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:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A strong stochastic component has been described for the appearance of senescent cells in cultures that have not completed their in vitro lifespan. The proliferative potential of individual clones show a bimodal distribution. Additionally, two cells arising from a single mitotic event can exhibit large differences in their doubling capacities. In this report we present a model and a computer simulation of the model that explains the observed stochastic phenomena. The model is based on both gradual and abrupt telomere shortening. Gradual telomere shortening (GTS) occurs during each cell division as a consequence of the inability of DNA polymerase to replicate the very ends of chromosomal DNA. It is responsible for the gradual decline in proliferative potential of a cell culture, but does not explain the stochastic aspects of cellular aging. Abrupt telomere shortening (ATS) occurs either through DNA recombination or nuclease digestion at the subtelomeric/telomeric border region of the chromosome. Recombination involves the invasion of a telomere single-strand three-prime protruding end at this border in the telomere of the same chromosome or in another subtelomeric/telomeric region. Shortening of one or more telomeres in the cell causes a sudden onset of cell senescence, referred to as sudden senescence syndrome (SSS). This is manifested as a stochastic and abrupt transition of cells from the larger to the smaller proliferative potential pool and can cause cell cycle arrest within one cell division. The computer simulation matches well with experimental data supporting the prediction that abrupt telomere shortening underlies the stochastic onset of cell senescence. Sudden senescence syndrome appears to be the most important mechanism in the control of the extent of proliferation of a cell culture because it prevents virtually every cell in the culture from reaching its maximum doubling capacity, that would otherwise be allowed by telomere shortening via the end-replication mechanism alone.
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PMID:Stochastic mechanism of cellular aging--abrupt telomere shortening as a model for stochastic nature of cellular aging. 1019 87

The ends of human chromosomes (telomeres) consist of tandem repeats of the sequence TTAGGG. Telomeres lose up to 200 base pairs of DNA per cell division due to the inability of DNA polymerase to completely replicate the chromosomal ends. Chromosomal shortening ultimately leads to senescence and cell death in normal cells. However, some immortal cells do not lose telomeric sequence during DNA replication. Many human carcinoma lines are immortal in vitro, suggesting that these cells have a mechanism for maintaining the ends of their chromosomes. Telomerase is a ribonucleoprotein complex that synthesizes telomeric DNA onto chromosomes using its RNA component as a template. To elucidate potential mechanisms for telomerase regulation, we tested human squamous cell carcinoma lines (SCCs) for telomerase activity. All SCC lines expressed high levels of telomerase activity. Synchronization in specific cell cycle phases caused marked reduction in telomerase activity in G0 and S, but not in G1 or M. Reduction in telomerase activity correlated with induction of Rb protein in these phases. Overexpression of full length Rb resulted in significant downregulation of telomerase activity. However, expression of an Rb N-terminal oligomerization domain deletion construct, a C-terminal DNA binding domain deletion construct, or a pocket domain mutant failed to downregulate telomerase activity. We concluded that functionally intact Rb was required for cell cycle-dependent downregulation of telomerase activity in SCC lines.
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PMID:Intact functional domains of the retinoblastoma gene product (pRb) are required for downregulation of telomerase activity. 1032 Jul 73

Telomerase activity was measured at each phase of the cell cycle in synchronized tobacco (Nicotiana tabacum) BY-2 cells in suspension culture with the use of the telomeric repeat amplification protocol assay. The activity was low or undetectable at most phases of the cell cycle but showed a marked increase at early S phase. The induction of telomerase activity was not affected by the S phase blockers aphidicolin (which inhibits DNA polymerase alpha) or hydroxyurea (which inhibits ribonucleotide reductase), but it was prevented by olomoucine, an inhibitor of Cdc2/Cdk2 kinases that blocks G(1)-S cell cycle transition. These results suggest that the induction of telomerase activity is not directly coupled to DNA replication by conventional DNA polymerases, but rather is triggered by the entry of cells into S phase. Various analogs of the plant hormone auxin, including indole-3-acetic acid, alpha-naphthaleneacetic acid, and 2,4-dichlorophenoxyacetic acid, potentiated the increase in telomerase activity at early S phase; the growth-inactive analog 2,3-dichlorophenoxyacetic acid, however, had no such effect. Potentiation by indole-3-acetic acid of the induction of telomerase activity was dose dependent. Together, these data indicate that telomerase activity in tobacco cells is regulated in a cell cycle-dependent manner, and that the increase in activity at S phase is specifically inducible by auxin.
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PMID:Auxin induction of cell cycle regulated activity of tobacco telomerase. 1040 48

Histological analysis of surgically removed adrenal masses often fails to differentiate between benign and malignant tumors. In normal cells, the telomeric ends of the chromosomes are shortened with each cell division, leading to chromosome destabilization and cellular senescence after a critical number of cell cycles. In tumor cells, telomere shortening is prevented by a specific DNA polymerase, called telomerase. In an effort to clarify the role of telomerase in the pathogenesis of adrenal tumors, and to test whether its activity could serve as marker of malignancy, we measured telomerase activity in 41 human adrenal tissue samples that were classified both by the clinical course and by histological examination. Telomerase activity was determined by TRAP ELISA and expressed as high (>50% of positive control telomerase activity), medium (31-50%), low (11-30%), very low (< or = 10%), or absent (0%). The 8 normal adrenal tissue samples showed very low levels of telomerase activity. Mean telomerase activity also very low in 3/3 incidentalomas, 6/6 Cushing adenomas, 6/6 Conn adenomas, 7/7 adrenocortical carcinomas, 8/8 benign pheochromocytomas, and 2/3 malignant pheochromocytomas. In contrast, one malignant pheochromocytoma showed high telomerase activity. These data indicate that telomerase activity may not be a suitable marker for malignancy in the adrenal gland. Our results also challenge the current dogma of close correlation between cell dedifferentiation and telomerase activity.
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PMID:Telomerase activity in benign and malignant adrenal tumors. 1043 67

The short flanking homology PCR strategy (Wach et al., 1994) was used to disrupt six open reading frames (ORFs) on chromosome X of diploid strains (FY1679 and W303) of the yeast Saccharomyces cerevisiae. Two of the six ORFs analysed (YJL069c and YJL066c) display no similarity to known sequences. Three others (YJL065c, YJL068c, and YJL070c) are similar to those respectively encoding the DNA polymerase epsilon subunit c, human esterase D and rat AMP deaminase 1. YJL071w has recently been identified as the ARG2 gene coding for acetylglutamate synthase. Inactivation of the YJL069c gene proved lethal and the yjl071w haploid disruptants were auxotrophic for arginine. For the four other gene inactivations, neither the heterozygous deletion diploids nor the corresponding haploid deletion mutants displayed any special phenotype when grown on rich glycerol or glucose medium or on synthetic minimal medium at three different temperatures, or on media containing compounds interfering with nucleic acid or protein synthesis. Mating and sporulation efficiencies were the same for the viable disruptants as for wild-type cells. The six kanMX4 disruption cassettes were cloned into the pUG7 vector and each of the cognate wild-type genes was inserted into the pRS416 centromeric plasmid. All strains and plasmids have been deposited in the EUROFAN collection (EUROSCARF, K. -D. Entian, Frankfurt, Germany).
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PMID:Disruption of six ORFs on Saccharomyces cerevisiae chromosome X: the YJL069c gene of unknown function is essential to cell viability. 1050 23

Human telomerase is a ribonucleoprotein DNA polymerase which maintains the telomeric region of human chromosomes and has been detected in all types of human cancer tested. We used the telomeric repeat amplification protocol (TRAP) assay to examine 71 non-small cell lung carcinomas (NSCLC) and their adjacent normal tissue. Telomerase activity was detected in 61 (86%) of the 71 NSCLC examined but not in any of the matched normal lung tissues. A significant correlation was found between the presence of telomerase activity and current smoking status at the time of diagnosis (p=0. 0076). In addition, a trend was found between telomerase activity and smoking exposure (p=0.06). Our findings demonstrate that telomerase activity is a common phenomenon in NSCLC cases but not in the normal lung. However, certain cases in former smokers may follow a telomerase independent pathway.
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PMID:Telomerase activity in non-small cell lung carcinomas correlates with smoking status. 1053 80

Telomeres are specific structures present at the end of liner chromosomes. DNA polymerase can not synthesize the end of liner DNA and, as a result, the telomeres become progressively shortened by successive cell divisions. To overcome the end replication problem, telomerase adds new telomeric sequences to the end of chromosomal DNA. The enzyme activity is undetectable in most normal human adult somatic cells, in which shortening of the telomere is thought to limit the somatic-cell life span. In contrast to normal somatic cells, many human tumors possess telomerase activity. The present study looked at whether telomerase activity might serve as a marker for canine tumors. Telomerase activity was measured using the telomeric repeat amplification protocol assay. Normal dog somatic tissues showed little or no telomerase activity, while normal testis exhibited a high level of telomerase activity. We measured telomerase activity in tumor samples from 45 dogs; 21 mammary gland tumors, 16 tumors developed in the skin and oral cavity, 7 vascular tumors and 1 Sertoli cell tumor. Greater than 95% of the tumor samples contained telomerase activity (3-924 U/2 micrograms protein). The results obtained in this study indicated that telomerase should be a useful diagnostic marker for a variety of dog tumors, and it may serve as a target for antitumor chemotherapy.
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PMID:Measurement of telomerase activity in dog tumors. 1056 90

Guanine-rich oligonucleotides and short telomeric DNA sequences can self-associate into G-quartet stabilized complexes. We discovered that this self-association can occur in sequencing reactions and that higher-order structures stimulate DNA polymerase to synthesize extended DNA strands. Base analogues were used to identify Hoogsteen base pairings as stabilizing forces in these stimulatory DNA structures. Scanning force microscopy confirmed that quartet-DNA was formed from these oligomers and that these extended, four-stranded structures could be bound by DNA polymerase. Since guanine quartet-stabilized structures are proposed to exist in vivo, such structures may stimulate DNA polymerization in vivo.
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PMID:Guanine-rich telomeric sequences stimulate DNA polymerase activity in vitro. 1060 Jan 7

Telomere length control is influenced by several factors, including telomerase, the components of telomeric chromatin structure, and the conventional replication machinery. Although known components of the replication machinery can influence telomere length equilibrium, little is known about why mutations in certain replication proteins cause dramatic telomere lengthening. To investigate the cause of telomere elongation in cdc17/pol1 (DNA polymerase alpha) mutants, we examined telomeric chromatin, as measured by its ability to repress transcription on telomere-proximal genes, and telomeric DNA end structures in pol1-17 mutants. pol1-17 mutants with elongated telomeres show a dramatic loss of the repression of telomere-proximal genes, or telomeric silencing. In addition, cdc17/pol1 mutants grown under telomere-elongating conditions exhibit significant increases in single-stranded character in telomeric DNA but not at internal sequences. The single strandedness is manifested as a terminal extension of the G-rich strand (G tails) that can occur independently of telomerase, suggesting that cdc17/pol1 mutants exhibit defects in telomeric lagging-strand synthesis. Interestingly, the loss of telomeric silencing and the increase in the sizes of the G tails at the telomeres temporally coincide and occur before any detectable telomere lengthening is observed. Moreover, the G tails observed in cdc17/pol1 mutants incubated at the semipermissive temperature appear only when the cells pass through S phase and are processed by the time cells reach G(1). These results suggest that lagging-strand synthesis is coordinated with telomerase-mediated telomere maintenance to ensure proper telomere length control.
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PMID:The function of DNA polymerase alpha at telomeric G tails is important for telomere homeostasis. 1062 35

Telomerase is a ribonucleoprotein DNA polymerase that maintains the telomeric region of chromosomes lost during successive rounds of cell division. We used the telomeric repeat amplification protocol (TRAP) assay to examine telomerase activity in bronchial lavage (BL) samples from individuals undergoing diagnosis of lung cancer. Telomerase activity was detected in 17 (47%) of 36 samples examined. In particular, 16 (70%) of 23 BL specimens obtained from lung cancer patients showed detectable telomerase activity, while only 1 of 13 (8%) specimens obtained from patients without lung cancer demonstrated activity (P=0.00038). Moreover, 9 (90%) of 10 BL specimens, which were cytologically positive for lung cancer, were also positive for telomerase activity, while 7 (54%) of 13 cytologically negative BL specimens for lung cancer showed detectable telomerase activity. Detection of telomerase activity combined with cytology were able to identify 17 (74%) of 23 lung cancer cases whereas cytology alone identified 10 (43%) of 23 such cases (P=0.035). Our findings indicate that telomerase is a specific marker for malignant lung disease and a potential complementary tool to cytology in the diagnosis of certain lung cancer cases.
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PMID:Evaluation of telomerase activity in bronchial lavage as a potential diagnostic marker for malignant lung disease. 1070 7


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