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)

We have investigated the physical distribution of the reverse transcriptase genes of Ty1-copia-like retrotransposable elements from 12 plant species belonging to different subdivisions by hybridization in situ on chromosome preparations. Ty1-copia-like elements showed different and non-random hybridization patterns. A dispersed distribution throughout most of the chromosomes with reduced hybridization at some regions or with some weak clustering at other regions was found in Allium cepa, Beta vulgaris, Brassica campestris, Brassica oleracea, Pennisetum glaucum, Pinus elliottii, Selaginella apoda, Vicia faba and Vicia narbonensis. Reduced hybridization occurred mainly at centromeric regions, nucleolus-organizing regions and regions known to be mainly composed of tandemly repeated sequences. In the fern Pteris cretica the retroelements showed a dispersed genomic organization with clustering at some chromosomal regions and whole chromosomes showing little signal. In Arabidopsis thaliana and Cicer arietinum Ty1-copia-like elements were found in clusters at the paracentromeric heterochromatin, a novel organization for a repetitive element in A. thaliana. New retroelement families were isolated from A. thaliana and from Beta vulgaris. Alignment of the deduced peptide sequences with Ty1-copia-like elements from other plants showed considerable divergence which was used to calculate their relationships, indicating the value of reverse transcriptase gene analysis in phylogenetic and biodiversity studies.
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PMID:Comparative analysis of the chromosomal and genomic organization of Ty1-copia-like retrotransposons in pteridophytes, gymnosperms and angiosperms. 903 55

The ribonucleoprotein enzyme telomerase adds telomeric DNA to chromosomal ends. In most eukaryotes the telomeric repeat units are repeated precisely, consistent with the action of a telomerase that faithfully copies its RNA template. In contrast, Saccharomyces cerevisiae telomeric repeats are degenerate, suggesting that its telomerase has unusual mechanistic properties. We mutated the S. cerevisiae telomerase RNA (TLC1) with a series of 3-base (GUG) substitutions in and next to the 17-nucleotide templating domain. All mutant telomerases were active in TLC1/tlc1 diploids and synthesized patterns of mixed wild-type and mutant telomeric repeats into telomeric DNA, consistent with nonprocessive action. Telomerase isolated from cells containing each mutated tlc1 allele by itself had altered reaction properties in vitro. One mutant template enzyme, 476GUG, was active in vivo and in vitro in the presence of wild-type TLC1 RNA but lacked detectable activity in its absence. Haploid tlc1-476GUG cells containing only this mutant tlc1 allele underwent senescence. Other tlc1 template region mutations allowed maintenance of shortened telomeres in vivo but altered specific enzymatic properties of telomerase in vitro, including induction of primer-template slippage (472GUG) or alteration of the 5' boundary of the template (467GUG). These data demonstrate that telomerase RNA bases influence enzyme activity profoundly, suggesting that their roles are not confined to serving simply as the template for this specialized reverse transcriptase.
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PMID:Telomerase RNA mutations in Saccharomyces cerevisiae alter telomerase action and reveal nonprocessivity in vivo and in vitro. 904 65

Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Telomerase RNA components have been identified from many organisms, but no protein component has been demonstrated to catalyze telomeric DNA extension. Telomerase was purified from Euplotes aediculatus, a ciliated protozoan, and one of its proteins was partially sequenced by nanoelectrospray tandem mass spectrometry. Cloning and sequence analysis of the corresponding gene revealed that this 123-kilodalton protein (p123) contains reverse transcriptase motifs. A yeast (Saccharomyces cerevisiae) homolog was found and subsequently identified as EST2 (ever shorter telomeres), deletion of which had independently been shown to produce telomere defects. Introduction of single amino acid substitutions within the reverse transcriptase motifs of Est2 protein led to telomere shortening and senescence in yeast, indicating that these motifs are important for catalysis of telomere elongation in vivo. In vitro telomeric DNA extension occurred with extracts from wild-type yeast but not from est2 mutants or mutants deficient in telomerase RNA. Thus, the reverse transcriptase protein fold, previously known to be involved in retroviral replication and retrotransposition, is essential for normal chromosome telomere replication in diverse eukaryotes.
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PMID:Reverse transcriptase motifs in the catalytic subunit of telomerase. 928 Oct 66

Telomeres in most species consist of repeat units of a small number of nucleotides that together with secondary structures and associated proteins stabilize the linear chromosomal DNA molecule. Chromosomes lose a small amount of telomeric DNA after each cell replication. It has been proposed that when telomeres shorten below a critical length, a DNA damage response pathway is activated and induces cell cycle arrest. In cells such as stem cells that maintain a proliferative capacity, telomere length is maintained by the reverse transcriptase, telomerase. In addition, telomerase activity is present in 90% of primary human tumors, suggesting a role for telomerase in providing a proliferative capacity to cells, which is a requirement in progression to malignancy. Telomerase activity can be involved in chromosome healing, although telomerase-independent processes also appear to be capable of capping broken chromosome ends. This review describes the structure and maintenance of telomeres, the importance of a critical telomere length to cell proliferation and the telomeric status of broken chromosome ends produced during development or by spontaneous or induced DNA damages.
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PMID:Telomeres, telomerase and chromosome stability. 929 61

The reverse transcriptase inhibitor 3'-azido-deoxythymidine (AZT) has previously been shown to be incorporated into specific regions near the telomeres and centromeres of Chinese hamster ovary cell chromosomes. Our investigation of the effects of AZT on chromosome stability has led to the discovery of a high frequency amplification of telomere-like centromeric DNA. The amplified structures, when analyzed cytogenetically, appear as tandem arrays of tightly clustered blocks of centromeric repeats containing telomeric sequences (TTAGGG)n. There were 5-13 blocks of amplified DNA per structure. These structures form rapidly within one or two cell cycles and can be observed with an incidence as high as 2%. Because the amplification was so rapid, we tested whether the amplification structures could be the result of aberrant overreplication by analyzing BrdU incorporation. Our results indicate that the amplified DNA does not undergo abnormal replication during its formation, but appears to form from existing centromeric regions. We propose a model that involves the excision of multiple centromeric DNA regions from other chromosomes and their relocalization to a new site.
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PMID:AZT induces high frequency, rapid amplification of centromeric DNA. 918 5

AZT (3'-azido-2',3'-dideoxythymidine), the first nucleoside analog approved for the treatment of AIDS (acquired immunodeficiency syndrome), induces significant toxic effects in humans exposed to therapeutic doses. As an inhibitor of the HIV-1 (human immunodeficiency virus 1) reverse transcriptase, AZT blocks the incorporation of nucleotides into the host's newly synthesized DNA. Incorporation of AZT into mammalian DNA as well as specific localization of the drug into telomeric DNA, has been previously documented by immunohistochemistry. As with other nucleoside analogs, AZT has affinity for polymerase-gamma, the enzyme responsible for the replication of mitochondrial DNA. In order to examine the mechanisms of toxic events induced by long-term AZT exposure, human T-lymphocytic H9 cells were cultured with 25 microM AZT for 7 months. In the resulting H9-AZT cells, incorporation of AZT into DNA was demonstrated by radioimmunoassay and immunohistochemistry, chromosomal aberrations and micronuclei were scored and intracellular lipid distribution was determined. Two pmol of AZT per microgram of DNA were detected by radioimmunoassay in H9-AZT cells. Control cells showed negative values in the radioimmunoassay. Cytogenetic observations on H9-AZT cells showed an increase in chromosomal aberrations and nuclear fragmentation when compared with unexposed H9 cells. Electron microscopy revealed mitochondrial damage and an elevated accumulation of neutral intracellular lipid deposits probably as a consequence of a distortion in the beta-oxidation of fatty acids normally carried out by this organelle. The toxicities explored here suggest that the mechanisms of AZT induced cytotoxicity in bone marrow of the patients chronically exposed to the drug in vivo may involve both chromosomal and mitochondrial DNA damage.
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PMID:Genotoxicity and mitochondrial damage in human lymphocytic cells chronically exposed to 3'-azido-2',3'-dideoxythymidine. 918 71

Telomeres are nucleoprotein structures at the ends of eukaryotic chromosomes that perform a number of vital functions. They allow a cell to distinguish between natural chromosome ends and chromosome breaks in order to delay the cell cycle and repair the broken end. Telomeres also compensate for the inability of DNA polymerase to replicate the chromosome completely. In most eukaryotes a special reverse transcriptase, telomerase, adds telomeric DNA repeats to the chromosome ends using an internal RNA template. However, evidence is accumulating for alternative elongation mechanisms in a variety of eukaryotes. In the yeast Saccharomyces cerevisiae, and possibly in humans, both of which normally use telomerase, a different mechanism can be used for chromosome length maintenance when telomerase is inactive or inactivated. Yeast apparently uses recombination for this purpose; the mechanism in humans is not known. Some insect and plant species, on the other hand, do not use telomerase as their primary mechanism for maintaining chromosome length. Drosophila makes use of specific retrotransposons for this purpose, while other dipterans use recombination. We summarize here the current knowledge of these alternative telomere elongation mechanisms.
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PMID:Telomere maintenance without telomerase. 921 55

Six copies of insertion elements accumulate in the subtelomeric region immediately proximal to the telomeric repeats on Chlorella chromosome I. The elements, designated Zepps, bear the characteristic features of non-viral (LINE-like) retrotransposons, including a poly(A) tail, 5'-truncations, a retroviral reverse transcriptase-like ORF and flanking target duplications. Detailed sequence analysis of the Chlorella subtelomeric region revealed a novel mechanism of Zepp transposition; successive insertions of each Zepp element into another Zepp as a target, leaving a tandem array of their 3'-regions with poly(A) tracts facing toward the centromere. Only the most distal Zepp copy was inverted to connect its poly(A) tail with the telomeric repeats. A similar Zepp cluster but without the telomeric repeats was also found at the terminus of another Chlorella chromosome. These structures contrast with that proposed for the addition of HeT-A and TART elements to Drosophila telomeres. Expression of Zepp elements is induced by heat shock treatment. Possible roles of the subtelomeric retrotransposons in formation and maintenance of telomeres are discussed.
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PMID:Zepp, a LINE-like retrotransposon accumulated in the Chlorella telomeric region. 921 12

The ends of vertebrate chromosome are composed of large tracts of a repeated sequence, TTAGGG, which are known as telomeres. Normal somatic cells progressively lose telomeric repeats with each successive cell division due to incomplete replication. Immortal and cancer cells compensate for telomeric loss by expressing the enzyme telomerase, an RNA-dependent DNA polymerase that maintains telomere length. Telomerase activity has been detected in almost 90% of all human cancers. Telomerase activity is generally absent in normal somatic tissues but is detected in adult testes, activated lymphocytes, and lower levels are expressed in proliferative cells of renewal tissues. Telomerase activity is downregulated in cells that exit the cell cycle via either terminal differentiation or (reversible) quiescence. Inhibition of telomerase activity in tumour cells may provide an effective way to treat cancer by potentially reducing the recurrence of tumours due to occult micro-metastases. An understanding of the pathways involved in telomerase regulation will be important for determining the most practical means of inhibiting its activity.
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PMID:Multiple pathways for the regulation of telomerase activity. 928 14

The genomic organisation of the Ty1-copia retrotransposons in rye (Secale cereale) has been studied. We have used the polymerase chain reaction (PCR) to amplify sequences from a conserved domain of the reverse transcriptase gene of the Ty1-copia retrotransposons in this species. Sequence analysis of 26 of these PCR products shows them to be a highly heterogeneous population, a feature that is common in plants. Slot blot analysis shows that there are about 100,000 individual Ty1-copia retrotransposons in rye. In situ hybridization of a heterogeneous probe, representing the whole population of rye Ty1-copia retrotransposon sequences, to chromosome spreads of triticale (xTriticosecale), a rye-wheat hybrid, shows that these sequences are present throughout all the rye chromosomes but absent from the centromeric regions and, in particular, from the terminal heterochromatin. Southern analysis of oat, barley, wheat, and rye, using as a probe R9, one of the rye sequences that is closely similar to the BARE-1 element of barley, shows that close relatives of this retrotransposon subgroup are present in all these species in high copy number. Northern analysis on RNAs from seedlings shows that the BARE-1 subgroup is transcribed in all these cereal plants but in variable amounts: high in barley, moderate in wheat and rye, and extremely low in oat.
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PMID:Characterization and genomic organization of Ty1-copia group retrotransposons in rye (Secale cereale). 935 43


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