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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthesis of telomeric repeats at chromosome ends requires telomerase, a ribonucleoprotein enzyme. The RNA subunit, which contains the template for DNA synthesis, has been identified in many organisms. Recently, the protein subunit that catalyzes telomeric DNA extension has also been identified in Euplotes aediculatus and Saccharomyces cerevisiae. It has sequence and functional characteristics of a reverse transcriptase related to retrotransposon and retroviral reverse transcriptases, so this new family of telomerase subunits has been named TRT (Telomerase Reverse Transcriptase). We find it remarkable that the same type of protein structure required for retroviral replication is now seen to be essential for normal chromosome telomere replication in diverse eukaryotes.
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PMID:Telomerase is a true reverse transcriptase. A review. 946 43

Telomeres, the natural ends of linear eukaryotic chromosomes, are essential for protecting chromosomes from degradation and fusion. The synthesis of telomere DNA repeats in most eukaryotes is performed by a special enzyme, telomerase. Telomerase, a ribonucleoprotein enzyme, is a specialized reverse transcriptase utilizing its RNA moiety as a template for synthesis of telomeric DNA. Enzymatic properties and results of comparative analysis of telomerase RNA and protein structures from different eukaryotic systems are discussed in this review.
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PMID:Telomerase is an unusual RNA-containing enzyme. A review. 946 44

Barbara McClintock began investigating plant telomeres during the 1930s, but little additional work was done in this area until a telomeric DNA sequence was isolated and characterized from Arabidopsis thaliana in 1988. This sequence, a simple repeat of the heptanucleotide 5'-TTTAGGG-3', has been found in telomeres of almost all plants analyzed. Telomere length in plants, which can be a long as 75 kb or as short as 2 kb, is controlled by both genetic and developmental factors. The major mechanism for synthesis of telomeres is telomerase, a ribonucleoprotein with reverse transcriptase activity. Telomerase expression is highly regulated in both plants and animals. For example, there is little or no detectable expression of telomerase in most vegetative tissues of plants nor in most somatic tissues of animals. In contrast to animals, plants do not specify a germ line until late in development, but telomerase is reactivated during flowering, possibly to ensure that gametes and embryos arising from them inherit fully functional chromosomes. Telomerase is also highly expressed in plant tissue culture cells, as might be expected for cells with an unlimited capacity for proliferation. Despite recent progress in investigating plant telomeres and telomerase at the molecular level, there is still much more to learn, especially concerning the developmental control of telomerase activity.
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PMID:Plant telomeres and telomerases. A review. 946 46

Two types of spontaneously transformed cells appear in the culture of senescent mouse embryonic fibroblasts. The first type are cells with restricted proliferative potential (up to 30 population doublings); the other type are immortalized cells. Cells of the first type, unlike those of the second, have no telomerase activity and undergo two rounds of senescence. Spontaneous transformation of mouse embryonic fibroblasts in the presence of the reverse transcriptase inhibitors azidothymidine and carbovir led to the formation of telomerase-free clones. A fraction of these clones have the ability to overcome senescence via the acquisition of high telomerase activity. Cells with a very high level of telomerase activity become resistant to azidothymidine and carbovir. Azidothymidine-induced artificial senescence of rat myoblasts in culture resembles the senescence of fibroblasts, but the resulting cells acquire sharp morphological peculiarities. The blockade of telomerase function by azidothymidine in human U-937 and MeWo cells leads to the shortening of telomeres, but does not result in senescence. A hypothesis of the generation of the signal that induces senescence is proposed. This hypothesis suggests a change in DNA conformation during telomere shortening as a result of a change of loop structure of telomeric chromatin.
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PMID:Blockade of telomerase function by nucleoside analogs. 946 54

Telomerase, a cellular reverse transcriptase, has been detected in the majority of human malignant tumors, where it provides an escape mechanism from proliferative limitations due to progressive telomere erosion with each cell division. In this study, we used a non-radioactive telomeric repeat amplification protocol (TRAP) with an internal telomerase assay standard for the detection and semiquantitative analysis of 98 single frozen sections of normal breast tissue and benign and malignant breast lesions on an automated laser-fluorescence sequencer. Telomerase activity was detected in 36 of 40 (90%) infiltrating breast carcinomas, whereas no activity was found in nonmalignant breast tissues including blunt duct adenosis, papilloma, ductal hyperplasia and atypical ductal hyperplasia. However, telomerase activity was detected in 59% of ductal in situ carcinomas, suggesting that telomerase reactivation is an early event in breast carcinogenesis. We found a positive correlation between telomerase activity levels and cell proliferation determined by MIB1 immunostaining. No correlation, however, could be demonstrated between telomerase activity and other known breast cancer prognostic indicators. Telomerase activity was also detected in 60% of fibroadenomas indicating that careful interpretation of analysis of telomerase activity in fine needle aspirates is required, since low telomerase activity may not necessarily be an indicator of malignancy in breast tissue.
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PMID:Telomerase activity in human proliferative breast lesions. 947 5

In addition to a reverse transcriptase activity, telomerase is associated with a DNA endonuclease that removes nucleotides from a primer 3' terminus prior to telomere repeat addition. Here we examine the DNA specificity of the primer cleavage-elongation reaction carried out by the Euplotes crassus telomerase. We show that the primer cleavage activity copurified with the E. crassus telomerase polymerase, indicating that it either is an intrinsic property of telomerase or is catalyzed by a tightly associated factor. Using chimeric primers containing stretches of telomeric DNA that could be precisely positioned on the RNA template, we found that the cleavage site is more flexible than originally proposed. Primers harboring mismatches in dT tracts that aligned opposite nucleotides 37 to 40 in the RNA template were cleaved to eliminate the mismatched residues along with the adjacent 3' sequence. The cleaved product was then elongated to generate perfect telomeric repeats. Mismatches in dG tracts were not removed, implying that the nuclease does not track coordinately with the polymerase active site. Our data indicate that the telomerase-associated nuclease could provide a rudimentary proofreading function in telomere synthesis by eliminating mismatches between the DNA primer and the 5' region of the telomerase RNA template.
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PMID:Flexible positioning of the telomerase-associated nuclease leads to preferential elimination of nontelomeric DNA. 948 71

Telomerase is a specialized reverse transcriptase that catalyzes telomeric repeat addition at the ends of existing telomeres or fragmented chromosomes. Two telomerase proteins from Tetrahymena thermophila, p80 and p95, were identified on the basis of their association with telomerase activity and telomerase RNA. Here we have produced recombinant versions of these proteins to characterize their functions in the ribonucleoprotein. Our findings indicate that the two proteins can form a complex whose association is independent of RNA. Each protein interacts directly with telomerase RNA, but the p80/p95 complex binds RNA with an affinity substantially greater than either protein alone. We have also characterized the DNA binding properties of p95 and show that it interacts with telomeric substrate DNAs with a specificity characteristic of the functionally defined Tetrahymena telomerase substrate anchor site. Together, these findings suggest a model in which protein-nucleic acid interactions separable from the active site contribute to positioning the template and primer, rather than exclusively the direct nucleic acid-active site interaction typical of other polymerases.
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PMID:Interaction of recombinant Tetrahymena telomerase proteins p80 and p95 with telomerase RNA and telomeric DNA substrates. 949 6

Centromeres are critical structures in cell division, and CENP-B is the most important protein of the centromeric complex recognized by autoantibodies from patients with scleroderma. Our major aim was to demonstrate whether CENP-B is a conserved protein along the phylogenic scale including the higher plants. Vegetal and human cell proteins were extracted from Phaseolus vulgaris and HEp-2 cells and were characterized by PAGE, Western blot, and human autoimmune sera containing anti-CENP-B autoantibodies. The aminoterminus of the gene encoding for CENP-B from HEp-2 cells and Phaseolus vulgaris was isolated by reverse transcriptase-PCR using complementary oligonucleotides to the human CENP-B gene. Also, in situ hybridization was performed on vegetal tissues and HEp-2 cells using human CENP-B box probes. Our main results were as follows: 1) Autoimmune sera were reactive to a vegetal protein of 80 kDa. 2) Affinity-purified anti-CENP-B antibodies recognized a protein from Phaseolus vulgaris with molecular mass similar to that found in human cells. Vegetal and HEp-2 cells CENP-B proteins were immunologically identical. 3) Using RT-PCR, we were able to amplify a cDNA encoding for the aminoterminus domain of CENP-B from Phaseolus vulgaris that had the same molecular behaviour as the cDNA from HEp-2 cells. 4) Complementary oligonucleotides for human CENP-B box hybridized a DNA sequence from Phaseolus vulgaris. In conclusion, CENP-B protein is a conserved protein along the phylogenic scale from humans to higher plants.
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PMID:CENP-B autoantigen is a conserved protein from humans to higher plants: identification of the aminoterminal domain in Phaseolus vulgaris. 951 8

HeT-A was the first transposable element shown to have a bona fide role in chromosome structure, maintenance of telomeres in Drosophila melanogaster. HeT-A has hallmarks of non-long-terminal-repeat (non-LTR) retrotransposable elements but also has several unique features. We have now isolated HeT-A elements from Drosophila yakuba, showing that the retrotransposon mechanism of telomere maintenance predates the separation of D. melanogaster and D. yakuba (5-15 million years ago). HeT-A elements from the two species show significant sequence divergence, yet unusual features seen in HeT-Amel are conserved in HeT-Ayak. In both species, HeT-A elements are found in head-to-tail tandem arrays in telomeric heterochromatin. In both species, nearly half of the HeT-A sequence is noncoding and shows a distinctive imperfect repeat pattern of A-rich segments. Neither element encodes reverse transcriptase. The HeT-Amel promoter appears to be intermediate between the promoters of non-LTR and of LTR retrotransposons. The HeT-Ayak promoter shows similar features. HeT-Amel has a frameshift within the coding region. HeT-Ayak does not require a frameshift but shows conservation of the polypeptide sequence of the frameshifted product of D. melanogaster.
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PMID:Unusual features of the Drosophila melanogaster telomere transposable element HeT-A are conserved in Drosophila yakuba telomere elements. 952 Apr 42

The past year has seen significant advances in our understanding of telomerase and other factors involved in chromosome end maintenance. The protein subunit of telomerase that provides the active site for telomeric DNA synthesis was identified in ciliates, yeast and mammals. It is structurally related to reverse transcriptase and thus represents the first member of this protein family with an essential cellular function. Telomere DNA-binding proteins that may mediate the interaction of telomerase with telomeres have been identified and further characterized in diverse eukaryotes. A further elucidation of telomeric DNA structure has influenced our view of how telomeres replicate.
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PMID:Telomerase and chromosome end maintenance. 961 Apr 14


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