Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Terminal deoxynucleotidyltransferase is the only DNA polymerase that is strongly inhibited in the presence of ATP. We have labeled calf terminal deoxynucleotidyltransferase with [32P]ATP in order to identify its binding site in terminal deoxynucleotidyltransferase. The specificity of ATP cross-linking to terminal deoxynucleotidyltransferase is shown by the competitive inhibition of the overall cross-linking reaction by deoxynucleoside triphosphates, as well as the ATP analogs Ap4A and Ap5A. Tryptic peptide mapping of [32P]ATP-labeled enzyme revealed a peptide fraction that contained the majority of cross-linked ATP. The properties, chromatographic characteristics, amino acid composition, and sequence analysis of this peptide fraction were identical with those found associated with dTTP cross-linked terminal deoxynucleotidyl-transferase peptide (Pandey, V. N., and Modak, M. J. (1988a). J. Biol. Chem. 263, 3744-3751). The involvement of the same 2 cysteine residues in the crosslinking of both nucleotides further confirmed the unity of the ATP and dTTP binding domain that contains residues 224-237 in the primary amino acid sequence of calf terminal deoxynucleotidyltransferase.
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PMID:Biochemistry of terminal deoxynucleotidyltransferase. Identification and unity of ribo- and deoxyribonucleoside triphosphate binding site in terminal deoxynucleotidyltransferase. 291 Aug 67

To assess the involvement of terminal transferase in generating immunoglobulin diversity, the mutagenic potential of this enzyme has been measured. The frequency of single base substitutions during copying of phi X174 DNA by DNA polymerase beta is increased by, at most, 3-fold upon the addition of terminal transferase. However, terminal transferase is highly mutagenic, either alone or with DNA polymerase beta, in a forward mutation assay using M13mp2 DNA. The frequency of complex mutants, as determined by DNA sequence, is increased by greater than 100-fold. These mutants involve the deletion of a variable number of bases initially present in the template sequence and the addition of a sequence of nucleotides rich in guanine residues. Analysis of these mutants suggests an antibody diversity model implicating terminal transferase in the imprecise linkage of variable, joining, and diversity segments during the formation of functional immunoglobulin genes.
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PMID:Rearrangements of DNA mediated by terminal transferase. 293 62

We have addressed the possibility of terminal transferase involvement in somatic mutagenesis and the creation of N-region diversity, by measuring the ability of TdT to enhance single-base substitution mutagenesis during in vitro DNA synthesis. Using 3 independent assays we find that terminal transferase produces only a small increase in base-substitution mutagenesis when assayed in the presence of DNA polymerase-beta. In the presence of either polymerase-alpha or E. coli polymerase-I, however, no detectable increase in TdT-induced mutagenesis is seen. Furthermore, in an assay capable of detecting a variety of mutational events, terminal transferase primarily produces complex addition/deletion mutations, as well as a few multiple, tightly-clustered, single-base mutations. We conclude that the majority of the scattered single-base changes that occur during antibody gene differentiation are not catalyzed by terminal transferase, but instead result from another error-prone DNA synthetic process (possibly utilizing DNA polymerase-beta).
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PMID:Base substitution mutagenesis by terminal transferase: its role in somatic mutagenesis. 295 4

Protein candidates for the attachment of DNA within eukaryotic cell nuclei were identified by isolating nuclear matrix proteins and determining which of those proteins co-sedimented with DNA within a 5.7 M CsCl gradient. The presence of attached nucleic acid was detected after the proteins were subjected to the denaturing conditions of isoelectric focusing/sodium dodecyl sulfate two-dimensional polyacrylamide gel electrophoresis. The attached nucleic acid was detected with silver staining, ethidium bromide, and Amido Black binding. The nucleic acid was identified as DNA based on its ability to be labeled in vitro by terminal deoxynucleotidyltransferase and DNA polymerase I (Klenow). Three proteins were identified as containing attached DNA, one of which was vimentin. The proteins had apparent Mr and pI values of 70,000, 4.3; 70,000, 5.3; and 57,000, 4.8, respectively. We propose that these proteins are within a class of nuclear proteins containing firmly attached DNA and have referred to them as DNA attachment proteins.
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PMID:Identification of attachment proteins for DNA in Chinese hamster ovary cells. 319 45

Chromosome ends in the lower eukaryotes terminate in variable numbers of tandem, simple DNA repeats. We tested predictions of a model in which these telomeric repeats provide a substrate for the addition of more repeats by a terminal transferase-like mechanism that, in concert with DNA polymerase and primase, effectively counterbalances the loss of DNA due to degradation or incomplete replication. For individual chromosome ends in yeast, the mean length of any given telomere was shown to vary between different clonal populations of the same strain and to be determined by the initial length of that telomere in the single cell giving rise to the clone. This type of variation was independent of the major yeast recombination pathway. The length heterogeneity at each telomeric end increased with additional rounds of cell division or DNA replication. Lengths of individual telomeres within a single clone varied independently of each other. Thus, this clonal variability is distinct from genetic regulation of chromosome length, which acts on all chromosome ends coordinately. These in vivo phenomena suggest that lengthening and shortening activities act on yeast telomeres during each round of replication.
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PMID:Generation of telomere-length heterogeneity in Saccharomyces cerevisiae. 327 78

The Protein Identification Resource (PIR) protein sequence data bank was searched for sequence similarity between known proteins and human DNA polymerase beta (Pol beta) or human terminal deoxynucleotidyltransferase (TdT). Pol beta and TdT were found to exhibit amino acid sequence similarity only with each other and not with any other of the 4750 entries in release 12.0 of the PIR data bank. Optimal amino acid sequence alignment of the entire 39-kDa Pol beta polypeptide with the C-terminal two thirds of TdT revealed 24% identical aa residues and 21% conservative aa substitutions. The Monte Carlo score of 12.6 for the entire aligned sequences indicates highly significant aa sequence homology. The hydropathicity profiles of the aligned aa sequences were remarkably similar throughout, suggesting structural similarity of the polypeptides. The most significant regions of homology are aa residues 39-224 and 311-333 of Pol beta vs. aa residues 191-374 and 484-506 of TdT. In addition, weaker homology was seen between a large portion of the 'nonessential' N-terminal end of TdT (aa residues 33-130) and the first region of strong homology between the two proteins (aa residues 31-128 of Pol beta and aa residues 183-280 of TdT), suggestive of genetic duplication within the ancestral gene. On the basis of nucleotide differences between conserved regions of Pol beta and TdT genes (aligned according to optimally aligned aa sequences) it was estimated that Pol beta and TdT diverged on the order of 250 million years ago, corresponding roughly to a time before radiation of mammals and birds.
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PMID:Genetic relatedness of human DNA polymerase beta and terminal deoxynucleotidyltransferase. 344

Terminal deoxynucleotidyltransferase (TdT) is a DNA polymerase expressed in immature lymphocytes of the thymus and bone marrow, as well as certain leukemic cells. Chromosomal assignment of the gene coding for human TdT was accomplished by in situ hybridization of a 3H-labeled cDNA probe to human chromosome preparations and by Southern blot analysis of somatic cell hybrid DNAs. The human TdT gene was mapped to the region q23----q24 of chromosome 10. Breaks at this site have been reported in different translocations in human leukemias. The mouse TdT gene was assigned to chromosome 19 by Southern blot analysis of mouse X Chinese hamster somatic cell hybrids. This result adds a fourth locus to the conserved syntenic group on mouse chromosome 19 and human chromosome 10.
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PMID:The terminal deoxynucleotidyltransferase gene is located on human chromosome 10 (10q23----q24) and on mouse chromosome 19. 346 97

Until recently, lineage fidelity was thought to be preserved in leukaemic cells, which by available tests showed surface markers and enzymatic patterns characteristic of an appropriate normal cell lineage and stage of differentiation. Our data indicate that this theory is too restrictive. If leukaemogenesis occurs in pluripotent progenitors in a relatively high percentage of cases, we would propose a model in which lymphoid and myeloid differentiation antigens are expressed simultaneously until the progenitor cell commits to a single lineage. Lineage commitment could involve external factors, e.g. growth factors (Sherr et al, 1985), that cause genes specific for the opposite lineage to be 'switched off'. The control of gene expression in mammalian cells and the specific chromosomal sites of genes coding for the various lineage-associated markers remain uncertain. However, recent studies indicate that most, if not all, leukaemic cells contain chromosomal abnormalities, many involving rearrangements of DNA (Williams et al, 1986). Since the control of eukaryotic gene expression is known to involve numerous sequence elements, some acting at a distance from the site of transcription (Dynan and Tjian, 1985), genetic perturbations within the cell (e.g. a reciprocal translocation) could be expected to deregulate certain genes, leading to their under- or overexpression analogous to activation of the c-myc oncogene by the 8;14 translocation in Burkitt's lymphoma. Thus, an almost infinite variety of cell lineage-related phenotypes could be expected from this mechanism alone, even if the transforming event did not involve a pluripotent stem cell. Also, we have hypothesized that enzymes such as TdT, a DNA polymerase that catalyses polymerization of deoxyribonucleotides without a DNA template, could serve as a modifier of DNA sequences, permitting otherwise inactive genes to be expressed (Stass and Mirro, 1985). It is interesting that most cases of childhood acute mixed-lineage leukaemia are TdT positive, even though this is not true for the chronic leukaemias of adults. It is now clear that unusual combinations of myeloid and lymphoid cell lineages are much more common in acute leukaemia than have been generally recognized or suspected. The traditional division of the acute leukaemias into ALL and AML may not be the most accurate way to represent this class of haematological malignancies. That mixed-lineage leukaemia may require alternative therapy is a clinically important observation and underscores the need for comprehensive testing of blast cells at diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lineage heterogeneity in acute leukaemia: acute mixed-lineage leukaemia and lineage switch. 353 42

We evaluated a newly developed solid-phase immunoassay (EIA) of terminal deoxynucleotidyl transferase (TdT, EC 2.7.7.3) and compared it with the enzymatic assay of TdT involving DNA polymerase. We assessed the precision, performance characteristics, and clinical efficacy of the EIA procedure, using 249 specimens of peripheral blood and bone marrow and 118 specimens of whole blood. On linear regression analysis of results for these 249 samples as measured by the two procedures, the correlation coefficient was 0.87. Distribution of TdT in mononuclear cells isolated from whole blood and bone marrow of subjects in several disease categories indicated good concordance between the two assay procedures. The EIA procedure is precise, can be performed on whole blood without first isolating mononuclear cells, is nonisotopic, and shows potential as a quantitative indicator for the differential diagnosis and monitoring of human leukemia.
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PMID:Solid-phase enzyme immunoassay of terminal deoxynucleotidyl transferase evaluated. 354

Nucleotide sequence analysis of the cDNA and the genomic clones for rat DNA polymerase beta revealed the existence of a 1,005-base pair open reading frame capable of encoding a Mr = 38,269 polypeptide of 335 amino acid residues. The region of 174 amino acid residues between the 42nd and 215th residues of the DNA polymerase beta polypeptide has extensive amino acid sequence homology with the region between the 195th and 366th residues of human terminal deoxynucleotidyltransferase. The two enzymes share extensive homology not only in primary structures but also in the computer-derived higher structures in these particular regions. The genes for DNA polymerase beta and terminal deoxynucleotidyltransferase are proposed to be derived from a common ancestral DNA polymerase gene.
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PMID:Homology between mammalian DNA polymerase beta and terminal deoxynucleotidyltransferase. 359 2


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