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)

Telomerase, the reverse transcriptase that maintains telomere DNA, is usually undetectable in adult human tissues, but is positive in embryonic tissues and in cancers. However, in rodents, several organs of normal adult animals express substantial amounts of telomerase activity. To elucidate relevant control mechanisms operating on the tissue-specific expression of telomerase in rodents, we examined the transcriptional regulation of telomerase reverse transcriptase (mTERT) gene in muscle cell differentiation. Reverse transcriptase-polymerase chain reaction analysis showed that the reduction of telomerase activity was caused by the decrease of mTERT mRNA level during myogenesis. Transfections of mTERT promoter showed that the proximal 225-base pair region is the core promoter responsible for basal transcriptional activity and also participates in the reduced transcription after muscle differentiation. Electrophoretic mobility shift assays showed that this region contained the GC-boxes, which bind to Sp1 family proteins, and the E-box, which binds to c-Myc. Furthermore, DNA binding activities of Sp1, Sp3, and c-Myc were down-regulated during myogenesis. These data suggest that Sp1, Sp3, and c-Myc have critical roles of TERT transactivation in mouse, and the lack of these transcription factors cause down-regulation of mTERT gene expression in muscle cells differentiation.
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PMID:Mechanism for the reduction of telomerase expression during muscle cell differentiation. 1127 34

Telomerase is an enzyme activity 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. Associations between telomerase activity and proliferation and differentiation of neural tumor cells and neural stem cells have been reported, but the role of telomerase in brain development is unknown. We now report analyses of telomerase activity, TERT mRNA levels and levels of mRNAs encoding the telomere-associated proteins TRF1 and TRF2 in three different brain regions (brainstem, hippocampus and cerebral cortex) and the eye of mice at increasing developmental time points. Telomerase activity is high in the brain at embryonic day 13 (E13), declines markedly between E13 and E18, remains at a low level until postnatal day 3 (P3) and becomes undetectable by P10. Surprisingly, the temporal pattern of change in telomerase activity is not paralleled by a decrease in levels of TERT mRNA that remain elevated from E13 to P5 (with fluctuations during this time window that vary among brain regions), and then decrease to a lower level that is maintained into adulthood. TRF1 and TRF2 mRNA levels are relatively constant throughout brain development. Our data are consistent with a role for telomerase activity in proliferation of neural progenitor cells, and further suggest that TERT may play roles in neuronal differentiation and survival. The dissociation between TERT expression and telomerase activity is a novel finding that suggests biological functions for TERT in addition to telomere maintenance. J. Neurosci. Res. 64:252-260, 2001. Published 2001 Wiley-Liss, Inc.
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PMID:Differential regulation of telomerase activity and TERT expression during brain development in mice. 1131 69

Telomerase is a reverse transcriptase that adds repeats of a DNA sequence (TTAGGG) to the ends of chromosomes (telomeres) in mitotic cells, thus maintaining their length and preventing cell cycle arrest and cell death (cellular senescence). During development of the nervous system, telomerase activity levels are high in neural progenitor cells, but then they decrease as cells differentiate or die. The catalytic subunit of telomerase (TERT) remains at relatively high levels during the process of neuronal differentiation and then decreases sharply during the period when synapses form and programmed cell death occurs. TERT promotes survival of developing brain neurons. Suppression of telomerase activity and TERT expression promotes apoptosis of neurons, whereas overexpression of TERT prevents apoptosis by suppressing cell death at a premitochondrial step in the death cascade TERT may suppress DNA damage and/or apoptotic signals activated by damaged DNA. Recent studies of the transcriptional regulation of the TERT gene suggest that this enzyme may mediate the cell survival-promoting actions of diverse signals including estrogen, cytokines and neurotrophic factors. The elucidation of the functions of telomerase activity and TERT in neuronal differentiation and survival may lead to novel approaches for preventing neuronal death and promoting recovery of function in various neurodegenerative conditions.
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PMID:Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist's perspective. 1132 91

The key protein subunit of the telomerase complex, known as TERT, possesses a reverse transcriptase (RT)-like domain that is conserved in enzymes encoded by retroviruses and retroelements. Structural and functional analysis of HIV-1 RT suggests that RT processivity is governed, in part, by the conserved motif C, motif E, and a C-terminal domain. Mutations in analogous regions of the yeast TERT were found to have anticipated effects on telomerase processivity in vitro, suggesting a great deal of mechanistic and structural similarity between TERT and retroviral RTs, and a similarity that goes beyond the homologous domain. A close correlation was uncovered between telomerase processivity and telomere length in vivo, suggesting that enzyme processivity is a limiting factor for telomere maintenance.
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PMID:Analysis of telomerase processivity: mechanistic similarity to HIV-1 reverse transcriptase and role in telomere maintenance. 1143 Aug 23

Functional human telomerase complexes are minimally composed of the human telomerase RNA (hTR) and a catalytic subunit (human telomerase reverse transcriptase [hTERT]) containing reverse transcriptase (RT)-like motifs. The N terminus of TERT proteins is unique to the telomerase family and has been implicated in catalysis, telomerase RNA binding, and telomerase multimerization, and conserved motifs have been identified by alignment of TERT sequences from multiple organisms. We studied hTERT proteins containing N-terminal deletions or substitutions to identify and characterize hTERT domains mediating telomerase catalytic activity, hTR binding, and hTERT multimerization. Using multiple sequence alignment, we identified two vertebrate-conserved TERT N-terminal regions containing vertebrate-specific residues that were required for human telomerase activity. We identified two RNA interaction domains, RID1 and RID2, the latter containing a vertebrate-specific RNA binding motif. Mutations in RID2 reduced the association of hTR with hTERT by 50 to 70%. Inactive mutants defective in RID2-mediated hTR binding failed to complement an inactive hTERT mutant containing an RT motif substitution to reconstitute activity. Our results suggest that functional hTERT complementation requires intact RID2 and RT domains on the same hTERT molecule and is dependent on hTR and the N terminus.
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PMID:Functional multimerization of human telomerase requires an RNA interaction domain in the N terminus of the catalytic subunit. 1180 15

The COOH-terminus of telomerase reverse transcriptase (hTERT) has been shown to participatein the nuclear translocation of TERT. Here, we constructed plasmids expressing the COOH-terminal M(r) 27,000 polypeptide of hTERT (hTERTC27) withthe telomerase RNA-binding domains and the reverse transcriptase domains deleted. We showed that ectopic overexpression of this polypeptide caused a defect in telomere maintenance in hTERT-positive HeLa cells, which led to senescence-like growth arrest and apoptosis. The hTERTC27 appears to work by inducing telomere dysfunction, exemplified by significantly increased anaphase chromosome end-to-end fusion events in transfected cells. Significantly, it had no effect on the cellular telomerase enzymatic activity or telomere length. The in vivo effect was further demonstrated as HeLa cells stably expressing hTERTC27 have significantly lower growth rate and reduced tumorigenicity in nude mice xenografts. Results from this study revealed an important function for the COOH terminus of hTERT in maintaining the integrity of telomere structure and chromosome ends, as well as in cell senescence and apoptosis. Furthermore, hTERTC27 provides a new strategy for cancer therapy by inducing telomere dysfunction in cancer cells without affecting the telomerase enzymatic activity.
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PMID:Ectopic expression of a COOH-terminal fragment of the human telomerase reverse transcriptase leads to telomere dysfunction and reduction of growth and tumorigenicity in HeLa cells. 1203 38

Telomerase is a ribonucleoprotein (RNP) complex that prevents telomeric erosion in eukaryotic cells. Although there are also other associated proteins in this complex, the catalytic activity of this complex is composed of two components. One is a reverse transcriptase subunit, TERT (telomerase reverse transcriptase); another is an RNA template subunit, TR (telomerase RNA). However, where these two parts are assembled in mammalian cells is unclear. In the present study, we investigated the intracellular distribution of human TERT (hTERT) protein and observed that hTERT protein in individual cells could concentrate in or be excluded from the nucleolus. Further we have identified a nucleolar targeting signal in the hTERT protein. Point mutations that disrupted this signal region interrupted telomerase RNP complex formation, decreased telomerase activity, and caused telomere shortening in cells transfected with mutated hTERT. Our results indicate that the amino acid sequence of the extreme N-terminus (1-15) of hTERT, which targets nucleolar localization of the protein, is required for full telomerase function.
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PMID:Nucleolar localization of hTERT protein is associated with telomerase function. 1208 2

Plant chromosomes terminate in telomeres as in other eukaryotes. Telomeres are vital to genome stability and their malfunctioning is lethal. One of the core components of the telomere complex is telomerase. The enzyme activity depends on RNA (TER) and reverse transcriptase (TERT) subunits. We describe here the isolation, sequencing and characterization of the telomerase reverse transcriptase catalytic subunit from the monocot plant Oryza sativa L. (OsTERT). A single copy of this gene is present in the rice genome. The protein predicted from the OsTERT sequence has all the signature motifs of the TERT family members. Our data indicate that rice telomerase activity is developmentally regulated and is high in in vitro tissue and cell culture. However, steady-state transcript levels of the TERT gene do not seem to correlate with enzyme activity. Northern and RT-PCR analyses of the OsTERT gene transcript profile show multiple differentially spliced transcripts in both telomerase-positive and telomerase-negative tissues. Based on quantitative analysis of these transcripts, we speculate that the overall balance between the quantities of particular alternatively spliced transcripts may determine whether the TERT protein(s) is active or not. The diversity of splicing variants detected suggests that, as recently discovered for mammalian TERT proteins, rice TERT protein variants may perform functions other than telomere maintenance.
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PMID:Cloning and characterization of rice (Oryza sativa L) telomerase reverse transcriptase, which reveals complex splicing patterns. 1210 Apr 84

The telomerase ribonucleoprotein reverse transcriptase uses its RNA subunit as a template to synthesize telomeric repeats and maintain telomere tracts on chromosome ends. In the ciliate Euplotes crassus, the core telomerase ribonucleoprotein particle undergoes a developmentally programmed assembly into three higher order complexes after mating. Here, we provide evidence using oligonucleotide-directed affinity purification that all of the E.crassus telomerase complexes contain at least two enzyme active sites. Furthermore, we show using co-immunoprecipitation experiments that EcTERT, the telomerase catalytic subunit, undergoes multimerization in vitro. Two independent interaction domains were identified in EcTERT, one at the N-terminus that spans amino acids 186-354 and one at the C-terminus that spans amino acids 755-857. Unexpectedly, we found that TERT can form head-to-head, tail-to-tail and head-to-tail oligomers in vitro, implying that E.crassus telomerase has the potential to assume different conformations in vivo. Together, these data indicate that oligomerization is a conserved feature of telomerase and that the minimal functional unit of the enzyme is a dimer.
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PMID:Oligomerization of the telomerase reverse transcriptase from Euplotes crassus. 1223 87

Expression of TERT, the reverse transcriptase component of telomerase, is necessary to convert normal human cells to cancer cells. Despite this, "telomerization" by hTERT does not appear to alter the normal properties of cells. In a cell transplantation model in which bovine adrenocortical cells form vascularized tissue structures beneath the kidney capsule in scid mice, telomerization does not perturb the functional tissue-forming capacity of the cells. This cell transplantation model was used to study the cooperation of hTERT with SV40 T antigen (SV40 TAg) and oncogenic Ras in tumorigenesis. Only cells expressing all three genes were tumorigenic; this required large T, but not small t, antigen. These cells produced a continuously expanding tissue mass; they were invasive with respect to adjacent organs and eventually destroyed the kidney. Cells expressing only hTERT or only Ras produced minimally altered tissues. In contrast, SV40 TAg alone produced noninvasive nodules beneath the kidney capsule that had high proliferation rates balanced by high rates of apoptosis. The use of cell transplantation techniques in a cell type that is able to form tissue structures with or without full neoplastic conversion allows the phenotypes produced by individual cooperating oncogenes to be observed.
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PMID:Cooperation of hTERT, SV40 T antigen and oncogenic Ras in tumorigenesis: a cell transplantation model using bovine adrenocortical cells. 1240 43


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