title: An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress.
abstract: 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.
authors.affiliation: Division of Neurofunctional Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshimura
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Sakumi
authors.forename: Mizuki
authors.initials: M
authors.lastname: Ohno
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakai
authors.forename: Masato
authors.initials: M
authors.lastname: Furuichi
authors.forename: Shigenori
authors.initials: S
authors.lastname: Iwai
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D020169:Caspases / Q000502:physiology; D016923:Cell Death; D019610:Cytoprotection; D004247:DNA / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide; D006868:Hydrolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D011755:Pyrophosphatases
chemical_list: C095141:2-hydroxydeoxyadenosine triphosphate; D003848:Deoxyguanine Nucleotides; D029968:Escherichia coli Proteins; C078206:8-oxodeoxyguanosine triphosphate; D000255:Adenosine Triphosphate; D004247:DNA; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D010744:Phosphoric Monoester Hydrolases; D020169:Caspases; D011755:Pyrophosphatases; C052211:mutT protein, E coli