title: Human DNA glycosylase enzyme TDG repairs thymine mispaired with exocyclic etheno-DNA adducts.
abstract: Lipid peroxidation directly reacts with DNA and produces various exocyclic etheno-base DNA adducts, some of which are considered to contribute to carcinogenesis. However, the system for repairing them in humans is largely unknown. We hypothesized that etheno-DNA adducts are repaired by base excision repair initiated by DNA glycosylase. To test this hypothesis, we examined the activities of the DNA glycosylase proteins OGG1, SMUG1, TDG, NEIL1, MUTYH, NTH1, MPG, and UNG2 against double-stranded oligonucleotides containing 1,N(6)-ethenoadenine (εA), 3,N(4)-ethenocytosine (εC), butanone-ethenocytosine (BεC), butanone-ethenoguanine (BεG), heptanone-ethenocytosine (HεC), or heptanone-ethenoguanine (HεG) using a DNA cleavage assay. We found that TDG is capable of removing thymine that has mispaired with εC, BεC, BεG, HεC, or HεG in vitro. We next examined the effect of TDG against etheno-DNA adducts in human cells. TDG-knockdown cells exhibited the following characteristics: (a) higher resistance to cell death caused by the induction of etheno-DNA adducts; (b) lower repair activity for εC; and (c) a modest acceleration of mutations caused by εC, compared with the rate in control cells. All these characteristics suggest that TDG exerts a repair activity against etheno-DNA adducts in human cells. These results suggest that TDG has novel repair activities toward etheno-DNA adducts.
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan. Electronic address: kzshinmu@hama-med.ac.jp.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: Department of Chemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Matsushima
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Pathology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Ishino
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Totsuka
authors.affiliation: Research Center for Environmental Quality Management, Kyoto University, Otsu, Shiga, 520-0811, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka 431-3192, Japan. Electronic address: hsugimur@hama-med.ac.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
mesh_terms: D002470:Cell Survival; D002478:Cells, Cultured; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D005030:Ethylenes / Q000737:chemistry*; D006801:Humans; D015227:Lipid Peroxidation; D013379:Substrate Specificity; D013941:Thymine / Q000737:chemistry / Q000378:metabolism*; D044502:Thymine DNA Glycosylase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018736:DNA Adducts; D005030:Ethylenes; C036216:ethylene; D044502:Thymine DNA Glycosylase; D013941:Thymine
keywords: 3N(4)-Ethenocytosine; Base excision repair enzyme; Etheno-DNA adducts; Lipid peroxidation; TDG