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DUT  -  deoxyuridine triphosphatase

Homo sapiens

Synonyms: Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial, dUTP pyrophosphatase, dUTPase
 
 
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Disease relevance of DUT

 

Psychiatry related information on DUT

 

High impact information on DUT

  • The high levels of dUTPase as well as the presence of RNA primers on most nascent DNA pieces (Tseng and Goulian, 1977) suggest that repair of uracil-containing DNA does not contribute to the generation of the small, nascent DNA pieces found during DNA synthesis in this in vitro system [6].
  • We demonstrate that virion-associated UNG2 catalytic activity can be replaced by the packaging of heterologous dUTPase into virion, indicating that UNG2 acts to counteract dUTP misincorporation in the viral genome [7].
  • Pfu dUTPase improves the yield of products amplified with Pfu DNA polymerase by preventing dUTP incorporation and subsequent inhibition of the polymerase by dU-containing DNA. dUTP was found to accumulate during PCR through dCTP deamination and to limit the efficiency of PCRs carried out with archaeal DNA polymerases [8].
  • P45 was shown to function as a dUTPase, converting dUTP to dUMP and inorganic pyrophosphate [8].
  • In this report we describe the identification of this polypeptide as the phosphorylated form of dUTPase (EC 3.6.1.23), following cDNA cloning of the gene, based on a partial amino acid sequence of the phosphopolypeptide [9].
 

Chemical compound and disease context of DUT

 

Biological context of DUT

 

Anatomical context of DUT

 

Associations of DUT with chemical compounds

  • In vitro binding assays indicate that rat dUTPase interacts with all three isoforms of mouse PPAR, but not with retinoid X receptor and thyroid hormone receptor [18].
  • Synthesis and high-throughput evaluation of triskelion uracil libraries for inhibition of human dUTPase and UNG2 [21].
  • Human nuclear uracil DNA glycosylase (UNG2) and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) are the primary enzymes that prevent the incorporation and accumulation of deoxyuridine in genomic DNA [21].
  • The resulting triskelion oximes were directly screened for inhibitory activity and the most potent of these showed micromolar binding affinities to UNG2 and dUTPase [21].
  • In previous work, this laboratory demonstrated that dUTPase is posttranslationally phosphorylated on serine residue(s) (Lirette, R., and Caradonna, S. (1990) J. Cell. Biochem. 43, 339-353) [15].
 

Other interactions of DUT

  • Together, these data suggest that the nuclear form of dUTPase may be a target for cyclin-dependent kinase phosphorylation in vivo [15].
  • Consistent with results using different inhibitors of TS, transfection of dUTPase into HT29 cells significantly reduced the cytotoxicity of a 24 h but not 48 h exposure to ZD9331 [22].
  • Furthermore, dUTPase gene expression was not stimulated by mutant p53, but instead by cellular events that involve DNA synthesis [23].
  • There were usually fewer dUTPase- than Ki-67-positive nuclei detectable [2].
  • Using Bax+/- cells as a model, proteomic analysis revealed four RSV-responsive events: fragmentation of lamin A/C protein; increase in concentration of a more basic isoelectric variant of the ribosomal protein P0; and decrease in concentration of dUTPase as well as stathmin 1 [24].
 

Analytical, diagnostic and therapeutic context of DUT

  • Northern blot hybridization shows that rat dUTPase is encoded by an abundant 1kilobase mRNA species present in all rat tissues [18].
  • The role of dUTPase and uracil-DNA repair in cancer chemotherapy [3].
  • The role of dUTPase expression in modulating therapeutic response is presented including evidence from yeast and mammalian cell culture models and clinical studies [3].
  • Immunofluorescence also confirmed DUT cytoplasm localization in RGV-infected cells [4].
  • Archaeal dUTPase enhances PCR amplifications with archaeal DNA polymerases by preventing dUTP incorporation [8].

References

  1. Human dUTP pyrophosphatase: cDNA sequence and potential biological importance of the enzyme. McIntosh, E.M., Ager, D.D., Gadsden, M.H., Haynes, R.H. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  2. Immunohistochemical detection of dUTPase in intracranial tumors. Romeike, B.F., Böckeler, A., Kremmer, E., Sommer, P., Krick, C., Grässer, F. Pathol. Res. Pract. (2005) [Pubmed]
  3. The role of dUTPase and uracil-DNA repair in cancer chemotherapy. Ladner, R.D. Curr. Protein Pept. Sci. (2001) [Pubmed]
  4. Characterization of an early gene encoding for dUTPase in Rana grylio virus. Zhao, Z., Ke, F., Gui, J., Zhang, Q. Virus Res. (2007) [Pubmed]
  5. Epstein-Barr virus-encoded dUTPase modulates immune function and induces sickness behavior in mice. Padgett, D.A., Hotchkiss, A.K., Pyter, L.M., Nelson, R.J., Yang, E., Yeh, P.E., Litsky, M., Williams, M., Glaser, R. J. Med. Virol. (2004) [Pubmed]
  6. The incorporation of uracil into animal cell DNA in vitro. Grafstrom, R.H., Tseng, B.Y., Goulian, M. Cell (1978) [Pubmed]
  7. HIV-1-associated uracil DNA glycosylase activity controls dUTP misincorporation in viral DNA and is essential to the HIV-1 life cycle. Priet, S., Gros, N., Navarro, J.M., Boretto, J., Canard, B., Quérat, G., Sire, J. Mol. Cell (2005) [Pubmed]
  8. Archaeal dUTPase enhances PCR amplifications with archaeal DNA polymerases by preventing dUTP incorporation. Hogrefe, H.H., Hansen, C.J., Scott, B.R., Nielson, K.B. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  9. Maturation stage and proliferation-dependent expression of dUTPase in human T cells. Strahler, J.R., Zhu, X.X., Hora, N., Wang, Y.K., Andrews, P.C., Roseman, N.A., Neel, J.V., Turka, L., Hanash, S.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  10. dUTP nucleotidohydrolase isoform expression in normal and neoplastic tissues: association with survival and response to 5-fluorouracil in colorectal cancer. Ladner, R.D., Lynch, F.J., Groshen, S., Xiong, Y.P., Sherrod, A., Caradonna, S.J., Stoehlmacher, J., Lenz, H.J. Cancer Res. (2000) [Pubmed]
  11. Induction of resistance to fluorodeoxyuridine cytotoxicity and DNA damage in human tumor cells by expression of Escherichia coli deoxyuridinetriphosphatase. Canman, C.E., Radany, E.H., Parsels, L.A., Davis, M.A., Lawrence, T.S., Maybaum, J. Cancer Res. (1994) [Pubmed]
  12. Incorporation of uracil into minus strand DNA affects the specificity of plus strand synthesis initiation during lentiviral reverse transcription. Klarmann, G.J., Chen, X., North, T.W., Preston, B.D. J. Biol. Chem. (2003) [Pubmed]
  13. Deoxyuridine triphosphate nucleotidohydrolase induced by herpes simplex virus type 1. Purification and characterization of induced enzyme. Williams, M.V. J. Biol. Chem. (1984) [Pubmed]
  14. Replication properties of dUTPase-deficient mutants of caprine and ovine lentiviruses. Turelli, P., Pétursson, G., Guiguen, F., Mornex, J.F., Vigne, R., Quérat, G. J. Virol. (1996) [Pubmed]
  15. Identification of a consensus cyclin-dependent kinase phosphorylation site unique to the nuclear form of human deoxyuridine triphosphate nucleotidohydrolase. Ladner, R.D., Carr, S.A., Huddleston, M.J., McNulty, D.E., Caradonna, S.J. J. Biol. Chem. (1996) [Pubmed]
  16. The human dUTPase gene encodes both nuclear and mitochondrial isoforms. Differential expression of the isoforms and characterization of a cDNA encoding the mitochondrial species. Ladner, R.D., Caradonna, S.J. J. Biol. Chem. (1997) [Pubmed]
  17. Assignment of the human dUTPase gene (DUT) to chromosome 15q15-q21. 1 by fluorescence in situ hybridization. Cohen, D., Heng, H.H., Shi, X.M., McIntosh, E.M., Tsui, L.C., Pearlman, R.E. Genomics (1997) [Pubmed]
  18. Cloning and identification of rat deoxyuridine triphosphatase as an inhibitor of peroxisome proliferator-activated receptor alpha. Chu, R., Lin, Y., Rao, M.S., Reddy, J.K. J. Biol. Chem. (1996) [Pubmed]
  19. Characterization of distinct nuclear and mitochondrial forms of human deoxyuridine triphosphate nucleotidohydrolase. Ladner, R.D., McNulty, D.E., Carr, S.A., Roberts, G.D., Caradonna, S.J. J. Biol. Chem. (1996) [Pubmed]
  20. Novel gain of function activity of p53 mutants: activation of the dUTPase gene expression leading to resistance to 5-fluorouracil. Pugacheva, E.N., Ivanov, A.V., Kravchenko, J.E., Kopnin, B.P., Levine, A.J., Chumakov, P.M. Oncogene (2002) [Pubmed]
  21. Synthesis and high-throughput evaluation of triskelion uracil libraries for inhibition of human dUTPase and UNG2. Jiang, Y.L., Chung, S., Krosky, D.J., Stivers, J.T. Bioorg. Med. Chem. (2006) [Pubmed]
  22. The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition. Webley, S.D., Welsh, S.J., Jackman, A.L., Aherne, G.W. Br. J. Cancer (2001) [Pubmed]
  23. No anti-apoptotic effects of single copies of mutant p53 genes in drug-treated tumor cells. Fritzsche, C., Zeller, G., Knaup, K.X., Roemer, K. Anticancer Drugs (2004) [Pubmed]
  24. Functional proteomics of resveratrol-induced colon cancer cell apoptosis: Caspase-6-mediated cleavage of lamin A is a major signaling loop. Lee, S.C., Chan, J., Clement, M.V., Pervaiz, S. Proteomics (2006) [Pubmed]
 
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