transcription factor, and resulting in the suppression of erythropoiesis. In addition to GATA-1, GATA-2 also plays a key role in the regulation of hematopoiesis. GATA-1 and GATA-2 have similar zinc finger domains (C4-type) that are structurally favorable for AsIII interactions. Taking this into consideration, we hypothesized that early stages of hematopoietic differentiation that are dependent on the function of GATA-2 may also be disrupted by AsIII exposure. We found that in vitro AsIII exposures disrupt the erythromegakaryocytic lineage commitment and differentiation of erythropoietin-stimulated primary mouse bone marrow hematopoietic progenitor cells (HPCs), producing an aberrant accumulation of cells in early stages of hematopoiesis and subsequent reduction of committed erythro-megakaryocyte progenitor cells. Arsenic significantly accumulated in the GATA-2 protein, causing the loss of zinc, and disruption of GATA-2 function, as measured by chromatin immunoprecipitation and the expression of GATA-2 responsive genes. Our results show that the attenuation of GATA-2 function is an important mechanism contributing to the aberrant lineage commitment and differentiation of early HPCs. Collectively, findings from the present study suggest that the AsIII-induced disruption of erythro-megakaryopoiesis may contribute to the onset and/or exacerbation of hematological disorders, such as anemia.
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10
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Bjørklund G, Rahaman MS, Shanaida M, Lysiuk R, Oliynyk P, Lenchyk L, Chirumbolo S, Chasapis CT, Peana M. Natural Dietary Compounds in the Treatment of Arsenic Toxicity. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27154871. [PMID: 35956821 PMCID: PMC9370003 DOI: 10.3390/molecules27154871] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 12/22/2022]
Abstract
Chronic exposure to arsenic (As) compounds leads to its accumulation in the body, with skin lesions and cancer being the most typical outcomes. Treating As-induced diseases continues to be challenging as there is no specific, safe, and efficacious therapeutic management. Therapeutic and preventive measures available to combat As toxicity refer to chelation therapy, antioxidant therapy, and the intake of natural dietary compounds. Although chelation therapy is the most commonly used method for detoxifying As, it has several side effects resulting in various toxicities such as hepatotoxicity, neurotoxicity, and other adverse consequences. Drugs of plant origin and natural dietary compounds show efficient and progressive relief from As-mediated toxicity without any particular side effects. These natural compounds have also been found to aid the elimination of As from the body and, therefore, can be more effective than conventional therapeutic agents in ameliorating As toxicity. This review provides an overview of the recently updated knowledge on treating As poisoning through natural dietary compounds. This updated information may serve as a basis for defining novel prophylactic and therapeutic formulations.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Toften 24, 8610 Mo i Rana, Norway
- Correspondence: (G.B.); (M.P.)
| | - Md. Shiblur Rahaman
- Department of Environmental and Preventive Medicine, Jichi Medical University School of Medicine, Shimotsuke 329-0498, Japan; or
- Graduate School of Environmental Science, Hokkaido University, Sapporo 060-0810, Japan
| | - Mariia Shanaida
- Department of Pharmacognosy and Medical Botany, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine;
| | - Roman Lysiuk
- Department of Pharmacognosy and Botany, Danylo Halytsky Lviv National Medical University, 79010 Lviv, Ukraine;
- CONEM Ukraine Life Science Research Group, Danylo Halytsky Lviv National Medical University, 79010 Lviv, Ukraine
| | - Petro Oliynyk
- Department of Disaster Medicine and Military Medicine, Danylo Halytsky Lviv National Medical University, 79010 Lviv, Ukraine;
| | - Larysa Lenchyk
- Department of Chemistry of Natural Compounds, National University of Pharmacy, 61002 Kharkiv, Ukraine;
- CONEM Ukraine Pharmacognosy and Natural Product Chemistry Research Group, National University of Pharmacy, 61002 Kharkiv, Ukraine
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy;
- CONEM Scientific Secretary, strada Le Grazie 9, 37134 Verona, Italy
| | - Christos T. Chasapis
- NMR Facility, Instrumental Analysis Laboratory, School of Natural Sciences, University of Patras, 265 04 Patras, Greece;
| | - Massimiliano Peana
- Department of Chemical, Physics, Mathematics and Natural Sciences, University of Sassari, Via Vienna 2, 07100 Sassari, Italy
- Correspondence: (G.B.); (M.P.)
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11
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Guéguen Y, Frerejacques M. Review of Knowledge of Uranium-Induced Kidney Toxicity for the Development of an Adverse Outcome Pathway to Renal Impairment. Int J Mol Sci 2022; 23:ijms23084397. [PMID: 35457214 PMCID: PMC9030063 DOI: 10.3390/ijms23084397] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 02/04/2023] Open
Abstract
An adverse outcome pathway (AOP) is a conceptual construct of causally and sequentially linked events, which occur during exposure to stressors, with an adverse outcome relevant to risk assessment. The development of an AOP is a means of identifying knowledge gaps in order to prioritize research assessing the health risks associated with exposure to physical or chemical stressors. In this paper, a review of knowledge was proposed, examining experimental and epidemiological data, in order to identify relevant key events and potential key event relationships in an AOP for renal impairment, relevant to stressors such as uranium (U). Other stressors may promote similar pathways, and this review is a necessary step to compare and combine knowledge reported for nephrotoxicants. U metal ions are filtered through the glomerular membrane of the kidneys, then concentrate in the cortical and juxtaglomerular areas, and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). The identified key events start with the inhibition of the mitochondria electron transfer chain and the collapse of mitochondrial membrane potential, due to cytochrome b5/cytochrome c disruption. In the nucleus, U directly interacts with negatively charged DNA phosphate, thereby inducing an adduct formation, and possibly DNA strand breaks or cross-links. U also compromises DNA repair by inhibiting zing finger proteins. Thereafter, U triggers the Nrf2, NF-κB, or endoplasmic reticulum stress pathways. The resulting cellular key events include oxidative stress, DNA strand breaks and chromosomal aberrations, apoptosis, and pro-inflammatory effects. Finally, the main adverse outcome is tubular damage of the S2 and S3 segments of the kidneys, leading to tubular cell death, and then kidney failure. The attribution of renal carcinogenesis due to U is controversial, and specific experimental or epidemiological studies must be conducted. A tentative construction of an AOP for uranium-induced kidney toxicity and failure was proposed.
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12
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Dreab A, Bayse CA. Molecular Dynamics Simulations of Reduced and Oxidized TFIIIA Zinc Fingers Free and Interacting with 5S RNA. J Chem Inf Model 2022; 62:903-913. [PMID: 35143196 DOI: 10.1021/acs.jcim.1c01272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Interactions of zinc finger (ZF) proteins with nucleic acids and proteins play an important role in DNA transcription and repair, biochemical recognition, and protein regulation. The release of Zn2+ through oxidation of cysteine thiolates is associated with disruption of gene expression and DNA repair, preventing tumor growth. Multi-microsecond molecular dynamics (MD) simulations were carried out to examine the effect of Cys oxidation on the ZF456 fragment of transcription factor III A (TFIIIA) and its complex with 5S RNA. In the absence of 5S RNA, the reduced ZF456 peptide undergoes conformational changes in the secondary structure due to the reorientation of the intact ZF domains. Upon oxidation, the individual ZF domains unfold to various degrees, yielding a globular ZF456 peptide with ZF4 and ZF6, responsible for base-specific hydrogen bonds with 5S RNA, losing their ββα-folds. ZF5, on the other hand, participates in nonspecific interactions through its α-helix that conditionally unravels early in the simulation. In the presence of RNA, oxidation of the ZF456 peptide disrupts the key hydrogen bonding interactions between ZF5/ZF6 and 5S RNA. However, interactions with ZF4 are dependent on the protonation state of His119.
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Affiliation(s)
- Ana Dreab
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia 23529, United States
| | - Craig A Bayse
- Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, Virginia 23529, United States
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13
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Cooper KL, Volk LB, Dominguez DR, Duran AD, Ke Jian Liu KJ, Hudson LG. Contribution of NADPH oxidase to the retention of UVR-induced DNA damage by arsenic. Toxicol Appl Pharmacol 2022; 434:115799. [PMID: 34798142 PMCID: PMC10115133 DOI: 10.1016/j.taap.2021.115799] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 12/16/2022]
Abstract
Arsenic is a naturally occurring element present in food, soil and water and human exposure is associated with increased cancer risk. Arsenic inhibits DNA repair at low, non-cytotoxic concentrations and amplifies the mutagenic and carcinogenic impact of other DNA-damaging agents, such as ultraviolet radiation (UVR). Arsenic exposure leads to oxidation of zinc coordinating cysteine residues, zinc loss and decreased activity of the DNA repair protein poly(ADP)ribose polymerase (PARP)-1. Because arsenic stimulates NADPH oxidase (NOX) activity leading to generation of reactive oxygen species (ROS), the goal of this study was to investigate the role of NOX in arsenic-induced inhibition of PARP activity and retention of DNA damage. NOX involvement in the arsenic response was assessed in vitro and in vivo. Keratinocytes were treated with or without arsenite, solar-simulated UVR, NOX inhibitors and/or isoform specific NOX siRNA. Knockdown or inhibition of NOX decreased arsenite-induced ROS, PARP-1 oxidation and DNA damage retention, while restoring arsenite inhibition of PARP-1 activity. The NOX2 isoform was determined to be the major contributor to arsenite-induced ROS generation and DNA damage retention. In vivo DNA damage was measured by immunohistochemical staining and analysis of dorsal epidermis sections from C57BI/6 and p91phox knockout (NOX2-/-) mice. There was no significant difference in solar-simulated UVR DNA damage as detected by percent PH2AX positive cells within NOX2-/- mice versus control. In contrast, arsenite-dependent retention of UVR-induced DNA damage was markedly reduced. Altogether, the in vitro and in vivo findings indicate that NOX is involved in arsenic enhancement of UVR-induced DNA damage.
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Affiliation(s)
- Karen L Cooper
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, United States of America
| | - Lindsay B Volk
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, United States of America
| | - Dayna R Dominguez
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, United States of America
| | - Antonia D Duran
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, United States of America; Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH 43210, United States of America
| | - K J Ke Jian Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, United States of America
| | - Laurie G Hudson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, United States of America.
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14
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Vergara-Gerónimo CA, León Del Río A, Rodríguez-Dorantes M, Ostrosky-Wegman P, Salazar AM. Arsenic-protein interactions as a mechanism of arsenic toxicity. Toxicol Appl Pharmacol 2021; 431:115738. [PMID: 34619159 DOI: 10.1016/j.taap.2021.115738] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 12/13/2022]
Abstract
Millions of people worldwide are exposed to arsenic, a metalloid listed as one of the top chemical pollutants of concern to human health. Epidemiological and experimental studies link arsenic exposure to the development of cancer and other diseases. Several mechanisms have been proposed to explain the effects induced by arsenic. Notably, arsenic and its metabolites interact with proteins by direct binding to individual cysteine residues, cysteine clusters, zinc finger motifs, and RING finger domains. Consequently, arsenic interactions with proteins disrupt the functions of proteins and may lead to the development and progression of diseases. In this review, we focus on current evidence in the literature that implicates the interaction of arsenic with proteins as a mechanism of arsenic toxicity. Data show that arsenic-protein interactions affect multiple cellular processes and alter epigenetic regulation, cause endocrine disruption, inhibit DNA damage repair mechanisms, and deregulate gene expression, among other adverse effects.
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Affiliation(s)
- Cristian A Vergara-Gerónimo
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Apartado Postal 70228, Ciudad de México, Mexico
| | - Alfonso León Del Río
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Apartado Postal 70228, Ciudad de México, Mexico
| | | | - Patricia Ostrosky-Wegman
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Apartado Postal 70228, Ciudad de México, Mexico
| | - Ana María Salazar
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Apartado Postal 70228, Ciudad de México, Mexico.
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15
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Zhou X, Speer RM, Volk L, Hudson LG, Liu KJ. Arsenic co-carcinogenesis: Inhibition of DNA repair and interaction with zinc finger proteins. Semin Cancer Biol 2021; 76:86-98. [PMID: 33984503 PMCID: PMC8578584 DOI: 10.1016/j.semcancer.2021.05.009] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 12/17/2022]
Abstract
Arsenic is widely present in the environment and is associated with various population health risks including cancers. Arsenic exposure at environmentally relevant levels enhances the mutagenic effect of other carcinogens such as ultraviolet radiation. Investigation on the molecular mechanisms could inform the prevention and intervention strategies of arsenic carcinogenesis and co-carcinogenesis. Arsenic inhibition of DNA repair has been demonstrated to be an important mechanism, and certain DNA repair proteins have been identified to be extremely sensitive to arsenic exposure. This review will summarize the recent advances in understanding the mechanisms of arsenic carcinogenesis and co-carcinogenesis, including DNA damage induction and ROS generation, particularly how arsenic inhibits DNA repair through an integrated molecular mechanism which includes its interactions with sensitive zinc finger DNA repair proteins.
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Affiliation(s)
- Xixi Zhou
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA
| | - Rachel M Speer
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA
| | - Lindsay Volk
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA
| | - Laurie G Hudson
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
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16
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Cirri D, Bartoli F, Pratesi A, Baglini E, Barresi E, Marzo T. Strategies for the Improvement of Metal-Based Chemotherapeutic Treatments. Biomedicines 2021; 9:504. [PMID: 34064364 PMCID: PMC8147839 DOI: 10.3390/biomedicines9050504] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/29/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022] Open
Abstract
This article provides an overview of the various research approaches we have explored in recent years to improve metal-based agents for cancer or infection treatments. Although cisplatin, carboplatin, and oxaliplatin remain the cornerstones in tumor chemotherapy, the discovery and approval of novel inorganic anticancer drugs is a very slow process. Analogously, although a few promising inorganic drugs have found clinical application against parasitic or bacterial infections, their use remains relatively limited. Moreover, the discovery process is often affected by small therapeutic enhancements that are not attractive for the pharmaceutical industry. However, the availability of increasing mechanistic information for the modes of action of established inorganic drugs is fueling the exploration of various approaches for developing effective inorganic chemotherapy agents. Through a series of examples, some from our own research experience, we focus our attention on a number of promising strategies, including (1) drug repurposing, (2) the simple modification of the chemical structures of approved metal-based drugs, (3) testing novel drug combinations, and (4) newly synthesized complexes coupling different anticancer drugs. Accordingly, we aim to suggest and summarize a series of reliable approaches that are exploitable for the development of improved and innovative treatments.
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Affiliation(s)
- Damiano Cirri
- Department of Chemistry and Industrial Chemistry (DCCI), Univerisity of Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy;
| | - Francesco Bartoli
- Department of Translational Research and of New Surgical and Medical Technologies, Univerisity of Pisa, Via Risorgimento, 36, 56126 Pisa, Italy;
| | - Alessandro Pratesi
- Department of Chemistry and Industrial Chemistry (DCCI), Univerisity of Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy;
| | - Emma Baglini
- Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy; (E.B.); (E.B.)
| | - Elisabetta Barresi
- Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy; (E.B.); (E.B.)
| | - Tiziano Marzo
- Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy; (E.B.); (E.B.)
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17
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Kung WM, Lin MS. The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases. Int J Mol Sci 2021; 22:934. [PMID: 33477809 PMCID: PMC7832822 DOI: 10.3390/ijms22020934] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/01/2021] [Accepted: 01/12/2021] [Indexed: 02/07/2023] Open
Abstract
Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.
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Affiliation(s)
- Woon-Man Kung
- Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei 11114, Taiwan;
| | - Muh-Shi Lin
- Division of Neurosurgery, Department of Surgery, Kuang Tien General Hospital, Taichung 43303, Taiwan
- Department of Biotechnology and Animal Science, College of Bioresources, National Ilan University, Yilan 26047, Taiwan
- Department of Biotechnology, College of Medical and Health Care, Hung Kuang University, Taichung 43302, Taiwan
- Department of Health Business Administration, College of Medical and Health Care, Hung Kuang University, Taichung 43302, Taiwan
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18
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Medina S, Zhou X, Lauer FT, Zhang H, Liu KJ, Lewis J, Burchiel SW. Modulation of PARP activity by Monomethylarsonous (MMA +3) acid and uranium in mouse thymus. Toxicol Appl Pharmacol 2021; 411:115362. [PMID: 33279514 PMCID: PMC7855914 DOI: 10.1016/j.taap.2020.115362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/02/2020] [Accepted: 12/01/2020] [Indexed: 01/01/2023]
Abstract
Arsenic exposure is well established to impair the function of zinc finger proteins, including PARP-1. Previous studies from our lab show that early developing T cells in the thymus are very sensitive to arsenite (As+3)-induced genotoxicity mediated through PARP-1 inhibition. Additionally, it has been shown that uranium (in the form of uranyl acetate, UA) also suppresses PARP-1 activity in HEK cells. However, very little is known about whether the As+3 metabolite, monomethylarsonous acid (MMA+3), also inhibits PARP-1 activity and if this is modified by combined exposures with other metals, such as uranium. In the present study, we found that MMA+3 significantly suppressed PARP-1 function, whereas UA at high concentrations significantly increased PARP-1 activity. To evaluate whether the effects on PARP-1 activity were mediated through oxidative stress, we measured the induction of hemoxygenase-1 (Hmox-1) expression by qPCR. MMA+3, but not UA, significantly induced oxidative stress; however, the inhibition of PARP-1 produced by MMA+3 was not reversed by the addition of the antioxidant, Tempol. Further evaluation revealed minimal interactive effects of MMA+3 and UA on PARP-1 function. Collectively, our results show that contrary to As+3, the suppressive effects of MMA+3 on PARP-1 were not substantially driven by oxidative stress. in mouse thymus cells. Results for this study provide important insights into the effects of MMA+3 and uranium exposures on PARP-1 function, which is essential for future studies focused on understanding the effects of complex environmentally relevant metal mixtures.
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Affiliation(s)
- Sebastian Medina
- Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM, USA; Department of Biology, New Mexico Highlands University, Las Vegas, NM, USA
| | - Xixi Zhou
- Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Fredine T Lauer
- Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Haikun Zhang
- Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Johnnye Lewis
- Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Scott W Burchiel
- Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM, USA.
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19
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Zhou X, Xue B, Medina S, Burchiel SW, Liu KJ. Uranium directly interacts with the DNA repair protein poly (ADP-ribose) polymerase 1. Toxicol Appl Pharmacol 2020; 410:115360. [PMID: 33279515 DOI: 10.1016/j.taap.2020.115360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 11/25/2020] [Accepted: 11/28/2020] [Indexed: 11/26/2022]
Abstract
People living in southwest part of United States are exposed to uranium (U) through drinking water, air, and soil. U is radioactive, but independent of this radioactivity also has important toxicological considerations as an environmental metal. At environmentally relevant concentrations, U is both mutagenic and carcinogenic. Emerging evidence shows that U inhibits DNA repair activity, but how U interacts with DNA repair proteins is still largely unknown. Herein, we report that U directly interacts with the DNA repair protein, Protein Poly (ADP-ribose) Polymerase 1 (PARP-1) through direct binding with the zinc finger motif, resulting in zinc release from zinc finger and DNA binding activity loss of the protein. At the peptide level, instead of direct competition with zinc ion in the zinc finger motif, U does not show thermodynamic advantages over zinc. Furthermore, zinc pre-occupied PARP-1 zinc finger is insensitive to U treatment, but U bound to PARP-1 zinc finger can be partially replaced by zinc. These results provide mechanistic basis on molecular level to U inhibition of DNA repair.
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Affiliation(s)
- Xixi Zhou
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Bingye Xue
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Sebastian Medina
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, USA; New Mexico Highlands University, Department of Biology, Las Vegas, NM 87701, United States
| | - Scott W Burchiel
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, USA
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, USA.
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20
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Zhou X, Medina S, Bolt AM, Zhang H, Wan G, Xu H, Lauer FT, Wang SC, Burchiel SW, Liu KJ. Inhibition of red blood cell development by arsenic-induced disruption of GATA-1. Sci Rep 2020; 10:19055. [PMID: 33149232 PMCID: PMC7643154 DOI: 10.1038/s41598-020-76118-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 10/21/2020] [Indexed: 01/16/2023] Open
Abstract
Anemia is a hematological disorder that adversely affects the health of millions of people worldwide. Although many variables influence the development and exacerbation of anemia, one major contributing factor is the impairment of erythropoiesis. Normal erythropoiesis is highly regulated by the zinc finger transcription factor GATA-1. Disruption of the zinc finger motifs in GATA-1, such as produced by germline mutations, compromises the function of this critical transcription factor and causes dyserythropoietic anemia. Herein, we utilize a combination of in vitro and in vivo studies to provide evidence that arsenic, a widespread environmental toxicant, inhibits erythropoiesis likely through replacing zinc within the zinc fingers of the critical transcription factor GATA-1. We found that arsenic interacts with the N- and C-terminal zinc finger motifs of GATA-1, causing zinc loss and inhibition of DNA and protein binding activities, leading to dyserythropoiesis and an imbalance of hematopoietic differentiation. For the first time, we show that exposures to a prevalent environmental contaminant compromises the function of a key regulatory factor in erythropoiesis, producing effects functionally similar to inherited GATA-1 mutations. These findings highlight a novel molecular mechanism by which arsenic exposure may cause anemia and provide critical insights into potential prevention and intervention for arsenic-related anemias.
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Affiliation(s)
- Xixi Zhou
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA
| | - Sebastian Medina
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA
- Department of Biology, New Mexico Highlands University, Las Vegas, NM, 87701, USA
| | - Alicia M Bolt
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA
| | - Haikun Zhang
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA
| | - Guanghua Wan
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA
| | - Huan Xu
- School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Fredine T Lauer
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA
| | - Shu Chun Wang
- Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China
| | - Scott W Burchiel
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM, 87131, USA.
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21
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Dashner-Titus EJ, Schilz JR, Simmons KA, Duncan TR, Alvarez SC, Hudson LG. Differential response of human T-lymphocytes to arsenic and uranium. Toxicol Lett 2020; 333:269-278. [PMID: 32866568 PMCID: PMC7590629 DOI: 10.1016/j.toxlet.2020.08.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 07/01/2020] [Accepted: 08/23/2020] [Indexed: 01/10/2023]
Abstract
Elevated levels of arsenic and uranium have been detected in water sources near abandoned uranium mines in the Southwest. Evidence suggests uranium exposure increases the likelihood of immune dysfunction and this study investigates the impact of arsenic and uranium on human immune cell lines. Concentration-dependent cytotoxicity occurred following exposure to arsenite, whereas cells remained viable after 48 -h treatment with up to 100 μM uranyl acetate despite uptake of uranium into cells. Arsenite stimulated an oxidative stress response as detected by Nrf-2 nuclear accumulation and induction of HMOX-1 and NQO1, which was not detected with up to 30 μM uranyl acetate. Cellular oxidative stress can promote DNA damage and arsenite, but not uranium, stimulated DNA damage as measured by pH2AX. Arsenic enhanced the cytotoxic response to etoposide suggesting an inhibition of DNA repair, unlike uranium. Similarly, uranium did not inhibit PARP-1 activity. Because uranium reportedly stimulates oxidative stress, DNA damage and cytotoxicity in adherent epithelial cells, the current study suggests distinct cell type differences in response to uranium that may relate to generation of oxidative stress and associated downstream consequences. Delineating the actions of uranium across different cell targets will be important for understanding the potential health effects of uranium exposures.
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Affiliation(s)
- Erica J Dashner-Titus
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM, United States.
| | - Jodi R Schilz
- Division of Physical Therapy, School of Medicine, University of New Mexico, 1 University of New Mexico, Albuquerque, NM, United States.
| | - Karen A Simmons
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM, United States.
| | - Tammi R Duncan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM, United States.
| | - Sandra C Alvarez
- Early Childhood Services Center, University of New Mexico, 1 University of New Mexico, Albuquerque, NM, United States.
| | - Laurie G Hudson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, 1 University of New Mexico, Albuquerque, NM, United States.
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22
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Gao L, Xue B, Xiang B, Liu KJ. Arsenic trioxide disturbs the LIS1/NDEL1/dynein microtubule dynamic complex by disrupting the CLIP170 zinc finger in head and neck cancer. Toxicol Appl Pharmacol 2020; 403:115158. [PMID: 32717241 PMCID: PMC8080511 DOI: 10.1016/j.taap.2020.115158] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/12/2020] [Accepted: 07/21/2020] [Indexed: 12/17/2022]
Abstract
Cancer mortality is mainly caused by metastasis, which requires dynamic remodeling of cytoskeletal components such as microtubules. Targeting microtubules presents a promising antimetastatic strategy that could prevent cancer spreading and recurrence. It is known that arsenic trioxide (ATO) is able to inhibit the migration and invasion of solid malignant tumors, but its exact molecular mechanism remains unclear. Here, we report a novel molecular target and antimetastatic mechanism of ATO in head and neck squamous cell carcinoma (HNSCC). We found that cytoplasmic linker protein 170 (CLIP170) was overexpressed in HNSCC tissues and cells compared to normal controls. ATO at non-cytotoxic level (1 μM) inhibited the migration and invasion of HNSCC cells by displacing zinc in the zinc finger motif of CLIP170, which is a key protein that controls microtubule dynamics. The antimetastatic effects of ATO were equivalent to those of siRNA-mediated CLIP170 knockdown. Furthermore, ATO dysregulated microtubule polymerization via the CLIP170/LIS1/NDEL1/dynein signaling pathway in Cal27 cells as a functional consequence of CLIP170 zinc finger disruption. The effect was partially reversed by zinc supplementation. Taken together, these findings reveal that CLIP170 is a novel molecular target of ATO and demonstrate the capability and underlying mechanisms of ATO as a potential antimetastatic agent for HNSCC treatment.
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Affiliation(s)
- Lu Gao
- Laboratory of Oral and Maxillofacial Disease, Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA; Department of Oral Anatomy, School of Stomatology, Dalian Medical University, Dalian, Liaoning 116044, China
| | - Bingye Xue
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA
| | - Bin Xiang
- Laboratory of Oral and Maxillofacial Disease, Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, China.
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA.
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23
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Teratani T, Tomita K, Toma-Fukai S, Nakamura Y, Itoh T, Shimizu H, Shiraishi Y, Sugihara N, Higashiyama M, Shimizu T, Inoue I, Takenaka Y, Hokari R, Adachi T, Shimizu T, Miura S, Kanai T. Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling. Free Radic Biol Med 2020; 156:45-56. [PMID: 32553752 DOI: 10.1016/j.freeradbiomed.2020.06.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/30/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023]
Abstract
The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPARγ plays an important role in PPARγ signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPARγ2 translocates to the nucleus and activates signal transduction through H2O2-dependent formation of a PPARγ2 and transportin (Tnpo)1 complex via redox-sensitive disulfide bonds between cysteine (Cys)176 and Cys180 of the former and Cys512 of the latter. Using hepatocyte cultures and mouse models, we show that cytosolic H2O2/Tnpo1-dependent nuclear translocation enhances the amount of DNA-bound PPARγ and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPARγ, and suggest that the PPARγ and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPARγ-related diseases.
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Affiliation(s)
- Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kengo Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan.
| | - Sachiko Toma-Fukai
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Complex Molecular Systems Laboratory, Nara Institute of Science and Technology, Takayama-cho, Ikoma-shi, Nara, 630-0192, Japan
| | - Yutaro Nakamura
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Toshimasa Itoh
- Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan
| | - Hikaru Shimizu
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yasunaga Shiraishi
- Division of Environmental Medicine, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan
| | - Nao Sugihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan
| | - Masaaki Higashiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan
| | - Takahiko Shimizu
- Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Ikuo Inoue
- Department of Endocrinology and Diabetes, Saitama Medical University, Moroyama, 350-0495, Japan
| | - Yasuhiro Takenaka
- Department of Endocrinology and Diabetes, Saitama Medical University, Moroyama, 350-0495, Japan; Department of Physiology, Graduate School of Medicine, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-8602, Japan
| | - Ryota Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan
| | - Takeshi Adachi
- Division of Cardiology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan
| | - Toshiyuki Shimizu
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Soichiro Miura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama, 359-8513, Japan; International University of Health and Welfare Graduate School, 1-24-1 Minami-Aoyama, Minato-ku, Tokyo, 107-0062, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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24
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Burchiel SW, Lauer FT, Factor-Litvak P, Liu X, Islam T, Eunus M, Abu Horayara M, Islam MT, Rahman M, Ahmed A, Cremers S, Nandakumar R, Ahsan H, Olopade C, Graziano J, Parvez F. Arsenic exposure associated T cell proliferation, smoking, and vitamin D in Bangladeshi men and women. PLoS One 2020; 15:e0234965. [PMID: 32574193 PMCID: PMC7310686 DOI: 10.1371/journal.pone.0234965] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/06/2020] [Indexed: 01/02/2023] Open
Abstract
There are limited data examining the consequences of environmental exposure to arsenic on the immune system in adults, particularly among smokers. Smoking has been shown to exacerbate or contribute to impaired immune function in men chronically exposed to arsenic. In contrast, vitamin D (VitD) is known to have a positive influence on innate and adaptive immune responses. The effect of circulating VitD on arsenic-associated immune dysfunction is not known. Here we examine the relationship of arsenic exposure and T cell proliferation (TCP), a measure of immune responsiveness, and circulating VitD among adult men and women in Bangladesh. Arsenic exposure was assessed using total urinary arsenic as well as urinary arsenic metabolites all adjusted for urinary creatinine. TCP was measured ex vivo in cryopreserved peripheral blood mononuclear cells from 614 adult participants enrolled in the Bangladesh Health Effects of Arsenic Longitudinal Study; serum VitD was also evaluated. The influence of cigarette smoking on arsenic-induced TCP modulation was assessed only in males as there was an inadequate number of female smokers. These studies show that arsenic suppressed TCP in males. The association was significantly strong in male smokers and to a lesser extent in male non-smokers. Interestingly, we found a strong protective effect of high/sufficient serum VitD levels on TCP among non-smoking males. Furthermore, among male smokers with low serum VitD (⊔20 ng/ml), we found a strong suppression of TCP by arsenic. On the other hand, high VitD (>20 ng/ml) was found to attenuate effects of arsenic on TCP among male-smokers. Overall, we found a strong protective effect of VitD, when serum levels were >20 ng/ml, on arsenic-induced inhibition of TCP in men, irrespective of smoking status. To our knowledge this is the first large study of immune function in healthy adult males and females with a history of chronic arsenic exposure.
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Affiliation(s)
- Scott W. Burchiel
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States of America
| | - Fredine T. Lauer
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States of America
| | - Pam Factor-Litvak
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States of America
| | - Xinhua Liu
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States of America
| | - Tariqul Islam
- University of Chicago and Columbia University Field Research Office, Dhaka, Bangladesh
| | - Mahbubul Eunus
- University of Chicago and Columbia University Field Research Office, Dhaka, Bangladesh
| | - M. Abu Horayara
- University of Chicago and Columbia University Field Research Office, Dhaka, Bangladesh
| | - Md. Tariqul Islam
- University of Chicago and Columbia University Field Research Office, Dhaka, Bangladesh
| | - Mizanour Rahman
- University of Chicago and Columbia University Field Research Office, Dhaka, Bangladesh
| | - Alauddin Ahmed
- University of Chicago and Columbia University Field Research Office, Dhaka, Bangladesh
| | - Serge Cremers
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States of America
| | - Renu Nandakumar
- Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, United States of America
| | - Habibul Ahsan
- Department of Health Studies, University of Chicago, Chicago, IL, United States of America
| | - Christopher Olopade
- University of Chicago Medical Center, University of Chicago, Chicago, IL, United States of America
| | - Joseph Graziano
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States of America
| | - Faruque Parvez
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States of America
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25
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Douki T. Oxidative Stress and Genotoxicity in Melanoma Induction: Impact on Repair Rather Than Formation of DNA Damage? Photochem Photobiol 2020; 96:962-972. [PMID: 32367509 DOI: 10.1111/php.13278] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/21/2020] [Indexed: 12/22/2022]
Abstract
Keratinocytes and melanocytes, two cutaneous cell types located within the epidermis, are the origin of most skin cancers, namely carcinomas and melanomas. These two types of tumors differ in many ways. First, carcinomas are almost 10 times more frequent than melanomas. In addition, the affected cellular pathways, the mutated genes and the metastatic properties of the tumors are not the same. This review addresses another specificity of melanomas: the role of photo-oxidative stress. UVA efficiently produces reactive oxygen species in melanocytes, which results in more frequent oxidatively generated DNA lesions than in other cell types. The question of the respective contribution of UVB-induced pyrimidine dimers and UVA-mediated oxidatively generated lesions to mutagenesis in melanoma remains open. Recent results based on next-generation sequencing techniques strongly suggest that the mutational signature associated with pyrimidine dimers is overwhelming in melanomas like in skin carcinomas. UVA-induced oxidative stress may yet be indirectly linked to the genotoxic pathways involved in melanoma through its ability to hamper DNA repair activities.
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Affiliation(s)
- Thierry Douki
- Université Grenoble Alpes, CEA, CNRS, IRIG, SyMMES, Grenoble, France
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26
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Shytaj IL, Lucic B, Forcato M, Penzo C, Billingsley J, Laketa V, Bosinger S, Stanic M, Gregoretti F, Antonelli L, Oliva G, Frese CK, Trifunovic A, Galy B, Eibl C, Silvestri G, Bicciato S, Savarino A, Lusic M. Alterations of redox and iron metabolism accompany the development of HIV latency. EMBO J 2020; 39:e102209. [PMID: 32157726 PMCID: PMC7196916 DOI: 10.15252/embj.2019102209] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 12/19/2022] Open
Abstract
HIV-1 persists in a latent form during antiretroviral therapy, mainly in CD4+ T cells, thus hampering efforts for a cure. HIV-1 infection is accompanied by metabolic alterations, such as oxidative stress, but the effect of cellular antioxidant responses on viral replication and latency is unknown. Here, we show that cells survive retroviral replication, both in vitro and in vivo in SIVmac-infected macaques, by upregulating antioxidant pathways and the intertwined iron import pathway. These changes are associated with remodeling of promyelocytic leukemia protein nuclear bodies (PML NBs), an important constituent of nuclear architecture and a marker of HIV-1 latency. We found that PML NBs are hyper-SUMOylated and that PML protein is degraded via the ubiquitin-proteasome pathway in productively infected cells, before latency establishment and after reactivation. Conversely, normal numbers of PML NBs were restored upon transition to latency or by decreasing oxidative stress or iron content. Our results highlight antioxidant and iron import pathways as determinants of HIV-1 latency and support their pharmacologic inhibition as tools to regulate PML stability and impair latency establishment.
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Affiliation(s)
- Iart Luca Shytaj
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Bojana Lucic
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Mattia Forcato
- Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
| | | | - James Billingsley
- Division of Microbiology and ImmunologyYerkes National Primate Research CenterEmory UniversityAtlantaGAUSA
| | - Vibor Laketa
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
| | - Steven Bosinger
- Division of Microbiology and ImmunologyYerkes National Primate Research CenterEmory UniversityAtlantaGAUSA
- Department of Pathology and Laboratory MedicineEmory UniversityAtlantaGAUSA
| | - Mia Stanic
- Heidelberg University HospitalHeidelbergGermany
| | | | - Laura Antonelli
- Institute for High Performance Computing and NetworkingICAR‐CNRNaplesItaly
| | - Gennaro Oliva
- Institute for High Performance Computing and NetworkingICAR‐CNRNaplesItaly
| | | | | | - Bruno Galy
- Division of Virus‐Associated CarcinogenesisGerman Cancer Research CentreHeidelbergGermany
| | - Clarissa Eibl
- Leibniz‐Forschungsinstitut für Molekulare PharmakologieBerlinGermany
- Institute of BiologyCellular BiophysicsHumboldt Universität zu BerlinBerlinGermany
| | - Guido Silvestri
- Division of Microbiology and ImmunologyYerkes National Primate Research CenterEmory UniversityAtlantaGAUSA
- Department of Pathology and Laboratory MedicineEmory UniversityAtlantaGAUSA
| | - Silvio Bicciato
- Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
| | | | - Marina Lusic
- Heidelberg University HospitalHeidelbergGermany
- German Center for Infection ResearchHeidelbergGermany
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27
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Banerjee M, Ferragut Cardoso AP, Lykoudi A, Wilkey DW, Pan J, Watson WH, Garbett NC, Rai SN, Merchant ML, States JC. Arsenite Exposure Displaces Zinc from ZRANB2 Leading to Altered Splicing. Chem Res Toxicol 2020; 33:1403-1417. [PMID: 32274925 DOI: 10.1021/acs.chemrestox.9b00515] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Exposure to arsenic, a class I carcinogen, affects 200 million people globally. Skin is the major target organ, but the molecular etiology of arsenic-induced skin carcinogenesis remains unclear. Arsenite (As3+)-induced disruption of alternative splicing could be involved, but the mechanism is unknown. Zinc finger proteins play key roles in alternative splicing. As3+ can displace zinc (Zn2+) from C3H1 and C4 zinc finger motifs (zfm's), affecting protein function. ZRANB2, an alternative splicing regulator with two C4 zfm's integral to its structure and splicing function, was chosen as a candidate for this study. We hypothesized that As3+ could displace Zn2+ from ZRANB2, altering its structure, expression, and splicing function. As3+/Zn2+ binding and mutual displacement experiments were performed with synthetic apo-peptides corresponding to each ZRANB2 zfm, employing a combination of intrinsic fluorescence, ultraviolet spectrophotometry, zinc colorimetric assay, and liquid chromatography-tandem mass spectrometry. ZRANB2 expression in HaCaT cells acutely exposed to As3+ (0 or 5 μM, 0-72 h; or 0-5 μM, 6 h) was examined by RT-qPCR and immunoblotting. ZRANB2-dependent splicing of TRA2B mRNA, a known ZRANB2 target, was monitored by reverse transcription-polymerase chain reaction. As3+ bound to, as well as displaced Zn2+ from, each zfm. Also, Zn2+ displaced As3+ from As3+-bound zfm's acutely, albeit transiently. As3+ exposure induced ZRANB2 protein expression between 3 and 24 h and at all exposures tested but not ZRANB2 mRNA expression. ZRANB2-directed TRA2B splicing was impaired between 3 and 24 h post-exposure. Furthermore, ZRANB2 splicing function was also compromised at all As3+ exposures, starting at 100 nm. We conclude that As3+ exposure displaces Zn2+ from ZRANB2 zfm's, changing its structure and compromising splicing of its targets, and increases ZRANB2 protein expression as a homeostatic response both at environmental/toxicological exposures and therapeutically relevant doses.
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Affiliation(s)
- Mayukh Banerjee
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, United States
| | - Ana P Ferragut Cardoso
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, United States
| | - Angeliki Lykoudi
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, United States
| | - Daniel W Wilkey
- Division of Nephrology & Hypertension, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, United States
| | - Jianmin Pan
- Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, United States
| | - Walter H Watson
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, United States.,Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, United States
| | - Nichola C Garbett
- Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, United States.,James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, United States
| | - Shesh N Rai
- Biostatistics and Bioinformatics Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, United States.,Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, Kentucky 40202, United States
| | - Michael L Merchant
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, United States.,Division of Nephrology & Hypertension, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, United States
| | - J Christopher States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, United States
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28
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Abstract
Exposure to arsenic in contaminated drinking water is an emerging public health problem that impacts more than 200 million people worldwide. Accumulating lines of evidence from epidemiological studies revealed that chronic exposure to arsenic can result in various human diseases including cancer, type 2 diabetes, and neurodegenerative disorders. Arsenic is also classified as a Group I human carcinogen. In this review, we survey extensively different modes of action for arsenic-induced carcinogenesis, with focus being placed on arsenic-mediated impairment of DNA repair pathways. Inorganic arsenic can be bioactivated by methylation, and the ensuing products are highly genotoxic. Bioactivation of arsenicals also elicits the production of reactive oxygen and nitrogen species (ROS and RNS), which can directly damage DNA and modify cysteine residues in proteins. Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.
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29
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Kumar N, Moreno NC, Feltes BC, Menck CF, Houten BV. Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins. Genet Mol Biol 2020; 43:e20190104. [PMID: 32141475 PMCID: PMC7198027 DOI: 10.1590/1678-4685-gmb-2019-0104] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 08/25/2019] [Indexed: 02/06/2023] Open
Abstract
Base and nucleotide excision repair (BER and NER) pathways are normally associated with removal of specific types of DNA damage: small base modifications (such as those induced by DNA oxidation) and bulky DNA lesions (such as those induced by ultraviolet or chemical carcinogens), respectively. However, growing evidence indicates that this scenario is much more complex and these pathways exchange proteins and cooperate with each other in the repair of specific lesions. In this review, we highlight studies discussing the involvement of NER in the repair of DNA damage induced by oxidative stress, and BER participating in the removal of bulky adducts on DNA. Adding to this complexity, UVA light experiments revealed that oxidative stress also causes protein oxidation, directly affecting proteins involved in both NER and BER. This reduces the cell’s ability to repair DNA damage with deleterious implications to the cells, such as mutagenesis and cell death, and to the organisms, such as cancer and aging. Finally, an interactome of NER and BER proteins is presented, showing the strong connection between these pathways, indicating that further investigation may reveal new functions shared by them, and their cooperation in maintaining genome stability.
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Affiliation(s)
- Namrata Kumar
- University of Pittsburgh, School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA, USA.,University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Natália C Moreno
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, SP, Brazil
| | - Bruno C Feltes
- Universidade Federal do Rio Grande do Sul, Instituto de Informática, Porto Alegre, RS, Brazil
| | - Carlos Fm Menck
- Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Microbiologia, São Paulo, SP, Brazil
| | - Bennett Van Houten
- University of Pittsburgh, School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA, USA.,University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, Pittsburgh, PA, USA
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30
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Peroxynitrite contributes to arsenic-induced PARP-1 inhibition through ROS/RNS generation. Toxicol Appl Pharmacol 2019; 378:114602. [PMID: 31152818 DOI: 10.1016/j.taap.2019.114602] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 01/14/2023]
Abstract
Arsenic, in the trivalent form (AsIII), is a human co-carcinogen reported to enhance mutagenesis effects of other carcinogens such as UV radiation by inhibiting DNA repair. The zinc finger DNA repair protein Poly (ADP-ribose) polymerase 1 (PARP-1) is a sensitive target of AsIII and both reactive oxygen and nitrogen species (ROS/RNS) generated by AsIII contribute to PARP-1 inhibition. However, the mechanisms of ROS/RNS-mediated PARP inhibition and how AsIII-generated ROS/RNS may be interconnected are still unclear. In this study, we found AsIII exposure of normal human keratinocyte (HEKn) cells generated peroxynitrite through superoxide and nitric oxide production in an AsIII concentration dependent manner. Peroxynitrite inhibited PARP-1 activity and caused zinc loss from PARP-1 protein while scavenging peroxynitrite was protective of the impacts on PARP-1. We identified peroxynitrite was responsible for S-nitrosation on cysteine residues resulting in PARP-1 zinc finger conformational changes. Taken together, the evidence indicates AsIII generates peroxynitrite through superoxide and nitric oxide production, induces S-nitrosation on PARP-1, leading to zinc loss and activity inhibition of PARP-1, thus enhancing DNA damage caused by UV radiation. These findings highlight a role for peroxynitrite as a key molecule of ROS/RNS mediated DNA repair inhibition by AsIII which should inform the development of prevention and intervention strategies against AsIII co-carcinogenesis.
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31
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Miodragović Đ, Merlino A, Swindell EP, Bogachkov A, Ahn RW, Abuhadba S, Ferraro G, Marzo T, Mazar AP, Messori L, O’Halloran TV. Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent. J Am Chem Soc 2019; 141:6453-6457. [PMID: 30943017 PMCID: PMC6830503 DOI: 10.1021/jacs.8b13681] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(μ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules-proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nε of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
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Affiliation(s)
- Đenana Miodragović
- Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois
60208, United States
- Northeastern Illinois University, 5500 North St Louis Avenue, Chicago, Illinois 60625, United
States
| | - Antonello Merlino
- Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario di Monte
Sant’Angelo, Via Cintia, I-80126 Napoli, Italy
| | - Elden P. Swindell
- Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois
60208, United States
| | - Abraham Bogachkov
- Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois
60208, United States
| | - Richard W. Ahn
- Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois
60208, United States
| | - Sara Abuhadba
- Northeastern Illinois University, 5500 North St Louis Avenue, Chicago, Illinois 60625, United
States
| | - Giarita Ferraro
- Department of Chemistry “Ugo Schiff”, Università degli Studi Firenze, via della
Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
| | - Tiziano Marzo
- Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy
| | - Andrew P. Mazar
- Pharmacology, Feinberg School of Medicine, Northwestern University, 2145 Sheridan Road, Evanston,
Illinois 60208, United States
| | - Luigi Messori
- Department of Chemistry “Ugo Schiff”, Università degli Studi Firenze, via della
Lastruccia 3-13, 50019 Sesto Fiorentino, Italy
| | - Thomas V. O’Halloran
- Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois
60208, United States
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Sun W, Dai L, Yu H, Puspita B, Zhao T, Li F, Tan JL, Lim YT, Chen MW, Sobota RM, Tenen DG, Prabhu N, Nordlund P. Monitoring structural modulation of redox-sensitive proteins in cells with MS-CETSA. Redox Biol 2019; 24:101168. [PMID: 30925293 PMCID: PMC6439307 DOI: 10.1016/j.redox.2019.101168] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/07/2019] [Accepted: 03/10/2019] [Indexed: 12/31/2022] Open
Abstract
Reactive oxygen species (ROS) induce different cellular stress responses but can also mediate cellular signaling. Augmented levels of ROS are associated with aging, cancer as well as various metabolic and neurological disorders. ROS can also affect the efficacy and adverse effects of drugs. Although proteins are key mediators of most ROS effects, direct studies of ROS-modulated-protein function in the cellular context are very challenging. Therefore the understanding of specific roles of different proteins in cellular ROS responses is still relatively rudimentary. In the present work we show that Mass Spectrometry-Cellular Thermal Shift Assay (MS-CETSA) can directly monitor ROS and redox modulations of protein structure at the proteome level. By altering ROS levels in cultured human hepatocellular carcinoma cell lysates and intact cells, we detected CETSA responses in many proteins known to be redox sensitive, and also revealed novel candidate ROS sensitive proteins. Studies in intact cells treated with hydrogen peroxide and sulfasalazine, a ROS modulating drug, identified not only proteins that are directly modified, but also proteins reporting on downstream cellular effects. Comprehensive changes are seen on rate-limiting proteins regulating key cellular processes, including known redox control systems, protein degradation, epigenetic control and protein translational processes. Interestingly, concerted shifts on ATP-binding proteins revealed redox-induced modulation of ATP levels, which likely control many cellular processes. Collectively, these studies establish CETSA as a novel method for cellular studies of redox modulations of proteins, which implicated in a wide range of processes and for the discovery of CETSA-based biomarkers reporting on the efficacy as well as adverse effects of drugs.
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Affiliation(s)
- Wendi Sun
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | - Lingyun Dai
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | - Han Yu
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | - Brenda Puspita
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | - Tianyun Zhao
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | - Feng Li
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Justin L Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Genome Institute of Singapore, A*STAR, 138672, Singapore
| | - Yan Ting Lim
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | - Ming Wei Chen
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | | | - Daniel G Tenen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Nayana Prabhu
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
| | - Pär Nordlund
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore; Institute of Molecular and Cell Biology, A*STAR, 138673, Singapore; Department of Oncology and Pathology, Karolinska Institutet, Stockholm, 17177, Sweden.
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33
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Alnajjar KS, Sweasy JB. A new perspective on oxidation of DNA repair proteins and cancer. DNA Repair (Amst) 2019; 76:60-69. [PMID: 30818170 DOI: 10.1016/j.dnarep.2019.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/07/2019] [Indexed: 02/07/2023]
Abstract
Reactive oxygen and nitrogen species (RONS) are formed as byproducts of many endogenous cellular processes, in response to infections, and upon exposure to various environmental factors. An increase in RONS can saturate the antioxidation system and leads to oxidative stress. Consequently, macromolecules are targeted for oxidative modifications, including DNA and protein. The oxidation of DNA, which leads to base modification and formation of abasic sites along with single and double strand breaks, has been extensively investigated. Protein oxidation is often neglected and is only recently being recognized as an important regulatory mechanism of various DNA repair proteins. This is a review of the current state of research on the regulation of DNA repair by protein oxidation with emphasis on the correlation between inflammation and cancer.
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Affiliation(s)
- Khadijeh S Alnajjar
- Department of Therapeutic Radiology and Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, United States.
| | - Joann B Sweasy
- Department of Therapeutic Radiology and Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, United States
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34
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Qi Z, Liu KJ. The interaction of zinc and the blood-brain barrier under physiological and ischemic conditions. Toxicol Appl Pharmacol 2019; 364:114-119. [PMID: 30594689 PMCID: PMC6331270 DOI: 10.1016/j.taap.2018.12.018] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 12/02/2018] [Accepted: 12/25/2018] [Indexed: 12/30/2022]
Abstract
Zinc is the second most abundant metal in human and serves as an essential trace element in the body. During the past decades, zinc has been found to play important roles in central nervous system, such as the development of neurons and synaptic activities. An imbalance of zinc is associated with brain diseases. The blood-brain barrier (BBB) maintains the homeostasis of the microenvironment, regulating the balance of zinc in the brain. A compromised BBB is the main cause of severe complications in cerebral ischemic patients, such as hemorrhage transformation, inflammation and edema. Recent studies reported that zinc in the brain may be a potential target for integrative protection against ischemic brain injury. Although zinc has long been regarded as important transmitters in central nervous system, the critical role of zinc dyshomeostasis in damage to the BBB has not been fully recognized. In this review, we summarize the role of the BBB in regulating homeostasis of zinc in physiological conditions and the effects of changes in zinc levels on the permeability of the BBB in cerebral ischemia. The integrity of BBB maintains the homeostasis of zinc in pathological conditions, while the balance of zinc in the brain and the circulation maintains the normal function of the BBB. Interrupting the zinc/BBB system will disturb the microenvironment in the brain, leading to pathological diseases. In stroke patients, zinc may serve as a potential target for protecting the BBB and reducing hemorrhage transformation, inflammation and edema.
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Affiliation(s)
- Zhifeng Qi
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Ke Jian Liu
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
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35
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Ramrath DJF, Niemann M, Leibundgut M, Bieri P, Prange C, Horn EK, Leitner A, Boehringer D, Schneider A, Ban N. Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes. Science 2018; 362:science.aau7735. [PMID: 30213880 DOI: 10.1126/science.aau7735] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 09/03/2018] [Indexed: 01/19/2023]
Abstract
Ribosomal RNA (rRNA) plays key functional and architectural roles in ribosomes. Using electron microscopy, we determined the atomic structure of a highly divergent ribosome found in mitochondria of Trypanosoma brucei, a unicellular parasite that causes sleeping sickness in humans. The trypanosomal mitoribosome features the smallest rRNAs and contains more proteins than all known ribosomes. The structure shows how the proteins have taken over the role of architectural scaffold from the rRNA: They form an autonomous outer shell that surrounds the entire particle and stabilizes and positions the functionally important regions of the rRNA. Our results also reveal the "minimal" set of conserved rRNA and protein components shared by all ribosomes that help us define the most essential functional elements.
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Affiliation(s)
- David J F Ramrath
- Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland
| | - Moritz Niemann
- Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland
| | - Marc Leibundgut
- Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland
| | - Philipp Bieri
- Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland
| | - Céline Prange
- Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland
| | - Elke K Horn
- Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland
| | - Alexander Leitner
- Department of Biology, Institute of Molecular Systems Biology, Auguste-Piccard-Hof 1, ETH Zurich, CH-8093 Zurich, Switzerland
| | - Daniel Boehringer
- Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland
| | - André Schneider
- Department of Chemistry and Biochemistry, University of Bern, CH-3012 Bern, Switzerland
| | - Nenad Ban
- Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland.
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36
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Garza-Lombó C, Posadas Y, Quintanar L, Gonsebatt ME, Franco R. Neurotoxicity Linked to Dysfunctional Metal Ion Homeostasis and Xenobiotic Metal Exposure: Redox Signaling and Oxidative Stress. Antioxid Redox Signal 2018; 28:1669-1703. [PMID: 29402131 PMCID: PMC5962337 DOI: 10.1089/ars.2017.7272] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
SIGNIFICANCE Essential metals such as copper, iron, manganese, and zinc play a role as cofactors in the activity of a wide range of processes involved in cellular homeostasis and survival, as well as during organ and tissue development. Throughout our life span, humans are also exposed to xenobiotic metals from natural and anthropogenic sources, including aluminum, arsenic, cadmium, lead, and mercury. It is well recognized that alterations in the homeostasis of essential metals and an increased environmental/occupational exposure to xenobiotic metals are linked to several neurological disorders, including neurodegeneration and neurodevelopmental alterations. Recent Advances: The redox activity of essential metals is key for neuronal homeostasis and brain function. Alterations in redox homeostasis and signaling are central to the pathological consequences of dysfunctional metal ion homeostasis and increased exposure to xenobiotic metals. Both redox-active and redox-inactive metals trigger oxidative stress and damage in the central nervous system, and the exact mechanisms involved are starting to become delineated. CRITICAL ISSUES In this review, we aim to appraise the role of essential metals in determining the redox balance in the brain and the mechanisms by which alterations in the homeostasis of essential metals and exposure to xenobiotic metals disturb the cellular redox balance and signaling. We focus on recent literature regarding their transport, metabolism, and mechanisms of toxicity in neural systems. FUTURE DIRECTIONS Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703.
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Affiliation(s)
- Carla Garza-Lombó
- 1 Redox Biology Center and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln , Lincoln, Nebraska.,2 Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas , Universidad Nacional Autónoma de México, Mexico City, México
| | - Yanahi Posadas
- 3 Departamentos de Farmacología y de, Centro de Investigación y de Estudios Avanzados (CINVESTAV) , Mexico City, México .,4 Departamentos de Química, Centro de Investigación y de Estudios Avanzados (CINVESTAV) , Mexico City, México
| | - Liliana Quintanar
- 4 Departamentos de Química, Centro de Investigación y de Estudios Avanzados (CINVESTAV) , Mexico City, México
| | - María E Gonsebatt
- 2 Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas , Universidad Nacional Autónoma de México, Mexico City, México
| | - Rodrigo Franco
- 1 Redox Biology Center and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln , Lincoln, Nebraska
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37
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Khan AQ, Travers JB, Kemp MG. Roles of UVA radiation and DNA damage responses in melanoma pathogenesis. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2018; 59:438-460. [PMID: 29466611 PMCID: PMC6031472 DOI: 10.1002/em.22176] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 01/18/2018] [Accepted: 01/22/2018] [Indexed: 05/10/2023]
Abstract
The growing incidence of melanoma is a serious public health issue that merits a thorough understanding of potential causative risk factors, which includes exposure to ultraviolet radiation (UVR). Though UVR has been classified as a complete carcinogen and has long been recognized for its ability to damage genomic DNA through both direct and indirect means, the precise mechanisms by which the UVA and UVB components of UVR contribute to the pathogenesis of melanoma have not been clearly defined. In this review, we therefore highlight recent studies that have addressed roles for UVA radiation in the generation of DNA damage and in modulating the subsequent cellular responses to DNA damage in melanocytes, which are the cell type that gives rise to melanoma. Recent research suggests that UVA not only contributes to the direct formation of DNA lesions but also impairs the removal of UV photoproducts from genomic DNA through oxidation and damage to DNA repair proteins. Moreover, the melanocyte microenvironment within the epidermis of the skin is also expected to impact melanomagenesis, and we therefore discuss several paracrine signaling pathways that have been shown to impact the DNA damage response in UV-irradiated melanocytes. Lastly, we examine how alterations to the immune microenvironment by UVA-associated DNA damage responses may contribute to melanoma development. Thus, there appear to be multiple avenues by which UVA may elevate the risk of melanoma. Protective strategies against excess exposure to UVA wavelengths of light therefore have the potential to decrease the incidence of melanoma. Environ. Mol. Mutagen. 59:438-460, 2018. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Aiman Q Khan
- Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, Ohio
| | - Jeffrey B Travers
- Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, Ohio
- Dayton Veterans Affairs Medical Center, Dayton, Ohio
| | - Michael G Kemp
- Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, Ohio
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38
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Sobolewski M, Conrad K, Marvin E, Allen JL, Cory-Slechta DA. Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption. Horm Behav 2018; 101:36-49. [PMID: 29355495 PMCID: PMC5970043 DOI: 10.1016/j.yhbeh.2018.01.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 01/05/2018] [Accepted: 01/14/2018] [Indexed: 11/24/2022]
Abstract
Metals, including lead (Pb), methylmercury (MeHg) and arsenic (As), are long-known developmental neurotoxicants. More recently, environmental context has been recognized to modulate metals toxicity, including nutritional state and stress exposure. Modulation of metal toxicity by stress exposure can occur through shared targeting of endocrine systems, such as the hypothalamic-pituitary-adrenal axis (HPA). Our previous rodent research has identified that prenatal stress (PS) modulates neurotoxicity of two endocrine active metals (EAMs), Pb and MeHg, by altering HPA and CNS systems disrupting behavior. Here, we review this research and further test the hypothesis that prenatal stress modulates metals neurotoxicity by expanding to test the effect of developmental As ± PS exposure. Serum corticosterone and behavior was assessed in offspring of dams exposed to As ± PS. PS increased female offspring serum corticosterone at birth, while developmental As exposure decreased adult serum corticosterone in both sexes. As + PS induced reductions in locomotor activity in females and reduced response rates on a Fixed Interval schedule of reinforcement in males, with the latter suggesting unique learning deficits only in the combined exposure. As-exposed males showed increased time in the open arms of an elevated plus maze and decreased novel object recognition whereas females did not. These data further confirm the hypothesis that combined exposure to chemical (EAMs) and non-chemical (PS) stressors results in enhanced neurobehavioral toxicity. Given that humans are exposed to multiple environmental risk factors that alter endocrine function in development, such models are critical for risk assessment and public health protection, particularly for children.
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Affiliation(s)
- Marissa Sobolewski
- Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, United States. marissa:
| | - Katherine Conrad
- Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, United States
| | - Elena Marvin
- Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, United States
| | - Joshua L Allen
- Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, United States
| | - Deborah A Cory-Slechta
- Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, United States
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39
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Cao K, Li N, Wang H, Cao X, He J, Zhang B, He QY, Zhang G, Sun X. Two zinc-binding domains in the transporter AdcA from Streptococcus pyogenes facilitate high-affinity binding and fast transport of zinc. J Biol Chem 2018; 293:6075-6089. [PMID: 29491141 DOI: 10.1074/jbc.m117.818997] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 02/25/2018] [Indexed: 11/06/2022] Open
Abstract
Zinc is an essential metal in bacteria. One important bacterial zinc transporter is AdcA, and most bacteria possess AdcA homologs that are single-domain small proteins due to better efficiency of protein biogenesis. However, a double-domain AdcA with two zinc-binding sites is significantly overrepresented in Streptococcus species, many of which are major human pathogens. Using molecular simulation and experimental validations of AdcA from Streptococcus pyogenes, we found here that the two AdcA domains sequentially stabilize the structure upon zinc binding, indicating an organization required for both increased zinc affinity and transfer speed. This structural organization appears to endow Streptococcus species with distinct advantages in zinc-depleted environments, which would not be achieved by each single AdcA domain alone. This enhanced zinc transport mechanism sheds light on the significance of the evolution of the AdcA domain fusion, provides new insights into double-domain transporter proteins with two binding sites for the same ion, and indicates a potential target of antimicrobial drugs against pathogenic Streptococcus species.
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Affiliation(s)
- Kun Cao
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Nan Li
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Hongcui Wang
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Xin Cao
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Jiaojiao He
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Bing Zhang
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Qing-Yu He
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Gong Zhang
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
| | - Xuesong Sun
- From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 601 Huang-Pu Avenue West, Guangzhou 510632, China
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40
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Zhou X, Cooper KL, Huestis J, Xu H, Burchiel SW, Hudson LG, Liu KJ. S-nitrosation on zinc finger motif of PARP-1 as a mechanism of DNA repair inhibition by arsenite. Oncotarget 2018; 7:80482-80492. [PMID: 27741521 PMCID: PMC5348335 DOI: 10.18632/oncotarget.12613] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 10/04/2016] [Indexed: 12/21/2022] Open
Abstract
Arsenic, a widely distributed carcinogen, is known to significantly amplify the impact of other carcinogens through inhibition of DNA repair. Our recent work suggests that reactive oxygen/nitrogen species (ROS/RNS) induced by arsenite (AsIII) play an important role in the inhibition of the DNA repair protein Poly(ADP-ribose) polymerase 1 (PARP-1). AsIII-induced ROS lead to oxidation of cysteine residues within the PARP-1 zinc finger DNA binding domain. However, the mechanism underlying RNS-mediated PARP inhibition by arsenic remains unknown. In this work, we demonstrate that AsIII treatment of normal human keratinocyte (HEKn) cells induced S-nitrosation on cysteine residues of PARP-1 protein, in a similar manner to a nitric oxide donor. S-nitrosation of PARP-1 could be reduced by 1400W (inducible nitric oxide synthase inhibitor) or c-PTIO (a nitric oxide scavenger). Furthermore, AsIII treatment of HEKn cells leads to zinc loss and inhibition of PARP-1 enzymatic activity. AsIII and 1400W/c-PTIO co-treatment demonstrate that these effects occur in an iNOS- and NO-dependent manner. Importantly, we confirmed S-nitrosation on the zinc finger DNA binding domain of PARP-1 protein. Taken together, AsIII induces S-nitrosation on PARP-1 zinc finger DNA binding domain by generating NO through iNOS activation, leading to zinc loss and inhibition of PARP-1 activity, thereby increasing retention of damaged DNA. These findings identify S-nitrosation as an important component of the molecular mechanism underlying AsIII inhibition of DNA repair, which may benefit the development of preventive and intervention strategies against AsIII co-carcinogenesis.
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Affiliation(s)
- Xixi Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Karen L Cooper
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Juliana Huestis
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Huan Xu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Scott W Burchiel
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Laurie G Hudson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
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41
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Yang G, Ibuki Y. α,β-Unsaturated Aldehyde-Induced Delays in Nucleotide Excision Repair and the Contribution of Reactive Oxygen Species. Chem Res Toxicol 2018; 31:145-155. [DOI: 10.1021/acs.chemrestox.7b00304] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Guang Yang
- Graduate Division of Nutritional
and Environmental Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan
| | - Yuko Ibuki
- Graduate Division of Nutritional
and Environmental Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan
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42
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Rea M, Eckstein M, Eleazer R, Smith C, Fondufe-Mittendorf YN. Genome-wide DNA methylation reprogramming in response to inorganic arsenic links inhibition of CTCF binding, DNMT expression and cellular transformation. Sci Rep 2017; 7:41474. [PMID: 28150704 PMCID: PMC5288714 DOI: 10.1038/srep41474] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 12/20/2016] [Indexed: 12/31/2022] Open
Abstract
Chronic low dose inorganic arsenic (iAs) exposure leads to changes in gene expression and epithelial-to-mesenchymal transformation. During this transformation, cells adopt a fibroblast-like phenotype accompanied by profound gene expression changes. While many mechanisms have been implicated in this transformation, studies that focus on the role of epigenetic alterations in this process are just emerging. DNA methylation controls gene expression in physiologic and pathologic states. Several studies show alterations in DNA methylation patterns in iAs-mediated pathogenesis, but these studies focused on single genes. We present a comprehensive genome-wide DNA methylation analysis using methyl-sequencing to measure changes between normal and iAs-transformed cells. Additionally, these differential methylation changes correlated positively with changes in gene expression and alternative splicing. Interestingly, most of these differentially methylated genes function in cell adhesion and communication pathways. To gain insight into how genomic DNA methylation patterns are regulated during iAs-mediated carcinogenesis, we show that iAs probably targets CTCF binding at the promoter of DNA methyltransferases, regulating their expression. These findings reveal how CTCF binding regulates DNA methyltransferase to reprogram the methylome in response to an environmental toxin.
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Affiliation(s)
- Matthew Rea
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
| | - Meredith Eckstein
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
| | - Rebekah Eleazer
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
| | - Caroline Smith
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA.,Bellarmine University, Louisville, KY 40205, USA
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Huestis J, Zhou X, Chen L, Feng C, Hudson LG, Liu KJ. Kinetics and thermodynamics of zinc(II) and arsenic(III) binding to XPA and PARP-1 zinc finger peptides. J Inorg Biochem 2016; 163:45-52. [PMID: 27521476 PMCID: PMC5096954 DOI: 10.1016/j.jinorgbio.2016.08.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 07/29/2016] [Accepted: 08/01/2016] [Indexed: 12/18/2022]
Abstract
Inhibition of DNA repair is an established mechanism of arsenic co-carcinogenesis, and may be perpetuated by the binding of As(III) to key zinc finger (zf) DNA repair proteins. Validated molecular targets of As(III) include the first zinc finger domain of Poly (ADP-Ribose) Polymerase 1 (PARP-1), and the zinc finger domain of Xeroderma Pigmentosum Complementation Group A (XPA). In order to gain an understanding of the thermodynamic and kinetic parameters of the interaction of As(III) with these two zinc finger motifs, a fluorescence based approach was used to investigate Zn(II) and As(III) binding to synthetic model peptides corresponding to the zf motif of XPA and first zf motif of PARP-1, referred to in this paper as XPAzf and PARP-1zf-1, respectively. While XPAzf and PARP-1zf-1 display similar relative affinities for As(III), PARP-1zf-1 shows a potential kinetic advantage over XPAzf for As(III) binding, with a rate constant for the fast phase of formation of As(III)-PARP-1zf-1 approximately 4-fold higher than for As(III)-XPAzf. However, the binding of Zn(II) with either peptide proceeds at a faster rate than As(III). Notably, XPAzf demonstrates comparable affinities for binding both metals, while PARP-1zf-1 shows a slightly higher affinity for Zn(II), suggesting that the relative concentrations of Zn(II) and As(III) in a system may significantly influence which species predominates in zinc finger occupancy. These results provide insight into the mechanisms underlying interactions between zinc finger structures and As(III), and highlight the potential utility of zinc supplementation in mitigating adverse effects of As(III) on zinc finger functions in vivo.
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Affiliation(s)
- Juliana Huestis
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Xixi Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Li Chen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Changjian Feng
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Laurie G Hudson
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
| | - Ke Jian Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
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Abstract
Solar UVB is carcinogenic. Nucleotide excision repair (NER) counteracts the carcinogenicity of UVB by excising potentially mutagenic UVB-induced DNA lesions. Despite this capacity for DNA repair, non-melanoma skin cancers and apparently normal sun-exposed skin contain huge numbers of mutations that are mostly attributable to unrepaired UVB-induced DNA lesions. UVA is about 20-times more abundant than UVB in incident sunlight. It does cause some DNA damage but this does not fully account for its biological impact. The effects of solar UVA are mediated by its interactions with cellular photosensitizers that generate reactive oxygen species (ROS) and induce oxidative stress. The proteome is a significant target for damage by UVA-induced ROS. In cultured human cells, UVA-induced oxidation of DNA repair proteins inhibits DNA repair. This article addresses the possible role of oxidative stress and protein oxidation in determining DNA repair efficiency - with particular reference to NER and skin cancer risk.
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Affiliation(s)
- Peter Karran
- Francis Crick Research Institute, Clare Hall Laboratory, South Mimms, Herts. EN6 3LD, UK.
| | - Reto Brem
- Francis Crick Research Institute, Clare Hall Laboratory, South Mimms, Herts. EN6 3LD, UK
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45
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Phillips MA, Cánovas A, Wu PW, Islas-Trejo A, Medrano JF, Rice RH. Parallel responses of human epidermal keratinocytes to inorganic SbIII and AsIII. ENVIRONMENTAL CHEMISTRY (COLLINGWOOD, VIC.) 2016; 13:963-970. [PMID: 28713220 PMCID: PMC5507681 DOI: 10.1071/en16019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
SbIII and AsIII are known to exhibit similar chemical properties, but the degree of similarity in their effects on biological systems merits further exploration. Present work compares the responses of human epidermal keratinocytes, a known target cell type for arsenite-induced carcinogenicity, to these metalloids after treatment for a week at environmentally relevant concentrations. Previous work with these cells has shown that arsenite and antimonite have parallel effects in suppressing differentiation, altering levels of several critical enzymes and maintaining colony forming ability. More globally, protein profiling now reveals parallels in SbIII and AsIII effects. The more sensitive technique of transcriptional profiling also shows considerable parallels. Thus, gene expression changes were almost entirely in the same directions for the two treatments, although the degree of change was sometimes significantly different. Inspection of the changes revealed that RYR1 and LRIG1 were among the genes strongly suppressed, consistent with reduced calcium-dependent differentiation and maintenance of EGF-dependent proliferative potential. Moreover, levels of miRNAs in the cells were altered in parallel, with nearly 90% of the 198 most highly expressed ones being suppressed. Among these was miR-203, which is known to decrease proliferative potential. Finally, both SbIII and AsIII were seen to attenuate bone morphogenetic protein 6 induction of dual specificity phosphatases 2 and 14, consistent with maintaining epidermal growth factor receptor signaling. These findings raise the question whether SbIII, like AsIII, could act as a human skin carcinogen.
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Affiliation(s)
- Marjorie A. Phillips
- Department of Environmental Toxicology, University of California, Davis, CA 95616
| | - Angela Cánovas
- Department of Animal Science, University of California, Davis, CA 95616
| | - Pei-Wen Wu
- Department of Environmental Toxicology, University of California, Davis, CA 95616
| | - Alma Islas-Trejo
- Department of Animal Science, University of California, Davis, CA 95616
| | - Juan F. Medrano
- Department of Animal Science, University of California, Davis, CA 95616
| | - Robert H. Rice
- Department of Environmental Toxicology, University of California, Davis, CA 95616
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