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 identified the mouse telomerase reverse transcriptase component (mTERT) and demonstrate both substantial sequence homology to the human ortholog (hTERT), and the presence of reverse transcriptase and telomerase specific motifs. Furthermore, we show functional interchangeability with hTERT in in vitro telomerase reconstitution experiments, as mTERT produces strong telomerase activity in combination with the human telomerase RNA component hTR. The mouse TERT is widely expressed at low levels in adult tissues, with greatest abundance during embryogenesis and in adult thymus and intestine. The mTERT component mRNA levels were regulated during both differentiation and proliferation, while mTR levels remained constant throughout both processes. Comparison of mTERT and mTR levels to telomerase activity indicates that mTERT expression is more tightly linked to the regulation of telomerase activity during these processes than is mTR. In contrast to the situation in human cell cultures, mTERT transcript levels are present at readily detectable levels in primary cultured cells and are not upregulated following crisis. The widespread expression of mTERT in primary cells and mouse tissues could explain the increased frequency of spontaneous immortalization of mouse cells in culture and tumorigenesis in vivo.
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PMID:Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. 958 20

On the basis of its predicted homology to human telomerase reverse transcriptase (hTERT), a cDNA for Arabidopsis thaliana TERT (AtTERT) has now been isolated from cultured cells. The cDNA contains an open reading frame of 3372 bp, encoding a protein with a predicted size of 131 kDa and isoelectric point of 9.9. The AtTERT protein contains the conserved reverse transcriptase motifs 1, 2 and A-E as well as the TERT-specific T motif. Reverse transcription-polymerase chain reaction analysis and an assay of telomerase activity revealed that both AtTERT mRNA and telomerase activity are abundant in shoot apical meristems but are not detectable in rosette leaves.
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PMID:Molecular cloning and characterization of AtTERT, a telomerase reverse transcriptase homolog in Arabidopsis thaliana. 1047 30

WRN encodes a RecQ helicase, which is mutated in Werner syndrome. Werner syndrome is a genetic condition of young adults characterized by premature aging, limited replicative capacity of cells in vitro, and increased cancer risk. Telomerase is a reverse transcriptase that extends the G-rich strand of telomeric DNA. Primary cells in vitro typically lack telomerase activity and undergo senescence, whereas telomerase is reactivated in many, but not all, tumors. The roles of the two genes are not known to be related. Here we report the development of an effective colony-forming assay in which a SV40-transformed Werner fibroblast cell line is 6-18-fold more sensitive to 4-nitroquinoline 1-oxide than SV40-transformed normal cell lines. The sensitivity can be partially reversed by transfecting a normal WRN gene but not a mutated WRN gene into the cells. Curiously, the sensitivity can be reversed equally well by transfecting a telomerase gene (TERT) into the cells. These data indicate the possibility of an interdependent function of these two genes.
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PMID:WRN or telomerase constructs reverse 4-nitroquinoline 1-oxide sensitivity in transformed Werner syndrome fibroblasts. 1081 Nov 12

The catalytic subunit of telomerase (TERT) is a specialized reverse transcriptase that has been associated with cell immortalization and cancer. It was reported recently that TERT is expressed in neurons throughout the brain in embryonic and early postnatal development, but is absent from neurons in the adult brain. We now report that suppression of TERT levels and function in embryonic mouse hippocampal neurons in culture using antisense technology and the telomerase inhibitor 3' -azido-2' 3' -dideoxythymidine significantly increases their vulnerability to cell death induced by amyloid beta-peptide, a neurotoxic protein believed to promote neuronal degeneration in Alzheimer's disease. Neurons in which TERT levels were reduced exhibited increased levels of oxidative stress and mitochondrial dysfunction following exposure to amyloid beta-peptide. Overexpression of TERT in pheochromocytoma cells resulted in decreased vulnerability to amyloid beta-peptide-induced apoptosis. Our findings demonstrate a neuroprotective function of TERT in an experimental model relevant to Alzheimer's disease, and suggest the possibility that restoration of TERT expression in neurons in the adult brain may protect against age-related neurodegeneration.
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PMID:The catalytic subunit of telomerase protects neurons against amyloid beta-peptide-induced apoptosis. 1085 54

Telomerase is a ribonucleoprotein reverse transcriptase responsible for the maintenance of one strand of telomere terminal repeats. The key protein subunit of the telomerase complex, known as TERT, possesses reverse transcriptase-like motifs that presumably mediate catalysis. These motifs are located in the C-terminal region of the polypeptide. Hidden Markov model-based sequence analysis revealed in the N-terminal region of all TERTs the presence of four conserved motifs, named GQ, CP, QFP, and T. Point mutation analysis of conserved residues confirmed the functional importance of the GQ motif. In addition, the distinct phenotypes of the GQ mutants suggest that this motif may play at least two distinct functions in telomere maintenance. Deletion analysis indicates that even the most N-terminal nonconserved region of yeast TERT (N region) is required for telomerase function. This N region exhibits a nonspecific nucleic acid binding activity that probably reflects an important physiologic function. Expression studies of various portions of the yeast TERT in Escherichia coli suggest that the N region and the GQ motif together may constitute a stable domain. We propose that all TERTs may have a bipartite organization, with an N-GQ domain connected to the other motifs through a flexible linker.
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PMID:Identification of functionally important domains in the N-terminal region of telomerase reverse transcriptase. 1086 75

Telomerases contain an essential RNA subunit (TER), as well as an essential protein reverse transcriptase subunit (TERT). The RNA subunit includes a short template region that is copied into telomeric DNA, but otherwise it is large and divergent. However, phylogenetic studies have revealed a conserved core secondary structure for TER. Much of the divergence can be accounted for by the acquisition of different types of RNA domains that function in RNA stabilization. Some of the nontemplate portions of TER, which include regions in the conserved core, are important for aspects of telomerase enzymatic activity independent of their role in telomerase assembly. Mutational studies indicate that telomerase enzyme function results from a collaboration of both protein and RNA functional groups contributed by TERT and TER.
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PMID:The end of the (DNA) line. 1101 90

The telomerase holoenzyme consists of two essential components, a reverse transcriptase, TERT (telomerase reverse transcriptase), and an RNA molecule, TR (telomerase RNA, also known as TERC), that contains the template for the synthesis of new telomeric repeats. Telomerase RNA has been isolated from 32 different vertebrates, and a common secondary structure has been proposed (Chen, J.-L., Blasco, M. A., and Greider, C. W. (2000) Cell 100, 503-514). We have generated 25 mutants in the four conserved structural domains of the mouse telomerase RNA molecule, mTR, and assayed their ability to reconstitute telomerase activity in mTR(-/-) cells in vivo. We found that the pseudoknot and the CR4/CR5 domains are required for telomerase activity but are not essential for mTR stability in the cell, whereas mutations in the BoxH/ACA and the CR7 domains affect mTR accumulation in the cell. We have also identified mTR mutants that are able to inhibit wild type telomerase in vivo.
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PMID:Identification of functional domains and dominant negative mutations in vertebrate telomerase RNA using an in vivo reconstitution system. 1105 67

Mammalian telomerase is essential for the maintenance of telomere length [1-5]. Its catalytic core comprises a reverse transcriptase component (TERT) and an RNA component. While the biochemical role of mammalian TERT is well established [6-11], it is unknown whether it is sufficient for telomere-length maintenance, chromosome stability or other cellular processes. Cells from mice in which the mTert gene had been disrupted showed progressive loss of telomere DNA, a phenotype similar to cells in which the gene encoding the telomerase RNA component (mTR) has been disrupted [1,12]. On prolonged growth, mTert-deficient embryonic stem (ES) cells exhibited genomic instability, aneuploidy and telomeric fusions. ES cells heterozygous for the mTert disruption also showed telomere attrition, a phenotype that differs from heterozygous mTR cells [12]. Thus, telomere maintenance in mammals is carried out by a single, limiting TERT.
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PMID:The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo. 1110 10

Telomerase is an enzyme consisting of a reverse transcriptase called TERT and an RNA component that adds repeats of a DNA sequence (TTAGGG) to the ends of chromosomes, thereby preventing their shortening and cell cycle arrest. Telomerase levels are high in neural progenitor cells and neurons during early development, and decrease in association with cell differentiation. A role for TERT in regulation of developmental death of neurons is suggested by a decrease in TERT expression that coincides with the period of neuronal death and by data showing that TERT promotes survival of developing brain neurons. Suppression of telomerase activity and TERT expression promotes apoptosis, whereas overexpression of TERT prevents apoptosis by suppressing cell death at a premitochondrial step in the death cascade Moreover, neurotrophic factors known to play important roles in brain development can regulate telomerase activity and TERT expression in cultured neural cells. A better understanding of the functions of telomerase and TERT in neuronal differentiation and survival may lead to novel approaches for preventing neuronal death and promoting recovery in various neurodegenerative conditions. J. Neurosci. Res. 63:1-9, 2001. Published 2001 Wiley-Liss, Inc.
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PMID:Emerging roles for telomerase in neuronal development and apoptosis. 1116 8

Telomerase is a specialized reverse transcriptase (RT) that is minimally composed of a protein catalytic subunit and an RNA component. The RNA subunit contains a short template sequence that directs the synthesis of DNA repeats at the ends of chromosomes. Human telomerase activity can be reconstituted in vitro by the expression of the human telomerase protein catalytic subunit (hTERT) in the presence of recombinant human telomerase RNA (hTR) in a rabbit reticulocyte lysate (RRL) system. We analyzed telomerase activity and binding of hTR to hTERT in RRL by expressing different hTERT and hTR variants. hTRs containing nucleotide substitutions that are predicted to disrupt base pairing in the P3 helix of the pseudoknot weakly reconstituted human telomerase activity yet retained their ability to bind hTERT. Our results also identified two distinct regions of hTR that can independently bind hTERT in vitro. Furthermore, sequences or structures between nucleotides 208 and 330 of hTR (which include the conserved CR4-CR5 domain) were found to be important for hTERT-hTR interactions and for telomerase activity reconstitution. Human TERT carboxy-terminal amino acid deletions extending to motif E or the deletion of the first 280 amino acids abolished human telomerase activity without affecting the ability of hTERT to associate with hTR, suggesting that the RT and RNA binding functions of hTERT are separable. These results indicate that the reconstitution of human telomerase activity in vitro requires regions of hTERT that (i) are distinct from the conserved RT motifs and (ii) bind nucleotides distal to the hTR template sequence.
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PMID:Functional regions of human telomerase reverse transcriptase and human telomerase RNA required for telomerase activity and RNA-protein interactions. 1123 25


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