Genomes and Genes
Summary: A non-template-directed DNA polymerase normally found in vertebrate thymus and bone marrow. It catalyzes the elongation of oligo- or polydeoxynucleotide chains and is widely used as a tool in the differential diagnosis of acute leukemias in man. EC 188.8.131.52.
- Doyen N, d Andon M, Bentolila L, Nguyen Q, Rougeon F. Differential splicing in mouse thymus generates two forms of terminal deoxynucleotidyl transferase. Nucleic Acids Res. 1993;21:1187-91 pubmed..Expression of this cDNA in mammalian cells shows that it encodes a functional protein capable of catalysing N region insertions at the recombination junction of an episomic recombination substrate. ..
- Nick McElhinny S, Ramsden D. Polymerase mu is a DNA-directed DNA/RNA polymerase. Mol Cell Biol. 2003;23:2309-15 pubmed
- Yang B, Gathy K, Coleman M. Mutational analysis of residues in the nucleotide binding domain of human terminal deoxynucleotidyl transferase. J Biol Chem. 1994;269:11859-68 pubmed..These results indicated that the aspartic acid residue at position 343 is located at or near the active site and is critical for the nucleotide binding and catalytic activity. ..
- Yang B, Gathy K, Coleman M. T-cell specific avian TdT: characterization of the cDNA and recombinant enzyme. Nucleic Acids Res. 1995;23:2041-8 pubmed..These data suggest that while TdT is probably involved in N region addition in chicken T-cell receptor genes, it is unlikely to play a role in diversification of immunoglobulin genes. ..
- Bertocci B, De Smet A, Weill J, Reynaud C. Nonoverlapping functions of DNA polymerases mu, lambda, and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivo. Immunity. 2006;25:31-41 pubmed
- Nick McElhinny S, Havener J, Garcia Diaz M, Juarez R, Bebenek K, Kee B, et al. A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. Mol Cell. 2005;19:357-66 pubmed..This apparent gradient of template dependence is largely attributable to a small structural element that is present but different in all three polymerases. ..
- Ruiz J, Dominguez O, Lain de Lera T, Garcia Diaz M, Bernad A, Blanco L. DNA polymerase mu, a candidate hypermutase?. Philos Trans R Soc Lond B Biol Sci. 2001;356:99-109 pubmed
- Purugganan M, Shah S, Kearney J, Roth D. Ku80 is required for addition of N nucleotides to V(D)J recombination junctions by terminal deoxynucleotidyl transferase. Nucleic Acids Res. 2001;29:1638-46 pubmed..Based on these data, we propose that TdT does not add to recombination junctions through random collision but is actively recruited to the V(D)J recombinase complex by Ku80. ..
- Strauchen J. Indolent T-lymphoblastic proliferation: report of a case with an 11-year history and association with myasthenia gravis. Am J Surg Pathol. 2001;25:411-5 pubmed..Indolent T-lymphoblastic proliferations of undetermined clonality may rarely occur; predilection for involvement of oropharynx and possible association with myasthenia gravis are suggested. ..
- Schelonka R, Ivanov I, Vale A, Szymanska E, Zemlin M, Gartland G, et al. The CDR-H3 repertoire from TdT-deficient adult bone marrow is a close, but not exact, homologue of the CDR-H3 repertoire from perinatal liver. J Immunol. 2010;185:6075-84 pubmed publisher..Thus, although differing in V(H) content, TdT-deficient mice appear to represent a good, although not perfect, model for testing the role of perinatal CDR-H3 limitations on late B cell development and Ab responses. ..
- Motea E, Berdis A. Terminal deoxynucleotidyl transferase: the story of a misguided DNA polymerase. Biochim Biophys Acta. 2010;1804:1151-66 pubmed publisher..Finally, the biomedical role of this specialized DNA polymerase is discussed focusing on its involvement in cancer development and its use in biomedical applications such as labeling DNA for detecting apoptosis. ..
- Nick McElhinny S, Ramsden D. Sibling rivalry: competition between Pol X family members in V(D)J recombination and general double strand break repair. Immunol Rev. 2004;200:156-64 pubmed..Recent work implicates several members of the Pol X family in end-joining and suggests surprising complexity in the control of how these different polymerases are employed in this pathway. ..
- Maezawa S, Hayano T, Koiwai K, Fukushima R, Kouda K, Kubota T, et al. Bood POZ containing gene type 2 is a human counterpart of yeast Btb3p and promotes the degradation of terminal deoxynucleotidyltransferase. Genes Cells. 2008;13:439-57 pubmed publisher..TdT was ubiquitinated only within the nucleus and degraded by the 26S proteasome. The ubiqutination or degradation of TdT was markedly promoted by co-expression of BPOZ-2 and CUL3 or BPOZ-2 in 293T cells, respectively. ..
- Cho Y, Kool E. Enzymatic synthesis of fluorescent oligomers assembled on a DNA backbone. Chembiochem. 2006;7:669-72 pubmed..The enzymatic synthesis of the pyrene excimer might have applications in homogeneous biological assays for DNA fragments, such as those that arise during apoptosis. ..
- Juarez R, Ruiz J, Nick McElhinny S, Ramsden D, Blanco L. A specific loop in human DNA polymerase mu allows switching between creative and DNA-instructed synthesis. Nucleic Acids Res. 2006;34:4572-82 pubmed..Recent in vivo and in vitro data suggest that such a dual capacity could be advantageous to resolve microhomology-mediated end-joining reactions. ..
- Lee A, Hsu E. Isolation and characterization of the Xenopus terminal deoxynucleotidyl transferase. J Immunol. 1994;152:4500-7 pubmed
- Di Santo R, Maga G. Human terminal deoxynucleotidyl transferases as novel targets for anticancer chemotherapy. Curr Med Chem. 2006;13:2353-68 pubmed..In this review, we will summarize the recent advances in the synthesis and characterization of the first classes of specific inhibitors of mammalian terminal transferases and their potential applications. ..
- Bentolila L, Wu G, Nourrit F, Fanton d Andon M, Rougeon F, Doyen N. Constitutive expression of terminal deoxynucleotidyl transferase in transgenic mice is sufficient for N region diversity to occur at any Ig locus throughout B cell differentiation. J Immunol. 1997;158:715-23 pubmed..Constitutive expression of TdT throughout B cell differentiation does not therefore appear deleterious and suggests that TdT is recruited only to participate in the V(D)J recombination process. ..
- Sandor Z, Calicchio M, Sargent R, Roth D, Wilson J. Distinct requirements for Ku in N nucleotide addition at V(D)J- and non-V(D)J-generated double-strand breaks. Nucleic Acids Res. 2004;32:1866-73 pubmed..We also found that N regions were abnormally long in the absence of Ku80, indicating that Ku80 may regulate TdT's activity at DNA ends in vivo. ..
- Ramadan K, Maga G, Shevelev I, Villani G, Blanco L, Hubscher U. Human DNA polymerase lambda possesses terminal deoxyribonucleotidyl transferase activity and can elongate RNA primers: implications for novel functions. J Mol Biol. 2003;328:63-72 pubmed..These two novel properties of human DNA polymerase lambda might suggest additional roles for this enzyme in DNA replication and repair processes. ..
- Dominguez O, Ruiz J, Lain de Lera T, Garcia Diaz M, Gonzalez M, Kirchhoff T, et al. DNA polymerase mu (Pol mu), homologous to TdT, could act as a DNA mutator in eukaryotic cells. EMBO J. 2000;19:1731-42 pubmed..Therefore, Pol mu is a good candidate to be the mutator polymerase responsible for somatic hyper- mutation of immunoglobulin genes. ..
- Repasky J, Corbett E, Boboila C, Schatz D. Mutational analysis of terminal deoxynucleotidyltransferase-mediated N-nucleotide addition in V(D)J recombination. J Immunol. 2004;172:5478-88 pubmed..We consider these results in light of the recently reported structure of the catalytic region of TdT. ..
- Koiwai O, Yokota T, Kageyama T, Hirose T, Yoshida S, Arai K. Isolation and characterization of bovine and mouse terminal deoxynucleotidyltransferase cDNAs expressible in mammalian cells. Nucleic Acids Res. 1986;14:5777-92 pubmed..Bovine TdT expressed in COS7 cells by nearly full-length cDNA clone was localized in the nucleus and the translational product of pOK103 lacking the nuclear-localization-sequence was localized in the cytoplasm. ..
- Bogue M, Gilfillan S, Benoist C, Mathis D. Regulation of N-region diversity in antigen receptors through thymocyte differentiation and thymus ontogeny. Proc Natl Acad Sci U S A. 1992;89:11011-5 pubmed
- Crespan E, Zanoli S, Khandazhinskaya A, Shevelev I, Jasko M, Alexandrova L, et al. Incorporation of non-nucleoside triphosphate analogues opposite to an abasic site by human DNA polymerases beta and lambda. Nucleic Acids Res. 2005;33:4117-27 pubmed..These results show for the first time that neither the base nor the sugar moieties of nucleotides are required for incorporation by family X DNA polymerases. ..
- Mahajan K, Gangi Peterson L, Sorscher D, Wang J, Gathy K, Mahajan N, et al. Association of terminal deoxynucleotidyl transferase with Ku. Proc Natl Acad Sci U S A. 1999;96:13926-31 pubmed..The physical association of TdT with Ku suggests a possible mechanism by which TdT is recruited to the sites of DSBs such as V(D)J recombination intermediates. ..
- Mahmoud T, Kearney J. Terminal deoxynucleotidyl transferase is required for an optimal response to the polysaccharide ?-1,3 dextran. J Immunol. 2010;184:851-8 pubmed publisher..These data show that TdT is essential for the generation of the predominant higher-affinity DEX-responsive J558 clone. ..
- Herzenberg L. B-1 cells: the lineage question revisited. Immunol Rev. 2000;175:9-22 pubmed
- Koiwai O, Morita A. Isolation of putative promoter region for human terminal deoxynucleotidyltransferase gene. Biochem Biophys Res Commun. 1988;154:91-100 pubmed..The typical octamer of 5'-ATGCAAAT and three octamer-like sequences, which are involved in the transcription of lymphoid-specific genes, were detected at 212, 293, 347 and 770 bp upstream from the first cap site. ..
- González Barrera S, Sánchez A, Ruiz J, Juarez R, Picher A, Terrados G, et al. Characterization of SpPol4, a unique X-family DNA polymerase in Schizosaccharomyces pombe. Nucleic Acids Res. 2005;33:4762-74 pubmed..Therefore, SpPol4 is a unique enzyme whose enzymatic properties are hybrid of those described for mammalian Polbeta, Pollambda and Polmu. ..
- Komori T, Okada A, Stewart V, Alt F. Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytes. Science. 1993;261:1171-5 pubmed
- Robey I, Peterson M, Horwitz M, Kono D, Stratmann T, Theofilopoulos A, et al. Terminal deoxynucleotidyltransferase deficiency decreases autoimmune disease in diabetes-prone nonobese diabetic mice and lupus-prone MRL-Fas(lpr) mice. J Immunol. 2004;172:4624-9 pubmed..We suggest that the paucity of autoreactive specificities created in the N region-lacking repertoire, and the resultant protection afforded to the newborn, may be the reason that TdT expression is delayed in ontogeny. ..
- Bentolila L, Fanton d Andon M, Nguyen Q, Martinez O, Rougeon F, Doyen N. The two isoforms of mouse terminal deoxynucleotidyl transferase differ in both the ability to add N regions and subcellular localization. EMBO J. 1995;14:4221-9 pubmed..All these characteristics could contribute to the functional difference between the two isoforms of TdT. However, the subcellular localization of TdTL on its own can account for its inability to add N regions. ..
- Bogue M, Wang C, Zhu C, Roth D. V(D)J recombination in Ku86-deficient mice: distinct effects on coding, signal, and hybrid joint formation. Immunity. 1997;7:37-47 pubmed..Furthermore, Ku86(-/-) joints are unexpectedly devoid of N-region diversity, suggesting a novel role for Ku in the addition of N nucleotides by terminal deoxynucleotidyl transferase. ..
- Benedict C, Kearney J. Increased junctional diversity in fetal B cells results in a loss of protective anti-phosphorylcholine antibodies in adult mice. Immunity. 1999;10:607-17 pubmed..These results show that maintenance of lower Ig diversity in early life is essential for the acquisition of a complete functional adult repertoire. ..
- Boulé J, Rougeon F, Papanicolaou C. Terminal deoxynucleotidyl transferase indiscriminately incorporates ribonucleotides and deoxyribonucleotides. J Biol Chem. 2001;276:31388-93 pubmed..An essential catalytic aspartate in TdT was identified, which is a first step toward understanding the apparent lack of sugar discrimination by TdT. ..
- Anderson R, Bollum F, Beattie K. Pyrophosphorolytic dismutation of oligodeoxy-nucleotides by terminal deoxynucleotidyltransferase. Nucleic Acids Res. 1999;27:3190-6 pubmed..These results may help explain the GC-richness of immunoglobulin gene segment joins (N regions) and the loss of bases that occur during gene rearrangements in pre-B and pre-T cells. ..
- Krayevsky A, Victorova L, Arzumanov A, Jasko M. Terminal deoxynucleotidyl transferase. catalysis of DNA (oligodeoxynucleotide) phosphorylation. Pharmacol Ther. 2000;85:165-73 pubmed..It has also been shown that TDT catalyzes primer extension with dinucleoside 5',5'-tetraphosphates as substrates. ..
- Gilfillan S, Dierich A, LeMeur M, Benoist C, Mathis D. Mice lacking TdT: mature animals with an immature lymphocyte repertoire. Science. 1993;261:1175-8 pubmed..Thus, switch-on of the TdT gene during the first week after birth provokes an even greater expansion of lymphocyte receptor diversity than had previously been thought. ..
- Nguyen H, Zemlin M, Ivanov I, Andrasi J, Zemlin C, Vu H, et al. Heterosubtypic immunity to influenza A virus infection requires a properly diversified antibody repertoire. J Virol. 2007;81:9331-8 pubmed
- Fujisaki S, Sato A, Toyomoto T, Hayano T, Sugai M, Kubota T, et al. Direct binding of TReP-132 with TdT results in reduction of TdT activity. Genes Cells. 2006;11:47-57 pubmed..5% of its maximum value in the in vitro assay system using double-stranded DNA with a 3' protrusion as a primer. These findings suggest that TdT synthesizes N region under a negative control of TReP-132 during V(D)J recombination. ..
- Krutyakov V, Kravetskaya T. DNA polymerases and carcinogenesis. Biochemistry (Mosc). 2010;75:959-64 pubmed..After the lesion is bypassed, DNA synthesis is switched to accurate polymerases ?, ?, ?, or ?. Mechanisms of direct and reverse switches of DNA polymerases as well as their modifications during carcinogenesis are discussed. ..
- Motea E, Lee I, Berdis A. A non-natural nucleoside with combined therapeutic and diagnostic activities against leukemia. ACS Chem Biol. 2012;7:988-98 pubmed publisher..The applications of this novel nucleoside are discussed, focusing on its use as a "theranostic" agent that can improve the accuracy of dosing regimens and accelerate clinical decisions regarding therapeutic intervention. ..
- Lindroos K, Liljedahl U, Raitio M, Syvanen A. Minisequencing on oligonucleotide microarrays: comparison of immobilisation chemistries. Nucleic Acids Res. 2001;29:E69-9 pubmed..The best genotyping results were observed using mercaptosilane-coated slides attaching disulfide-modified oligonucleotides. ..
- Shichijo K, Shin T, Wen C, Nakayama T, Nakashima M, Kaimovich A, et al. Expression of apoptotic epithelial cells in biopsy specimens of patients with colitis. Dig Dis Sci. 2007;52:2037-43 pubmed..Our results suggest that interventions directed toward the apoptotic process may be beneficial in the treatment of colitis. ..
- Mahajan K, Mitchell B. Role of human Pso4 in mammalian DNA repair and association with terminal deoxynucleotidyl transferase. Proc Natl Acad Sci U S A. 2003;100:10746-51 pubmed..Loss of hPso4 expression induced by siRNA results in accumulation of DSBs, apoptosis, and decreased cell survival after DNA damage. We conclude that hPso4 plays a major and previously undefined role in mammalian DNA DSB repair. ..
- Potts R, Notarianni L, Jefferies T. Seminal plasma reduces exogenous oxidative damage to human sperm, determined by the measurement of DNA strand breaks and lipid peroxidation. Mutat Res. 2000;447:249-56 pubmed..05), when the amount of plasma added exceeded 60% v/v. The results indicate that spermatozoal oxidative damage induced by exogenous ROS, specifically DNA damage and lipid peroxidation, is reduced by the presence of seminal plasma. ..
- Pandey V, Modak M. Biochemistry of terminal deoxynucleotidyltransferase. Identification and unity of ribo- and deoxyribonucleoside triphosphate binding site in terminal deoxynucleotidyltransferase. J Biol Chem. 1989;264:867-71 pubmed
- Fine J, Silverstone A, Gasiewicz T. Impairment of prothymocyte activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Immunol. 1990;144:1169-76 pubmed..These data suggest that TCDD-induced thymic atrophy is the result, at least in part, of impaired thymic seeding by prothymocytes. ..
- Koduri P. The diagnostic approach to mediastinal masses. Ann Thorac Surg. 2004;78:1888; author reply 1888 pubmed
- Schrader C, Bradley S, Vardo J, Mochegova S, Flanagan E, Stavnezer J. Mutations occur in the Ig Smu region but rarely in Sgamma regions prior to class switch recombination. EMBO J. 2003;22:5893-903 pubmed..Finally, we find that mice expressing a transgene for terminal deoxynucleotidyl transferase (TdT) have nucleotide insertions at S-S junctions, indicating that the recombining DNA ends are accessible to end-processing enzyme activities. ..
- Lucas D, Bentley G, Dan M, Tabaczka P, Poulik J, Mott M. Ewing sarcoma vs lymphoblastic lymphoma. A comparative immunohistochemical study. Am J Clin Pathol. 2001;115:11-7 pubmed..Both epitopes are well preserved in fixed and decalcified tissue. A panel composed of antibodies to CD99 and TdT, in conjunction with other lymphocytic markers and vimentin, is highly sensitive and specific. ..