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)

The ribonucleoprotein telomerase is a specialized reverse transcriptase minimally composed of an RNA, TER, and a protein catalytic subunit, TERT. The TER and TERT subunits of telomerase associate to form a dimeric enzyme in several organisms, including human. A small portion of TER, the template domain, is used by telomerase for the synthesis of tandem repeats of telomeric DNA. We studied some of the requirements for processive template usage by human telomerase. A blunt-ended duplex DNA primer was not utilized by telomerase. With a duplex telomeric DNA primer, a single-stranded 3' overhang with a minimum length of approximately 6 bases was required for efficient priming activity. Large substitutions in the human TER templating domain did not abolish enzymatic activity, although insertion of two residues into this sequence reduced processivity, as did a template mutation that results in a mismatch between the template region used for copying DNA and the region used for alignment of the substrate primer. Finally, by using a complementary pair of catalytically inactive telomerase RNA pseudoknot mutants in combination with a marked template, we demonstrated that processive synthesis by an obligatory dimer of human telomerase does not require template switching. These results indicate that processive template usage by human telomerase, like that of Tetrahymena telomerase, is strongly dependent on the base identities in the template domain and that a dimeric human telomerase can processively utilize a single template.
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PMID:Processive utilization of the human telomerase template: lack of a requirement for template switching. 1545 73

Telomerase is a ribonucleoprotein reverse transcriptase responsible for the maintenance of one strand of the telomere terminal repeats. It consists minimally of a catalytic protein component (TERT) and an RNA subunit that provides the template. Compared with prototypical reverse transcriptases, telomerase is unique in possessing a DNA binding domain (anchor site) that is distinct from the catalytic site. Yeast TERT mutants bearing deletion or point mutations in an N-terminal domain (known as N-GQ) were found to be selectively impaired in extending primers that form short hybrids with telomerase RNA. The mutants also suffered a significant loss of repeat addition processivity but displayed an enhancement in nucleotide addition processivity. Furthermore, the mutants manifested altered primer utilization properties for oligonucleotides containing non-telomeric residues in the 5'-region. Cross-linking studies indicate that the N-GQ domain physically contacts the 5'-region of the DNA substrate in the context of a telomerase-telomere complex. Together, these results implicate the N-GQ domain of TERT as a physical and functional constituent of the telomerase anchor site. Coupled with previous genetic analysis, our data confirm that anchor site interaction is indeed important for telomerase function in vivo.
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PMID:A physical and functional constituent of telomerase anchor site. 1590 72

The enzyme telomerase is essential for maintaining the ends of linear chromosomes. It plays an important role in cell proliferation, differentiation, tumorigenesis and aging. Telomerase is composed of an RNA subunit (TR) and a reverse transcriptase catalytic subunit (TERT). We report here the cloning and characterization of the gene encoding the TERT subunit from a teleost fish, Fugu rubripes. This is the first fish TERT gene to be cloned. The fugu TERT (fTERT) gene comprises of 16 exons and 15 introns similar to the human TERT (hTERT), and encodes a 1074 amino acid protein. The fTERT protein showed 33% to 35% sequence identity to other vertebrate TERTs, and contained all the signature motifs of the TERT family. Analysis of the promoter region of fTERT showed the presence of several transcription factor binding sites (E2F-1, E-box, ER, Sp1 and USF sites) in common with the hTERT promoter, and whose binding factors are known to regulate hTERT. The fTERT gene is expressed in a variety of tissues, with high expression detected in the gill, testis, and ovary. fTERT expression was detected in an immortalized fugu eye-derived cell line. The level of expression was found to be higher in actively dividing cells and reduced at quiescence, suggesting cell cycle regulation of TERT and possibly telomerase activity, in this cell line.
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PMID:Cloning and expression of the reverse transcriptase component of pufferfish (Fugu rubripes) telomerase. 1596 Dec 61

Telomerase biology is complicated by studies that show that telomere expression and telomere biology differs between species, and that existing animal models do not closely resemble the human situation. We have previously reported a description of telomere/telomerase biology in the dog and have suggested this as an alternative model system. To further elucidate telomerase biology in this species we have cloned and characterised the canine reverse transcriptase (dogTERT) promoter. We demonstrate that core promoter activity is contained within a region extending approximately 300 bp upstream of the ATG codon. Transient transfections in telomerase-positive canine cell lines and telomerase negative fibroblasts showed that the promoter is only active in telomerase positive cell lines. Sequence analysis demonstrated that the 5' regulatory region is GC-rich and contains no TATA or CAAT box, similar to the human TERT promoter. Motif searches revealed the presence of multiple transcription factor binding sites common to both the human and canine TERT promoters, including a single E-box, Sp1, AP1, MZF-2 and ER/Sp1 binding sites. These findings suggest that the dogTERT gene shares similar transcriptional control to hTERT. Identification of the core promoter necessary for activity may allow the use of naturally occurring cancers in dogs as a preclinical testing ground for telomerase targeted therapies in human cancer patients.
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PMID:The canine telomerase catalytic subunit (dogTERT): characterisation of the gene promoter and identification of proximal core sequences necessary for specific transcriptional activity in canine telomerase positive cell lines. 1605 48

Several types of tumors are known to originate from the pineal region, among them pineal parenchymal tumors (PPTs) and papillary tumors of the pineal region (PTPRs), probably derived from the subcommissural organ. As a result of their rarity, their histologic diagnosis remains difficult. To identify molecular markers, using CodeLink oligonucleotide arrays, gene expression was studied in 3 PPTs (2 pineocytomas and one pineoblastoma), 2 PTPRs, and one chordoid glioma, another rare tumor of the third ventricle. Because PTPR and chordoid glioma may present ependymal differentiation, gene expression was also analyzed in 4 ependymomas. The gene patterns of the 3 PPTs fell in the same cluster. The pineocytomas showed high expression of TPH, HIOMT, and genes related to phototransduction in the retina (OPN4, RGS16, and CRB3), whereas the pineoblastoma showed high expression of UBEC2, SOX4, TERT, TEP1, PRAME, CD24, POU4F2, and HOXD13. Using reverse transcriptase-polymerase chain reaction on 13 PPTs, we demonstrated that PRAME, CD24, POU4F2, and HOXD13 might be candidates for grading PPT with intermediate differentiation. PTPRs, classified with chordoid glioma and separately from ependymomas, showed high expression of SPEDF, KRT18, and genes encoding proteins reported to be expressed in the subcommissural organ, namely ZFH4, RFX3, TTR, and CGRP. Our results highlight the usefulness of gene expression profiling for classify tumors of the pineal region and identify genes with potential use as diagnostic markers.
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PMID:Microarray analysis reveals differential gene expression patterns in tumors of the pineal region. 1682 54

Telomerase is a ribonucleoprotein reverse transcriptase which RNA component (TERC) and reverse transcriptase (TERT) function together to elongate telomeres. If cells are to survive and proliferate indefinitely, telomere preservation is essential for the immortalization process. Somatic cells rarely possess TA, but over 90% of tumor cells express active telomerase. Increased cell proliferation and deregulation of cell cycle occur in human cancers, including cutaneous melanoma. The exact nature of links between TA, cell proliferation and apoptosis has not been extensively elucidated in cutaneous melanoma. We hypothesize a relationship between TA and cutaneous melanoma cell proliferation in a way that TA in telomere elongation is only an early event in cell immortalization. The telomere elongation makes their proliferation possible and being, at the same time, one of its limiting factors. But the TA other than telomere elongation (TERC independent) is crucial to initiate or restore melanoma cell proliferation. On the other hand, TA in telomere elongation, together with other factors (for example TNF), has an active anti-apoptotic role. This way melanoma cells overwhelm the apoptotic defense mechanisms, finally resulting in their indefinite proliferation. In evaluation of our hypothesis, we suggest thorough studies of both telomerase activity and proliferation in cutaneous melanoma on multiple checkpoints and targets. We also suggest combined analyses of TA and telomere length. This approach seems inevitable since it is obvious that telomerase is no longer just for the elongation of telomeres and, to our knowledge, most of the studies conducted so far evaluated TA as an expression of a single subunit or associated molecule.
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PMID:The relationship between telomerase activity and proliferation in cutaneous melanoma. 1689 Oct 62

Telomerase is a ribonucleoprotein that extends the telomeric ends of the chromosomes to counterbalance the natural shortening due to incomplete DNA replication in eukaryotic cells. The core enzyme consists of catalytic reverse transcriptase subunit TERT (Telomerase Reverse Transcriptase) and RNA subunit TER (Telomerase RNA), a short specific region of which serves as a template for synthesis of the telomeric repeats. In this review we focus on the telomerase from yeast Saccharomyces cerevisiae. Despite the intensive research of telomerase in different organisms, the enzyme mechanism remains unclear. The observed peculiarities of the yeast telomerase is of great interest too. Unlike ciliate and human telomerases, yeast enzyme can add only one telomeric repeat to a DNA oligonucleotide (primer) imitating the single-stranded telomeric end of the chromosome and remains stably bound to it after elongation. This review is an attempt to summarise results of numerous studies of the structure and functions of the core enzyme components, their interactions between each other and with a primer, telomerase activity on different substrates in vitro. Also the peculiarities of the telomerase functioning in a cell and accessory proteins of the telomerase complex are discussed.
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PMID:[Telomerase: structure and properties of the enzyme, characteristics of the yeast telomerase]. 1691 18

Marek's disease virus (MDV) is an alphaherpesvirus that induces a highly malignant T-lymphoma in chickens. The viral genome encodes two identical copies of a viral telomerase RNA subunit (vTR) that exhibits 88% sequence identity to its chicken ortholog chTR. The minimal telomerase ribonucleoprotein complex consists of a protein subunit with reverse transcriptase activity (TERT) and an RNA subunit (TR). The active complex compensates for the progressive telomere shortening that occurs during mitosis and is involved in the cell immortalization process. We show here that the upregulation of telomerase activity is associated with an increase in vTR gene expression in chickens infected with the highly oncogenic MDV strain RB-1B. A comparative functional analysis of the viral and chicken TR promoters, based on luciferase reporter assays, revealed that the vTR promoter was up to threefold more efficient than the chTR promoter in avian cells. We demonstrated, by directed mutagenesis of the vTR promoter region, that the stronger transcriptional activity of the vTR promoter resulted largely from an E-box located two nucleotides downstream from the transcriptional start site of the vTR gene. Furthermore, transactivation assays and chromatin immunoprecipitation assays demonstrated the involvement of the c-Myc oncoprotein in the transcriptional regulation of vTR. Finally, an Ets binding site was specifically implicated in the transcriptional regulation of vTR in the MDV-transformed lymphoblastoid cell line MSB-1.
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PMID:Involvement of the oncoprotein c-Myc in viral telomerase RNA gene regulation during Marek's disease virus-induced lymphomagenesis. 1731 64

Telomerase is a cellular reverse transcriptase, which utilizes an integral RNA template to extend single-stranded telomeric DNA. We used site-specific photocrosslinking to map interactions between DNA primers and the catalytic protein subunit (tTERT) of Tetrahymena thermophila telomerase in functional enzyme complexes. Our assays reveal contact of the single-stranded DNA adjacent to the primer-template hybrid and tTERT residue W187 at the periphery of the N-terminal domain. This contact was detected in complexes with three different registers of template in the active site, suggesting that it is maintained throughout synthesis of a complete telomeric repeat. Substitution of nearby residue Q168, but not W187, alters the K(m) for primer elongation, implying that it plays a role in the DNA recognition. These findings are the first to directly demonstrate the physical location of TERT-DNA contacts in catalytically active telomerase and to identify amino acid determinants of DNA binding affinity. Our data also suggest a movement of the TERT active site relative to the template-adjacent single-stranded DNA binding site within a cycle of repeat synthesis.
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PMID:High-resolution physical and functional mapping of the template adjacent DNA binding site in catalytically active telomerase. 1749 34

Telomerase is a cellular reverse transcriptase that extends one strand (the G-strand) of the telomere terminal repeats. Aside from this role in telomere length maintenance, telomerase has been proposed to serve a protective function at chromosome ends, although this is not well understood mechanistically. Earlier analysis suggests that, in the pathogenic yeast Candida albicans, the catalytic reverse transcriptase subunit of telomerase (TERT/EST2) can protect telomeres against nucleolytic degradation. In this report we demonstrate that the RNA component (TER1) has a similar function; in addition to complete loss of telomerase activity and progressive telomere attrition, the ter1-DeltaDelta strains manifested a dramatic increase in the amount of G-strand overhangs, consistent with aberrant degradation of the complementary C-strand. We also demonstrate that a catalytically incompetent EST2 protein can suppress such overhang accumulation in the est2-DeltaDelta mutant to the same extent as the wild-type protein. Altogether, our data support the notion that the Candida telomerase core components mediate a protective function through a mechanism that is independent of its catalytic activity.
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PMID:Telomerase core components protect Candida telomeres from aberrant overhang accumulation. 1760 87


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