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Biochemistry. Biokhimiia Dec 2010Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in... (Review)
Review
Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells proliferation potential is strictly limited and senescence follows approximately 50-70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. No doubt, DNA polymerase is not capable to completely copy DNA at the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during each cell cycle, which results in gradual telomere length shortening. Critically short telomeres cause senescence, following crisis, and cell death. However, in tumor cells the system of telomere length maintenance is activated. Besides catalytic telomere elongation, independent telomerase functions can be also involved in cell cycle regulation. Inhibition of the telomerase catalytic function and resulting cessation of telomere length maintenance will help in restriction of tumor cell replication potential. On the other hand, formation of temporarily active enzyme via its intracellular activation or due to stimulation of expression of telomerase components will result in telomerase activation and telomere elongation that can be used for correction of degenerative changes. Data on telomerase structure and function are summarized in this review, and they are compared for evolutionarily remote organisms. Problems of telomerase activity measurement and modulation by enzyme inhibitors or activators are considered as well.
Topics: Animals; Enzyme Activation; Enzyme Inhibitors; Humans; Neoplasms; Protein Conformation; Structure-Activity Relationship; Telomerase
PubMed: 21417995
DOI: 10.1134/s0006297910130055 -
Cold Spring Harbor Perspectives in... Dec 2019Telomerase is a DNA polymerase that extends the 3' ends of chromosomes by processively synthesizing multiple telomeric repeats. It is a unique ribonucleoprotein (RNP)... (Review)
Review
Telomerase is a DNA polymerase that extends the 3' ends of chromosomes by processively synthesizing multiple telomeric repeats. It is a unique ribonucleoprotein (RNP) containing a specialized telomerase reverse transcriptase (TERT) and telomerase RNA (TER) with its own template and other elements required with TERT for activity (catalytic core), as well as species-specific TER-binding proteins important for biogenesis and assembly (core RNP); other proteins bind telomerase transiently or constitutively to allow association of telomerase and other proteins with telomere ends for regulation of DNA synthesis. Here we describe how nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography of TER and protein domains helped define the structure and function of the core RNP, laying the groundwork for interpreting negative-stain and cryo electron microscopy (cryo-EM) density maps of and human telomerase holoenzymes. As the resolution has improved from ∼30 Å to ∼5 Å, these studies have provided increasingly detailed information on telomerase architecture and mechanism.
Topics: Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Telomerase
PubMed: 31451513
DOI: 10.1101/cshperspect.a032383 -
Trends in Genetics : TIG Sep 2013Although cancer and aging have been studied as independent diseases, mounting evidence suggests that cancer is an aging-associated disease and that cancer and aging... (Review)
Review
Although cancer and aging have been studied as independent diseases, mounting evidence suggests that cancer is an aging-associated disease and that cancer and aging share many molecular pathways. In particular, recent studies validated telomerase activation as a potential therapeutic target for age-related diseases; in addition, abnormal telomerase expression and telomerase mutations have been associated with many different types of human tumor. Here, we revisit the connection between telomerase and cancer and aging in light of recent findings supporting a role for telomerase not only in telomere elongation, but also in metabolic fitness and Wnt activation. Understanding the physiological impact of telomerase regulation is fundamental given the therapeutic strategies that are being developed that involve telomerase modulation.
Topics: Aging; Animals; Gene Expression Regulation; Humans; Models, Animal; Neoplasms; Sequence Analysis, DNA; Telomerase
PubMed: 23876621
DOI: 10.1016/j.tig.2013.06.007 -
Nature Reviews. Molecular Cell Biology Mar 2017The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through... (Review)
Review
The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.
Topics: Chromothripsis; Genomic Instability; Humans; Neoplasms; Telomerase; Telomere; Telomere Shortening
PubMed: 28096526
DOI: 10.1038/nrm.2016.171 -
Current Opinion in Structural Biology Apr 2014The telomerase reverse transcriptase has an essential role in telomere maintenance and in cancer biology. Progress during the last year has revealed the... (Review)
Review
The telomerase reverse transcriptase has an essential role in telomere maintenance and in cancer biology. Progress during the last year has revealed the three-dimensional architecture of both human and ciliate telomerase at about 25Å resolution, obtained using single particle electron microscopy (EM). The structural analysis of the two holoenzyme complexes isolated from cells shows that whilst the ciliate telomerase is monomeric, the human telomerase is dimeric and only functional as a dimer. We critically discuss the approaches taken to assign the location of protein and RNA subunits, as well as fitting the crystal structure of the catalytic protein subunit in the medium resolution EM density maps. Comparison of the two structural interpretations reveals not only a common RNA/reverse transcriptase core, but also significant differences due to different RNA subunit size and protein composition. These differences suggest that the oligomeric state and subunit composition of telomerase in evolutionary distant organism have evolved.
Topics: Animals; Humans; Protein Structure, Tertiary; RNA; Telomerase
PubMed: 24704747
DOI: 10.1016/j.sbi.2014.02.003 -
Mutation Research Feb 2012The intimate connection between telomerase regulation and human disease is now well established. The molecular basis for telomerase regulation is highly complex and... (Review)
Review
The intimate connection between telomerase regulation and human disease is now well established. The molecular basis for telomerase regulation is highly complex and entails multiple layers of control. While the major target of enzyme regulation is the catalytic subunit TERT, the RNA subunit of telomerase is also implicated in telomerase control. In addition, alterations in gene dosage and alternative isoforms of core telomerase components have been described. Finally, telomerase localization, recruitment to the telomere and enzymology at the chromosome terminus are all subject to modulation. In this review we summarize recent advances in understanding fundamental mechanisms of telomerase regulation.
Topics: Animals; Chromosomes; Gene Dosage; Gene Expression Regulation, Enzymologic; Humans; Models, Molecular; RNA Processing, Post-Transcriptional; Telomerase; Telomere-Binding Proteins; Transcription, Genetic
PubMed: 22032831
DOI: 10.1016/j.mrfmmm.2011.10.003 -
International Journal of Molecular... Jun 2023Seventeen papers published in 2019 and early 2020 demonstrate the ongoing interest and research concerning telomeres and telomerase in aging and cancer [...].
Seventeen papers published in 2019 and early 2020 demonstrate the ongoing interest and research concerning telomeres and telomerase in aging and cancer [...].
Topics: Humans; Telomerase; Aging; Telomere; Neoplasms
PubMed: 37373080
DOI: 10.3390/ijms24129932 -
Science (New York, N.Y.) Feb 2013Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here,...
Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.
Topics: Binding Sites; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Melanoma; Mutation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-ets; Telomerase; Transcription, Genetic
PubMed: 23348506
DOI: 10.1126/science.1229259 -
International Journal of Molecular... Apr 2019Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of... (Review)
Review
Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to metastasize to distant organs. Studies to date have examined the mechanisms involved in the survival of cancer cells as targets for cancer therapeutics. These efforts led to the development of telomerase inhibitors as anticancer drugs, drugs targeting telomere DNA, viral vectors carrying a promoter for human telomerase reverse transcriptase (hTERT) genome, and immunotherapy targeting hTERT. Among these novel therapeutics, this review focuses on immunotherapy targeting hTERT and discusses the current evidence and future perspectives.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cancer Vaccines; Cell- and Tissue-Based Therapy; Dendritic Cells; Genetic Therapy; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Telomerase; Vaccines, DNA
PubMed: 31013796
DOI: 10.3390/ijms20081823 -
Cellular & Molecular Biology Letters Dec 2013The classical activity of telomerase is to synthesize telomeric repeats and thus maintain telomere length, which in turn ensures chromosome stability and cellular... (Review)
Review
The classical activity of telomerase is to synthesize telomeric repeats and thus maintain telomere length, which in turn ensures chromosome stability and cellular proliferation. However, there is growing evidence that implicates telomerase in many other functions that are independent of TERC being used as its template. Telomerase has an RNA-dependent RNA polymerase (RdRP) activity in the mitochondria. Other than viral RdRPs, it is the only RNA-dependent RNA polymerase that has been identified in mammals. It also plays a role in the Wnt signaling pathway by acting as a transcriptional modulator. Telomerase acts as a reverse transcriptase independent of its core subunit, TERC. Studies indicate that telomerase is also involved in apoptosis and DNA repair.
Topics: Animals; Apoptosis; Gene Expression Regulation; Humans; RNA-Dependent RNA Polymerase; Telomerase; Telomere
PubMed: 24048710
DOI: 10.2478/s11658-013-0105-0