Tel1p Preferentially Associates with Short Telomeres to Stimulate Their Elongation
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Keywords:
Elongation
Telomerase RNA component
Elongation factor
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.
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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.
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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.
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Maintenance of functional telomeres, the highly complex nucleo-protein structures, at the end of linear eukaryotic chromosomes appears to be essential for growth and survival of the cells. The compelling correlation between telomerase reactivation and cellular immortalization led to the idea that inhibition of telomerase may provide a way for effective hindrance of cancer cell growth by interfering with telomere maintenance. In addition to targeting the components of telomerase enzyme directly to prevent telomere synthesis, several approaches including disruption of telomeres, interference with telomerase component assembly, translocation of the catalytic component of telomerase have also been under extensive investigation due to the advances in understanding the biology of telomeres and telomerase in recent years. This review will focus on the so far identified approaches to prevent cancer cell growth by targeting telomerase and telomeres with a brief introduction about structure and function of telomeres and telomerase.
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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.
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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.
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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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According to the telomere hypothesis of senescence, the progressive shortening of telomeres that occurs upon division of normal somatic cells eventually leads to cellular senescence. The immortalisation of human cells is associated with the acquisition of a telomere maintenance mechanism which is usually dependent upon expression of the enzyme telomerase. About one third of in vitro immortalised human cell lines, however, have no detectable telomerase but contain telomeres that are abnormally long. The nature of the alternative telomere maintenance mechanism (referred to as ALT, for Alternative Lengthening of Telomeres) that must exist in these telomerase-negative cells has not been elucidated. It has previously been shown that abnormal lengthening of yeast telomeres may occur due to mutations in the yeast telomerase RNA gene. That this is not the mechanism of the abnormally long telomeres in ALT cell lines was demonstrated by the finding that seven of seven ALT lines have wild-type human telomerase RNA (hTR) sequence, including a novel polymorphism that is present in 30% of normal individuals. We found that two ALT cell lines have no detectable expression of the hTR gene. This shows that the ALT mechanism in these cell lines is not dependent on hTR. Expression of exogenous hTR via infection of these cells with a recombinant hTR-adenovirus vector did not result in telomerase activity, indicating that their lack of telomerase activity is not due to absence of hTR expression. We conclude that the ALT mechanism is not dependent on the expression of hTR, and does not involve mutations in the hTR sequence.
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Telomerase can compensate for telomere shortening and helps prevent cellular senescence in eukaryotic cells. In humans, only specific germline cells and the vast majority of cancer cells have sufficient activity for indefinite proliferation. Lymphocytes and stem/progenitor cells in self-renewal tissues have weak activity for extension of their lifespan, but they still undergo replicative senescence. In contrast, most somatic cells do not have telomerase activity and display a finite replicative lifespan. Heterozygous mutations in either of principal telomerase components, TERT or TERC, cause telomere dysfunction and unexpectedly early senescence to stem cells of renewal tissues. Thus, restoration of telomere function in regenerative medicine via telomerase expression and inhibition of telomerase as an anticancer strategy is a double-edged sword of telomeres and telomerase in clinical medicine.
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