title: Homologous recombination repair signaling in chemical carcinogenesis: prolonged particulate hexavalent chromium exposure suppresses the Rad51 response in human lung cells.
abstract: The aim of this study was to focus on hexavalent chromium, [Cr(VI)], a chemical carcinogen and major public health concern, and consider its ability to impact DNA double strand break repair. We further focused on particulate Cr(VI), because it is the more potent carcinogenic form of Cr(VI). DNA double strand break repair serves to protect cells against the detrimental effects of DNA double strand breaks. For particulate Cr(VI), data show DNA double strand break repair must be overcome for neoplastic transformation to occur. Acute Cr(VI) exposures reveal a robust DNA double strand break repair response, however, longer exposures have not been considered. Using the comet assay, we found longer exposures to particulate zinc chromate induced concentration-dependent increases in DNA double strand breaks indicating breaks were occurring throughout the exposure time. Acute (24 h) exposure induced DNA double strand break repair signaling by inducing Mre11 foci formation, ATM phosphorylation and phosphorylated ATM foci formation, Rad51 protein levels and Rad51 foci formation. However, longer exposures reduced the Rad51 response. These data indicate a major chemical carcinogen can simultaneously induce DNA double strand breaks and alter their repair and describe a new and important aspect of the carcinogenic mechanism for Cr(VI).
authors.affiliation: The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, Maine 04104-9300.
authors.forename: Qin
authors.initials: Q
authors.lastname: Qin
authors.affiliation: The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, Maine 04104-9300.
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.affiliation: The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, Maine 04104-9300.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Wise
authors.affiliation: The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, Maine 04104-9300.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Browning
authors.affiliation: The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, Maine 04104-9300.
authors.forename: Kelsey N
authors.initials: KN
authors.lastname: Thompson
authors.affiliation: The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, Maine 04104-9300.
authors.forename: Amie L
authors.initials: AL
authors.lastname: Holmes
authors.affiliation: The Wise Laboratory of Environmental and Genetic Toxicology, Maine Center for Toxicology and Environmental Health, Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth Street, Portland, Maine 04104-9300 John.Wise@usm.maine.edu.
authors.forename: John Pierce
authors.initials: JP
authors.lastname: Wise
mesh_terms: D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D018929:Cell Culture Techniques; D002460:Cell Line; D002840:Chromates / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000139:chemically induced; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009153:Mutagens / Q000633:toxicity; D051135:Rad51 Recombinase / Q000235:genetics*; D059767:Recombinational DNA Repair; D013997:Time Factors; D017967:Zinc Compounds / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D002840:Chromates; D009153:Mutagens; D017967:Zinc Compounds; C023616:zinc chromate; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: DNA double strand break repair; Rad51; chromate; hexavalent chromium; homologous recombination repair; particulate Cr(VI)