An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress

Daisuke Yoshimura, Kunihiko Sakumi, Mizuki Ohno, Yasunari Sakai, Masato Furuichi, Shigenori Iwai, Yusaku Nakabeppu

研究成果: ジャーナルへの寄稿学術誌査読

119 被引用数 (Scopus)


MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-2′-deoxyguanosine 5′-triphosphate (8-oxo-dGTP) and 2-hydroxy-2′-deoxyadenosine 5′-triphosphate (2-OH-dATP) and thus protects cells from damage caused by their misincorporation into DNA. In the present study, we established MTH1-null mouse embryo fibroblasts that were highly susceptible to cell dysfunction and death caused by exposure to H 2O2, with morphological features of pyknosis and electron-dense deposits accumulated in mitochondria. The cell death observed was independent of both poly(ADP-ribose) polymerase and caspases. A high performance liquid chromatography tandem mass spectrometry analysis and immunofluorescence microscopy revealed a continuous accumulation of 8-oxo-guanine both in nuclear and mitochondrial DNA after exposure to H 2O2. All of the H2O2-induced alterations observed in MTH1-null mouse embryo fibroblasts were effectively suppressed by the expression of wild type human MTH1 (hMTH1), whereas they were only partially suppressed by the expression of mutant hMTH1 defective in either 8-oxo-dGTPase or 2-OH-dATPase activity. Human MTH1 thus protects cells from H2O2-induced cell dysfunction and death by hydrolyzing oxidized purine nucleotides including 8-oxo-dGTP and 2-OH-dATP, and these alterations may be partly attributed to a mitochondrial dysfunction.

ジャーナルJournal of Biological Chemistry
出版ステータス出版済み - 9月 26 2003

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学


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