title: NDX-1 protein hydrolyzes 8-oxo-7, 8-dihydrodeoxyguanosine-5'-diphosphate to sanitize oxidized nucleotides and prevent oxidative stress in Caenorhabditis elegans.
abstract: 8-oxo-dGTP is generated in the nucleotide pool by direct oxidation of dGTP or phosphorylation of 8-oxo-dGDP. It can be incorporated into DNA during replication, which would result in mutagenic consequences. The frequency of spontaneous mutations remains low in cells owing to the action of enzymes degrading such mutagenic substrates. Escherichia coli MutT and human MTH1 hydrolyze 8-oxo-dGTP to 8-oxo-dGMP. Human NUDT5 as well as human MTH1 hydrolyze 8-oxo-dGDP to 8-oxo-dGMP. These enzymes prevent mutations caused by misincorporation of 8-oxo-dGTP into DNA. In this study, we identified a novel MutT homolog (NDX-1) of Caenorhabditis elegans that hydrolyzes 8-oxo-dGDP to 8-oxo-dGMP. NDX-1 did not hydrolyze 8-oxo-dGTP, 2-hydroxy-dATP or 2-hydroxy-dADP. Expression of NDX-1 significantly reduced spontaneous A:T to C:G transversions and mitigated the sensitivity to a superoxide-generating agent, methyl viologen, in an E. coli mutT mutant. In C. elegans, RNAi of ndx-1 did not affect the lifespan of the worm. However, the sensitivity to methyl viologen and menadione bisulfite of the ndx-1-RNAi worms was enhanced compared with that of the control worms. These facts indicate that NDX-1 is involved in sanitization of 8-oxo-dGDP and plays a critical role in defense against oxidative stress in C. elegans.
authors.affiliation: Laboratory of Stress Response Biology, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: U
authors.initials: U
authors.lastname: Sanada
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Yonekura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hashiguchi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Nakamura
authors.forename: Shuji
authors.initials: S
authors.lastname: Yonei
authors.forename: Qiu-Mei
authors.initials: QM
authors.lastname: Zhang-Akiyama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D004789:Enzyme Activation; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005816:Genetic Complementation Test; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D009711:Nucleotides / Q000378:metabolism*; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016415:Sequence Alignment; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: C515742:8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-monophosphate; D029742:Caenorhabditis elegans Proteins; D009711:Nucleotides; D024483:Vitamin K 3; D006157:Guanosine Monophosphate; D006861:Hydrogen Peroxide; D010744:Phosphoric Monoester Hydrolases; C557890:NDX-4 protein, C elegans; D010269:Paraquat