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The FEBS Journal Jul 2013Telomeres are nucleoprotein structures found at the ends of linear chromosomes. Telomeric DNA shortens with each cell division, effectively restricting the proliferative... (Review)
Review
Telomeres are nucleoprotein structures found at the ends of linear chromosomes. Telomeric DNA shortens with each cell division, effectively restricting the proliferative capacity of human cells. Telomerase, a specialized reverse transcriptase, is responsible for de novo synthesis of telomeric DNA, and is the major physiological means by which mammalian cells extend telomere length. Telomerase activity in human soma is developmentally regulated according to cell type. Failure to tightly regulate telomerase has dire consequences: dysregulated telomerase activity is observed in more than 90% of human cancers, while haplo-insufficient expression of telomerase components underlies several inherited premature aging syndromes. Over the past decade, we have significantly improved our understanding of the structure-activity relationships between the two core telomerase components: telomerase reverse transcriptase and telomerase RNA. Genetic screening for telomerase deficiency syndromes has identified new partners in the biogenesis of telomerase and its catalytic functions. These data revealed a level of regulation complexity that is unexpected when compared with the other cellular polymerases. In this review, we summarize current knowledge on the structure-activity relationships of telomerase reverse transcriptase and telomerase RNA, and discuss how the biogenesis of telomerase provides additional regulation of its actions.
Topics: Amino Acid Sequence; Animals; Base Sequence; Biocatalysis; Catalytic Domain; Humans; Models, Molecular; Nucleic Acid Conformation; Protein Folding; Protein Transport; RNA; Telomerase; Telomere
PubMed: 23551398
DOI: 10.1111/febs.12272 -
The EMBO Journal Sep 2009The telomeres of most eukaryotes are characterized by guanine-rich repeats synthesized by the reverse transcriptase telomerase. Complete loss of telomerase is tolerated... (Review)
Review
The telomeres of most eukaryotes are characterized by guanine-rich repeats synthesized by the reverse transcriptase telomerase. Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer. Differences in telomerase deficiency phenotypes between species most likely reflect a tumour suppressor function of telomeres in long-lived mammals that does not exist as such in short-lived organisms. Another puzzle provided by current observations is that family members with the same genetic defect, haplo-insufficiency for one of the telomerase genes, can present with widely different diseases. Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective. It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof.
Topics: Animals; DNA Repair; Disease; Humans; Neoplasms; Stem Cells; Telomerase; Telomere
PubMed: 19629041
DOI: 10.1038/emboj.2009.172 -
The Journal of Biological Chemistry Jun 2009Telomeres, protein-DNA complexes at the ends of eukaryotic linear chromosomes, are essential for genome stability. The accumulation of chromosomal abnormalities in the... (Review)
Review
Telomeres, protein-DNA complexes at the ends of eukaryotic linear chromosomes, are essential for genome stability. The accumulation of chromosomal abnormalities in the absence of proper telomere function is implicated in human aging and cancer. Repetitive telomeric sequences are maintained by telomerase, a ribonucleoprotein complex containing a reverse transcriptase subunit, a template RNA, and accessory components. Telomere elongation is regulated at multiple levels, including assembly of the telomerase holoenzyme, recruitment of telomerase to the chromosome terminus, and telomere accessibility. This minireview provides an overview of telomerase structure, function, and regulation and the role of telomerase in human disease.
Topics: Aging; Animals; Chromosomes; Humans; Telomerase
PubMed: 19286666
DOI: 10.1074/jbc.R900011200 -
Mutation Research Feb 2012The ideal cancer treatment would specifically target cancer cells yet have minimal or no adverse effects on normal somatic cells. Telomerase, the ribonucleoprotein... (Review)
Review
The ideal cancer treatment would specifically target cancer cells yet have minimal or no adverse effects on normal somatic cells. Telomerase, the ribonucleoprotein reverse transcriptase that maintains the ends of human chromosome, is an attractive cancer therapeutic target for exactly this reason [1]. Telomerase is expressed in more than 85% of cancer cells, making it a nearly universal cancer marker, while the majority of normal somatic cells are telomerase negative. Telomerase activity confers limitless replicative potential to cancer cells, a hallmark of cancer which must be attained for the continued growth that characterizes almost all advanced neoplasms [2]. In this review we will summarize the role of telomeres and telomerase in cancer cells, and how properties of telomerase are being exploited to create targeted cancer therapies including telomerase inhibitors, telomerase-targeted immunotherapies and telomerase-driven virotherapies. A frank and balanced assessment of the current state of telomerase inhibitors with caveats and potential limitations will be included.
Topics: Enzyme Inhibitors; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Oncolytic Virotherapy; Telomerase; Telomere; Telomere Homeostasis
PubMed: 21802433
DOI: 10.1016/j.mrfmmm.2011.07.006 -
Blood Mar 2022
Topics: Biology; Telomerase; Telomere
PubMed: 35323880
DOI: 10.1182/blood.2021014855 -
Cell Death & Disease Jan 2024Abnormal activation of telomerase occurs in most cancer types, which facilitates escaping from cell senescence. As the key component of telomerase, telomerase reverse... (Review)
Review
Abnormal activation of telomerase occurs in most cancer types, which facilitates escaping from cell senescence. As the key component of telomerase, telomerase reverse transcriptase (TERT) is regulated by various regulation pathways. TERT gene changing in its promoter and phosphorylation respectively leads to TERT ectopic expression at the transcription and protein levels. The co-interacting factors play an important role in the regulation of TERT in different cancer types. In this review, we focus on the regulators of TERT and these downstream functions in cancer regulation. Determining the specific regulatory mechanism will help to facilitate the development of a cancer treatment strategy that targets telomerase and cancer cell senescence. As the most important catalytic subunit component of telomerase, TERT is rapidly regulated by transcriptional factors and PTM-related activation. These changes directly influence TERT-related telomere maintenance by regulating telomerase activity in telomerase-positive cancer cells, telomerase assembly with telomere-binding proteins, and recruiting telomerase to the telomere. Besides, there are also non-canonical functions that are influenced by TERT, including the basic biological functions of cancer cells, such as proliferation, apoptosis, cell cycle regulation, initiating cell formation, EMT, and cell invasion. Other downstream effects are the results of the influence of transcriptional factors by TERT. Currently, some small molecular inhibitors of TERT and TERT vaccine are under research as a clinical therapeutic target. Purposeful work is in progress.
Topics: Telomerase; Cellular Senescence; Phosphorylation; Telomere; Neoplasms
PubMed: 38278800
DOI: 10.1038/s41419-024-06454-7 -
Mutation Research Feb 2012Telomerase is a reverse transcriptase specialized in the addition of telomeric DNA repeats onto the ends of chromosomes. Telomere extension offsets the loss of telomeric... (Review)
Review
Telomerase is a reverse transcriptase specialized in the addition of telomeric DNA repeats onto the ends of chromosomes. Telomere extension offsets the loss of telomeric repeats from the failure of DNA polymerases to fully replicate linear chromosome ends. Telomerase functions as a ribonucleoprotein, requiring an integral telomerase RNA (TR) component, in addition to the catalytic telomerase reverse transcriptase (TERT). Extensive studies have identified numerous structural and functional features within the TR and TERT essential for activity. A number of accessory proteins have also been identified with various functions in enzyme biogenesis, localization, and regulation. Understanding the molecular mechanism of telomerase function has significance for the development of therapies for telomere-mediated disorders and cancer. Here we review telomerase structural and functional features, and the techniques for assessing telomerase dysfunction.
Topics: DNA Mutational Analysis; Humans; Mutation; Ribonucleoproteins; Telomerase; Telomere; Telomere Homeostasis
PubMed: 22093366
DOI: 10.1016/j.mrfmmm.2011.11.002 -
Seminars in Hematology Apr 2013Telomeres are ribonucleoprotein structures capping the end of every linear chromosome. In all vertebrates, they are composed of TTAGGG repeats coated with specific... (Review)
Review
Telomeres are ribonucleoprotein structures capping the end of every linear chromosome. In all vertebrates, they are composed of TTAGGG repeats coated with specific protecting proteins. Telomeres shorten with each mitotic cell division, but telomerase, a reverse transcriptase, elongate telomeres in very specific cells, such as embryonic and adult stem cells. Although telomere sequence is identical in mice and humans and telomeres serve the same role of protecting chromosomes and genetic information from damage and erosion in both species, abnormalities in telomere maintenance and in telomerase function do not coincide in phenotype in humans and mice. The telomeres of most laboratory mice are 5 to 10 times longer than in humans, but their lifespan is 30 times shorter. Complete absence of telomerase has little expression in phenotype over several generations in mice, whereas heterozygosity for telomerase mutations in humans is sufficient to result in organ regeneration defect and cancer development. Patients with telomerase deficiency and very short telomeres may develop aplastic anemia, pulmonary fibrosis, or cirrhosis, whereas telomerase-null murine models display only modest hematopoietic deficiency and develop emphysema when exposed to cigarette smoke. In summary, telomerase deficiency in both humans and mice accelerate telomere shortening, but its consequences in the different organs and in the organism diverge, mainly due to telomere length differences.
Topics: Aging; Animals; Humans; Mice; Mutation; Neoplasms; Phenotype; Telomerase; Telomere
PubMed: 23956466
DOI: 10.1053/j.seminhematol.2013.03.030 -
Cold Spring Harbor Perspectives in... May 2011Telomerase is a eukaryotic ribonucleoprotein (RNP) whose specialized reverse transcriptase action performs de novo synthesis of one strand of telomeric DNA. The... (Review)
Review
Telomerase is a eukaryotic ribonucleoprotein (RNP) whose specialized reverse transcriptase action performs de novo synthesis of one strand of telomeric DNA. The resulting telomerase-mediated elongation of telomeres, which are the protective end-caps for eukaryotic chromosomes, counterbalances the inevitable attrition from incomplete DNA replication and nuclease action. The telomerase strategy to maintain telomeres is deeply conserved among eukaryotes, yet the RNA component of telomerase, which carries the built-in template for telomeric DNA repeat synthesis, has evolutionarily diverse size and sequence. Telomerase shows a distribution of labor between RNA and protein in aspects of the polymerization reaction. This article first describes the underlying conservation of a core set of structural features of telomerase RNAs important for the fundamental polymerase activity of telomerase. These include a pseudoknot-plus-template domain and at least one other RNA structural motif separate from the template-containing domain. The principles driving the diversity of telomerase RNAs are then explored. Much of the diversification of telomerase RNAs has come from apparent gain-of-function elaborations, through inferred evolutionary acquisitions of various RNA motifs used for telomerase RNP biogenesis, cellular trafficking of enzyme components, and regulation of telomerase action at telomeres. Telomerase offers broadly applicable insights into the interplay of protein and RNA functions in the context of an RNP enzyme.
Topics: Base Sequence; Binding Sites; DNA; DNA Replication; Evolution, Molecular; Nucleic Acid Conformation; Polymerization; RNA; Telomerase; Telomere
PubMed: 20660025
DOI: 10.1101/cshperspect.a003558 -
Mechanisms of Ageing and Development 2008Telomerase is a specialized reverse transcriptase conserved throughout almost all eukaryotic life. It plays a fundamental role in genome maintenance, adding back the... (Review)
Review
Telomerase is a specialized reverse transcriptase conserved throughout almost all eukaryotic life. It plays a fundamental role in genome maintenance, adding back the telomeric DNA repeats lost from chromosome ends due to incomplete replication or damage. The protein and RNA subunits of telomerase fold and function in a co-dependent manner to establish a high fidelity of telomeric repeat synthesis. Over the past two decades, studies of telomerase have uncovered previously unanticipated levels of complexity in its assembly, activity and regulation. This review describes the current understanding of telomerase in humans, with particular focus on telomerase biogenesis and regulation in its cellular context.
Topics: Humans; RNA; Ribonucleoproteins; Telomerase; Telomere
PubMed: 18054989
DOI: 10.1016/j.mad.2007.10.008