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Originally published In Press as doi:10.1074/jbc.M306201200 on July 11, 2003 Originally published In Press as doi:10.1074/jbc.M306201200 on July 10, 2003

J. Biol. Chem., Vol. 278, Issue 39, 37965-37973, September 26, 2003
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An Oxidized Purine Nucleoside Triphosphatase, MTH1, Suppresses Cell Death Caused by Oxidative Stress*

Daisuke Yoshimura {ddagger}, Kunihiko Sakumi {ddagger}, Mizuki Ohno {ddagger}, Yasunari Sakai {ddagger}, Masato Furuichi {ddagger}, Shigenori Iwai § and Yusaku Nakabeppu {ddagger} ¶

From the {ddagger}Division of Neurofunctional Genomics, Medical Institute of Bioregulation, Kyushu University and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Fukuoka 812-8582 and the §Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan

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 H2O2, 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 H2O2. 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.

Received for publication, June 12, 2003 , and in revised form, July 10, 2003.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-92-642-6800; Fax: 81-92-642-6791; E-mail: yusaku{at}bioreg.kyushu-u.ac.jp.


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