Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics
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Telomere-binding protein
Telomerase RNA component
Telomerase, the enzyme that replenishes telomeres, is essential for most eukaryotes to maintain their generations. Telomere length homeostasis is achieved via a balance between telomere lengthening by telomerase, and erosion over successive cell divisions. Impaired telomerase regulation leads to shortened telomeres and can cause defects in tissue maintenance. Telomeric DNA is composed of a repetitive sequence, which recruits the protective protein complex, shelterin. Shelterin, together with chromatin remodelling proteins, shapes the heterochromatic structure at the telomere and protects chromosome ends. Shelterin also provides a foothold for telomerase to be recruited and facilitates telomere extension. Such mechanisms of telomere recruitment and activation are conserved from unicellular eukaryotes to humans, with the rate of telomere extension playing an important role in determining the length maintained. Telomerase can be processive, adding multiple telomeric repeats before dissociating. However, a question remains: how does telomerase determine the number of repeats to add? In this review, I will discuss about how telomerase can monitor telomere extension using fission yeast as a model. I propose a model whereby the accumulation of the Pot1 complex on the synthesised telomere single-strand counteracts retention of telomerase via chromatin proteins and the similar system may be conserved in mammals.
Shelterin
Telomere-binding protein
Telomerase RNA component
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Establishment of immortalized cell line was one of the hot and difficult subjects in cell biology.Telomeres at chromosome ends in eukaryotes stable the chromosome.Telomerase,an RNA-protein complex,adds multiple telomeric repeats to its 3-prime end by using RNA component as template.Thus ectopic expression of the telomerase reverse transcriptase(TERT) and subsequent activation of telomerase can allow normal eukaryotes to over-come senescence and crisis,and become immortal.An overview of the advance in the telomere,applications of telomerase in the cell immortalization,applications of telomerase in the cell line as well as question and prospect was given,in order to give reference to the researcher.
Telomerase RNA component
Senescence
Cellular senescence
Ectopic expression
Immortalised cell line
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The stable linearity of eukaryotic chromosomes depends on special characteristics of their ends, the telomeres. Accurate telomere function in turn requires a sustained presence of repeated DNA elements, which are maintained by the enzyme telomerase. The telomerase holoenzyme is composed of both protein and RNA, and its functions rely on proper expression, maturation, trafficking and assembly of these components. Conflicting models for the recruitment of telomerase at telomeres have been proposed; one suggests a local activation of telomerase at short telomeres, while the other proposes that telomerase is recruited only at short telomeres. To discriminate between these models and investigate the cell cycle-dependent regulation of telomerase in living cells, a GFP reporter system to visualize the yeast telomerase RNA has been recently developed. This assay shed new light on the mechanism of recruitment of telomerase to telomeres, and it uncovered a hitherto unrecognized mechanism for restricting telomerase access to telomeres.
Telomerase RNA component
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Abstract. The ribonucleoprotein, telomerase, is responsible for the maintenance of telomere length in most immortal and cancer cells. Telomerase appears to be a marker of human malignancy with at least 85% of human cancers expressing its activity. In the present study, we examined a series of tumor‐derived and in vitro immortalized cell lines for telomerase activity levels, telomere lengths, and expression levels of the RNA and catalytic components of telomerase. We found significant variability in both telomere lengths and telomerase activity in clones from tumor cells. In addition, the levels of telomerase components or telomerase activity were not predictive of telomere length. Data from clonally derived cells suggest that critically shortened telomeres in these tumor‐derived cell lines may signal activation of telomerase activity through an increase in the expression of the catalytic subunit of telomerase. Although clones with low telomerase shorten their telomeres over time, their subclones all have high levels of telomerase activity with no telomere shortening. In addition, analysis of early clones for telomerase activity indicates substantial variability, which suggests that activity levels fluctuate in individual cells. Our data imply that cell populations exhibit a cyclic expression of telomerase activity, which may be partially regulated by telomere shortening.
Telomerase RNA component
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The ribonucleoprotein (RNP) enzyme telomerase synthesizes telomere DNA and maintains telomere length in eukaryotic cells. This review describes recent findings that provide new understanding, of the functions of telomeres and telomerase. Telomerase has an essential RNA moiety in which a short sequence acts as the template for synthesis of telomeric DNA. Recent results show that, besides acting as a template, the telomerase RNA plays essential roles in the enzymatic functions of telomerase that are as critical as those provided by the protein reverse transcriptase subunit of telomerase. Analysis of telomerase RNA mutants in yeast has provided evidence that telomerase is an oligomeric/dimeric enzyme containing at least two telomerase RNA molecules and two enzyme-active sites. Recent data suggest that this telomerase RNP also plays a critical role in capping short telomeres. Thus, the length of a telomere is only one determinant of whether it is sufficiently long to function as a cap, stabilizing the chromosome end. Several lines of evidence converge on the notion that for telomere length regulation and other telomere functions, the very few last repeats at the tip of the telomere are the most crucial.
Telomerase RNA component
Telomere-binding protein
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Shay, J. W. and Wright, W. E. Telomeres and Telomerase: Implications for Cancer and Aging.Maintenance of telomere stability is required for cells to escape from replicative senescence and proliferate indefinitely. Telomere length is maintained by a balance between processes that lengthen telomeres (telomerase) and processes that shorten telomeres (the end-replication problem). Telomerase is a cellular ribonucleoprotein reverse transcriptase which stabilizes telomere length by adding hexameric (TTAGGG) repeats to the telomeric ends of the chromosomes, thus compensating for the continued erosion of telomeres. Introduction of the telomerase catalytic protein component into normal telomerase-negative human cells results in restoration of telomerase activity and extension of cellular life span. Human cells with introduced telomerase maintain a normal chromosome complement and continue to grow in a normal manner. Telomerase-induced manipulations of telomere length may thus be important not only for cell and tissue engineering but also for dissecting the molecular mechanisms underlying inherited genetic diseases, as well as defining the genetic pathways leading to cancer. Because almost all human tumors express telomerase activity, inhibition of telomerase may result in gradual erosion of telomeres and eventual cessation of cell proliferation or induction of apoptosis. Thus telomerase may also be a promising target for cancer therapy.
Telomerase RNA component
Senescence
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Telomerase RNA component
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The ribonucleoprotein, telomerase, is responsible for the maintenance of telomere length in most immortal and cancer cells. Telomerase appears to be a marker of human malignancy with at least 85% of human cancers expressing its activity. In the present study, we examined a series of tumor-derived and in vitro immortalized cell lines for telomerase activity levels, telomere lengths, and expression levels of the RNA and catalytic components of telomerase. We found significant variability in both telomere lengths and telomerase activity in clones from tumor cells. In addition, the levels of telomerase components or telomerase activity were not predictive of telomere length. Data from clonally derived cells suggest that critically shortened telomeres in these tumor-derived cell lines may signal activation of telomerase activity through an increase in the expression of the catalytic subunit of telomerase. Although clones with low telomerase shorten their telomeres over time, their subclones all have high levels of telomerase activity with no telomere shortening. In addition, analysis of early clones for telomerase activity indicates substantial variability, which suggests that activity levels fluctuate in individual cells. Our data imply that cell populations exhibit a cyclic expression of telomerase activity, which may be partially regulated by telomere shortening.
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Telomerase RNA component
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Abstract The minimal vertebrate telomerase enzyme is composed of a protein component (telomerase reverse transcriptase, TERT) and an RNA component (telomerase RNA, TR). Expression of these two subunits is sufficient to reconstitute telomerase activity in vitro, while the formation of a holoenzyme comprising telomerase-associated proteins is necessary for proper telomere length maintenance. Previous reports demonstrated the high processivity of the human telomerase complex and the interspecies compatibility of human TERT (hTERT). In this study, we tested the function of the only known viral telomerase RNA subunit (vTR) in association with human telomerase, both in a cell-free system and in human cells. When vTR is assembled with hTERT in a cell-free environment, it is able to interact with hTERT and to reconstitute telomerase activity. However, in human cells, vTR does not reconstitute telomerase activity and could not be detected in the human telomerase complex, suggesting that vTR is not able to interact properly with the proteins constituting the human telomerase holoenzyme.
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