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      Homologous Recombination and Translesion DNA Synthesis Play Critical Roles on Tolerating DNA Damage Caused by Trace Levels of Hexavalent Chromium

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          Abstract

          Contamination of potentially carcinogenic hexavalent chromium (Cr(VI)) in the drinking water is a major public health concern worldwide. However, little information is available regarding the biological effects of a nanomoler amount of Cr(VI). Here, we investigated the genotoxic effects of Cr(VI) at nanomoler levels and their repair pathways. We found that DNA damage response analyzed based on differential toxicity of isogenic cells deficient in various DNA repair proteins is observed after a three-day incubation with K 2CrO 4 in REV1-deficient DT40 cells at 19.2 μg/L or higher as well as in TK6 cells deficient in polymerase delta subunit 3 (POLD3) at 9.8 μg/L or higher. The genotoxicity of Cr(VI) decreased ~3000 times when the incubation time was reduced from three days to ten minutes. TK mutation rate also significantly decreased from 6 day to 1 day exposure to Cr(VI). The DNA damage response analysis suggest that DNA repair pathways, including the homologous recombination and REV1- and POLD3-mediated error-prone translesion synthesis pathways, are critical for the cells to tolerate to DNA damage caused by trace amount of Cr(VI).

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          Most cited references37

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          Chromium in Drinking Water: Sources, Metabolism, and Cancer Risks

          Drinking water supplies in many geographic areas contain chromium in the +3 and +6 oxidation states. Public health concerns are centered on the presence of hexavalent Cr that is classified as a known human carcinogen via inhalation. Cr(VI) has high environmental mobility and can originate from anthropogenic and natural sources. Acidic environments with high organic content promote the reduction of Cr(VI) to nontoxic Cr(III). The opposite process of Cr(VI) formation from Cr(III) also occurs, particularly in the presence of common minerals containing Mn(IV) oxides. Limited epidemiological evidence for Cr(VI) ingestion is suggestive of elevated risks for stomach cancers. Exposure of animals to Cr(VI) in drinking water induced tumors in the alimentary tract, with linear and supralinear responses in the mouse small intestine. Chromate, the predominant form of Cr(VI) at neutral pH, is taken up by all cells through sulfate channels and is activated nonenzymatically by ubiquitously present ascorbate and small thiols. The most abundant form of DNA damage induced by Cr(VI) is Cr-DNA adducts, which cause mutations and chromosomal breaks. Emerging evidence points to two-way interactions between DNA damage and epigenetic changes that collectively determine the spectrum of genomic rearrangements and profiles of gene expression in tumors. Extensive formation of DNA adducts, clear positivity in genotoxicity assays with high predictive values for carcinogenicity, the shape of tumor–dose responses in mice, and a biological signature of mutagenic carcinogens (multispecies, multisite, and trans-sex tumorigenic potency) strongly support the importance of the DNA-reactive mutagenic mechanisms in carcinogenic effects of Cr(VI). Bioavailability results and kinetic considerations suggest that 10–20% of ingested low-dose Cr(VI) escapes human gastric inactivation. The directly mutagenic mode of action and the incompleteness of gastric detoxification argue against a threshold in low-dose extrapolation of cancer risk for ingested Cr(VI).
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            Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI).

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              The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder.

              Mutations in any of at least sixteen FANC genes (FANCA-Q) cause Fanconi anemia, a disorder characterized by sensitivity to DNA interstrand crosslinking agents. The clinical features of cytopenia, developmental defects, and tumor predisposition are similar in each group, suggesting that the gene products participate in a common pathway. The Fanconi anemia DNA repair pathway consists of an anchor complex that recognizes damage caused by interstrand crosslinks, a multisubunit ubiquitin ligase that monoubiquitinates two substrates, and several downstream repair proteins including nucleases and homologous recombination enzymes. We review progress in the use of structural and biochemical approaches to understanding how each FANC protein functions in this pathway.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 December 2016
                2016
                : 11
                : 12
                : e0167503
                Affiliations
                [1 ]Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
                [2 ]Department of Neurology, UNC Neuroscience center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
                [3 ]Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina
                [4 ]Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina
                [5 ]Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan
                [6 ]Department of Radiation Genetics Graduate School of Medicine, Kyoto University, Kyoto, Japan
                [7 ]Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
                [8 ]Department of Statistics, North Carolina State University, Raleigh, North Carolina
                [9 ]Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
                Universitatsklinikum Hamburg-Eppendorf, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: JN.

                • Formal analysis: XT YZ FW JN.

                • Funding acquisition: J. Swenberg JN.

                • Investigation: XT KP JR JC DN JN.

                • Methodology: JN.

                • Project administration: JN.

                • Resources: J. Sale ST MT.

                • Supervision: JN.

                • Validation: XT JN.

                • Visualization: XT JN.

                • Writing – original draft: XT YC JN.

                • Writing – review & editing: XT YC JN.

                Author information
                http://orcid.org/0000-0001-8174-5669
                Article
                PONE-D-16-28085
                10.1371/journal.pone.0167503
                5132242
                27907204
                2570327d-107d-4feb-8c11-271ab8b4965e
                © 2016 Tian et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 July 2016
                : 15 November 2016
                Page count
                Figures: 4, Tables: 0, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000066, National Institute of Environmental Health Sciences;
                Award ID: P30-ES10126
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000066, National Institute of Environmental Health Sciences;
                Award ID: P42-ES05948
                Award Recipient :
                This work was fully supported by grants from the National Institutes of Health (P42 ES005948, P30 ES010126 to JAS and JN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                DNA
                DNA damage
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                Nucleic acids
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