title: Homologous Recombination and Translesion DNA Synthesis Play Critical Roles on Tolerating DNA Damage Caused by Trace Levels of Hexavalent Chromium.
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 K2CrO4 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).
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Xu
authors.identifier: http://orcid.org/0000-0001-8174-5669
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: John R
authors.initials: JR
authors.lastname: Ridpath
authors.affiliation: Department of Neurology, UNC Neuroscience center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina.|Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Zhou
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Dayna
authors.initials: D
authors.lastname: Neo
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jean
authors.initials: J
authors.lastname: Clement
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.affiliation: Department of Radiation Genetics Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Sale
authors.affiliation: Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina.|Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.|Department of Statistics, North Carolina State University, Raleigh, North Carolina.
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jun
authors.initials: J
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002645:Chickens; D002857:Chromium / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D059765:Homologous Recombination / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D013997:Time Factors
chemical_list: D002274:Carcinogens, Environmental; D002857:Chromium; C074702:chromium hexavalent ion