Genes and Environment
Online ISSN : 1880-7062
Print ISSN : 1880-7046
35 巻 , 1 号
選択された号の論文の4件中1~4を表示しています
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  • Hiroshi Kasai, Kazuaki Kawai, Ming-Fen Song, Yun-Shan Li, Tomomi Hatto ...
    2013 年 35 巻 1 号 p. 5-9
    発行日: 2013年
    公開日: 2013/02/21
    ジャーナル フリー
    To examine whether methyl radical-induced DNA damage occurs in vivo, cumene hydroperoxide (CuOOH) and methionine sulfoxide (MetO) were administered to mice as methyl radical generators, and 8-methyldeoxyadenosine (m8dA) and 8-methyldeoxyguanosine (m8dG) in the tissue DNA were analyzed by the LC/MS/MS method. After mouse skin was treated with CuOOH and Fe2+, both m8dA and m8dG were detected in the epidermal DNA. m8dA formation was also detected in the liver DNA from MetO-treated, non-alcoholic steatohepatitis (NASH) mice. Since 5-methyldeoxycytidine, m8dA, and m8dG are formed in DNA by methyl radicals, these results support our hypothesis that de novo DNA methylation at the cytosine C-5 position is triggered by a free radical mechanism and may initiate epigenetic changes.
  • Petr Grúz, Takehiko Nohmi
    2013 年 35 巻 1 号 p. 10-20
    発行日: 2013年
    公開日: 2013/02/21
    ジャーナル フリー
    DNA polymerase η (hPolη) is a key protein in translesion DNA synthesis (TLS) in human cells. Its primary function is the error free replication through UV-induced TT cyclobutane dimers which present a barrier to DNA synthesis by other eukaryotic replicative polymerases. hPolη defects underlie the genetic disease xeroderma pigmentosum variant (XPV) characterized by higher susceptibility to UV-light induced skin cancers due to erroneous replication of the UV adducts. However, hPolη is also a very low fidelity enzyme when copying undamaged DNA or DNA with other adducts and is actively recruited during the somatic hypermutation of the immunoglobulin genes. Here, we demonstrate that hPolη restores partially the mutability and completely the survival of a UV non-mutable umuDC-deletion mutant of Escherichia coli after UVB irradiation. We chose UVB instead of UVC as a radiation source because UVB is a major cause of human skin cancer induced by sunlight. The umuDC genes encode endogenous TLS DNA polymerase V. The catalytic core lacking the C-terminal part of hPolη was even more biologically active than the full size protein and its activity was further enhanced by attaching the prokaryotic β-subunit binding motif to it. The mutagenicity and survival effects were enhanced upon the induction of hPolη expression and its catalytically inactive variant was unable to promote any mutagenesis. This suggests that hPolη directly participates in the replication of damaged DNA in the prokaryotic bacteria. To demonstrate that our system can be useful in studying different variants of hPolη in vivo we have constructed 4 amino acid substitution mutants with altered geometry of the catalytic site analyzed previously biochemically and confirmed their altered abilities to promote mutagenesis and survival after UVB irradiation. This study paves a way to generate a variety of useful derivatives of hPolη in prokaryotic systems.
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  • Toshinori Suzuki, Yoshiko Ninomiya, Michiyo Inukai
    2013 年 35 巻 1 号 p. 21-26
    発行日: 2013年
    公開日: 2013/02/21
    ジャーナル フリー
    Addition of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dGuo), a common oxidative-damaged nucleoside of 2′-deoxyguanosine, to the reaction of N-acetylcysteine with diethylamine NONOate, an NO donor, at neutral pH increased the yield of N-acetyl-S-nitrosocysteine. Addition of 8-oxo-dGuo to the reaction of N-acetyltryptophan with diethylamine NONOate accelerated decomposition of the formed N-acetyl-N′-nitrosotryptophan. In the reaction of N-acetylcysteine with N-acetyl-N′-nitrosotryptophan, the concentration of N-acetyl-S-nitrosocysteine greatly increased with the addition of 8-oxo-dGuo. In all experiments, no change in 8-oxo-dGuo concentration was observed. These results indicate that 8-oxo-dGuo can act as a vehicle of NO, and may affect signal transduction associated with NO in humans.
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