title: An increase of oxidised nucleotides activates DNA damage checkpoint pathway that regulates post-embryonic development in Caenorhabditis elegans.
abstract: 8-Oxo-dGTP, an oxidised form of dGTP generated in the nucleotide pool, can be incorporated opposite adenine or cytosine in template DNA, which can in turn induce mutations. In this study, we identified a novel MutT homolog (NDX-2) of Caenorhabditis elegans that hydrolyzes 8-oxo-dGDP to 8-oxo-dGMP. In addition, we found that NDX-1, NDX-2 and NDX-4 proteins have 8-oxo-GTPase or 8-oxo-GDPase activity. The sensitivity of ndx-2 knockdown C. elegans worms to methyl viologen and menadione bisulphite was increased compared with that of control worms. This sensitivity was rescued by depletion of chk-2 and clk-2, suggesting that growth of the worms is regulated by the checkpoint pathway in response to the accumulation of oxidised nucleotides. Moreover, we found that the sensitivity to menadione bisulphite of ndx-1 and ndx-2-double knockdown worms was enhanced by elimination of XPA-1, a factor involved in nucleotide excision repair. The rescue effect by depletion of chk-2 and clk-2 was limited in the xpa-1 mutant, suggesting that the chk-2 and clk-2 checkpoint pathway is partially linked to the function of XPA-1.
authors.affiliation: Department of Zoology, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sanada
authors.forename: Qiu-Mei
authors.initials: QM
authors.lastname: Zhang-Akiyama
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D045643:DNA Repair Enzymes / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004926:Escherichia coli; D055785:Gene Knockdown Techniques; D009711:Nucleotides / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010269:Paraquat; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D024483:Vitamin K 3; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism
chemical_list: C490485:8-oxo-7,8-dihydrodeoxyguanosine diphosphate; D029742:Caenorhabditis elegans Proteins; D017931:DNA Primers; D003848:Deoxyguanine Nucleotides; D009711:Nucleotides; D034501:Telomere-Binding Proteins; C553374:XPA-1 protein, C elegans; D051760:Xeroderma Pigmentosum Group A Protein; C438752:clk-2 protein, C elegans; D024483:Vitamin K 3; D064447:Checkpoint Kinase 2; C444421:CHK-2 protein, C elegans; D010744:Phosphoric Monoester Hydrolases; C000592480:NDX-2 protein, C elegans; D011755:Pyrophosphatases; D045643:DNA Repair Enzymes; D010269:Paraquat