Publications

• Structural basis for the specificity of human NUDT16 and its regulation by inosine monophosphate.

  Tresaugues L., Lundbaeck T., Welin M., Flodin S., Nyman T., Silvander C., Graeslund S., Nordlund P.

  Human NUDT16 is a member of the NUDIX hydrolase superfamily. After having been initially described as an mRNA decapping enzyme, recent studies conferred it a role as an "housecleaning" enzyme specialized in the removal of hazardous (deoxy)inosine diphosphate from the nucleotide pool. Here we prese ... >> More

  Human NUDT16 is a member of the NUDIX hydrolase superfamily. After having been initially described as an mRNA decapping enzyme, recent studies conferred it a role as an "housecleaning" enzyme specialized in the removal of hazardous (deoxy)inosine diphosphate from the nucleotide pool. Here we present the crystal structure of human NUDT16 both in its apo-form and in complex with its product inosine monophosphate (IMP). NUDT16 appears as a dimer whose formation generates a positively charged trench to accommodate substrate-binding. Complementation of the structural data with detailed enzymatic and biophysical studies revealed the determinants of substrate recognition and particularly the importance of the substituents in position 2 and 6 on the purine ring. The affinity for the IMP product, harboring a carbonyl in position 6 on the base, compared to purine monophosphates lacking a H-bond acceptor in this position, implies a catalytic cycle whose rate is primarily regulated by the product-release step. Finally, we have also characterized a phenomenon of inhibition by the product of the reaction, IMP, which might exclude non-deleterious nucleotides from NUDT16-mediated hydrolysis regardless of their cellular concentration. Taken together, this study details structural and regulatory mechanisms explaining how substrates are selected for hydrolysis by human NUDT16. << Less

  PLoS ONE 10:E0131507-E0131507(2015) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest.

  Iyama T., Abolhassani N., Tsuchimoto D., Nonaka M., Nakabeppu Y.

  Nucleotides function in a variety of biological reactions; however, they can undergo various chemical modifications. Such modified nucleotides may be toxic to cells if not eliminated from the nucleotide pools. We performed a screen for modified-nucleotide binding proteins and identified human nucl ... >> More

  Nucleotides function in a variety of biological reactions; however, they can undergo various chemical modifications. Such modified nucleotides may be toxic to cells if not eliminated from the nucleotide pools. We performed a screen for modified-nucleotide binding proteins and identified human nucleoside diphosphate linked moiety X-type motif 16 (NUDT16) protein as an inosine triphosphate (ITP)/xanthosine triphosphate (XTP)/GTP-binding protein. Recombinant NUDT16 hydrolyzes purine nucleoside diphosphates to the corresponding nucleoside monophosphates. Among 29 nucleotides examined, the highest k(cat)/K(m) values were for inosine diphosphate (IDP) and deoxyinosine diphosphate (dIDP). Moreover, NUDT16 moderately hydrolyzes (deoxy)inosine triphosphate ([d]ITP). NUDT16 is mostly localized in the nucleus, and especially in the nucleolus. Knockdown of NUDT16 in HeLa MR cells caused cell cycle arrest in S-phase, reduced cell proliferation, increased accumulation of single-strand breaks in nuclear DNA as well as increased levels of inosine in RNA. We thus concluded that NUDT16 is a (deoxy)inosine diphosphatase that may function mainly in the nucleus to protect cells from deleterious effects of (d)ITP. << Less

  Nucleic Acids Res. 38:4834-4843(2010) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• Evolutionary conservation supports ancient origin for Nudt16, a nuclear-localized, RNA-binding, RNA-decapping enzyme.

  Taylor M.J., Peculis B.A.

  Nudt16p is a nuclear RNA decapping protein initially identified in Xenopus (X29) and known to exist in mammals. Here, we identified putative orthologs in 57 different organisms ranging from humans to Cnidaria (anemone/coral). In vitro analysis demonstrated the insect ortholog can bind RNA and hydr ... >> More

  Nudt16p is a nuclear RNA decapping protein initially identified in Xenopus (X29) and known to exist in mammals. Here, we identified putative orthologs in 57 different organisms ranging from humans to Cnidaria (anemone/coral). In vitro analysis demonstrated the insect ortholog can bind RNA and hydrolyze the m(7)G cap from the 5'-end of RNAs indicating the Nudt16 gene product is functionally conserved across metazoans. This study also identified a closely related paralogous protein, known as Syndesmos, which resulted from a gene duplication that occurred in the tetrapod lineage near the amniote divergence. While vertebrate Nudt16p is a nuclear RNA decapping protein, Syndesmos is associated with the cytoplasmic membrane in tetrapods. Syndesmos is inactive for RNA decapping but retains RNA-binding activity. This structure/function analysis demonstrates evolutionary conservation of the ancient Nudt16 protein suggesting the existence and maintenance of a nuclear RNA degradation pathway in metazoans. << Less

  Nucleic Acids Res. 36:6021-6034(2008) [PubMed] [EuropePMC]

  This publication is cited by 4 other entries.