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Titia De Lange - One of the best experts on this subject based on the ideXlab platform.
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13 Mammalian Telomeres
Cold Spring Harbor Monograph Archive, 2006Co-Authors: Titia De LangeAbstract:As in most other eukaryotes, the ends of mammalian chromosomes are protected by the combined action of telomeric DNA, Telomere-associated proteins, and telomerase. In the decade since the last Cold Spring Harbor Laboratory Telomere Monograph was published, substantial progress has been made on each aspect of mammalian Telomere biology. Important facets of the DNA component, including the t-loop configuration and the structure of the Telomere terminus, have been illuminated; a Telomere-specific protein complex, now referred to as shelterin, has been identified; and several DNA-damage response and repair factors have been implicated in Telomere function. Studies of Telomere pathology, resulting from shelterin inhibition or other insults, have revealed the fate of dysfunctional Telomeres and their impact on chromosomes and cells. Furthermore, the principles of Telomere length homeostasis and the role of shelterin in controlling Telomere elongation by telomerase have emerged. This chapter focuses on the DNA and protein components of mammalian Telomeres and the mechanisms of Telomere function. The details of mammalian telomerases are discussed in Chapters 2 and 3 and aspects of Telomere function that relate to cancer and aging are covered in Chapters 4–6. TELOMERIC DNA The Telomeric TTAGGG Repeat Array Mammals and all other vertebrates have Telomeres made up of tandem TTAGGG repeats (Fig. 1) (Moyzis et al. 1988; Meyne et al. 1989). This sequence is dictated by telomerase and may be the oldest telomeric repeat sequence because it is also found in several fungi, protozoa, and plants. The length of the TTAGGG repeat tract is an...
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pot1 as a terminal transducer of trf1 Telomere length control
Nature, 2003Co-Authors: Diego Loayza, Titia De LangeAbstract:Human Telomere maintenance is essential for the protection of chromosome ends, and changes in Telomere length have been implicated in ageing and cancer1,2,3,4. Human Telomere length is regulated by the TTAGGG-repeat-binding protein TRF1 and its interacting partners tankyrase 1, TIN2 and PINX1 (refs 5–9). As the TRF1 complex binds to the duplex DNA of the Telomere, it is unclear how it can affect telomerase, which acts on the single-stranded 3′ telomeric overhang. Here we show that the TRF1 complex interacts with a single-stranded telomeric DNA-binding protein—protection of Telomeres 1 (POT1)—and that human POT1 controls telomerase-mediated Telomere elongation. The presence of POT1 on Telomeres was diminished when the amount of single-stranded DNA was reduced. Furthermore, POT1 binding was regulated by the TRF1 complex in response to Telomere length. A mutant form of POT1 lacking the DNA-binding domain abrogated TRF1-mediated control of Telomere length, and induced rapid and extensive Telomere elongation. We propose that the interaction between the TRF1 complex and POT1 affects the loading of POT1 on the single-stranded telomeric DNA, thus transmitting information about Telomere length to the Telomere terminus, where telomerase is regulated.
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different Telomere damage signaling pathways in human and mouse cells
The EMBO Journal, 2002Co-Authors: Agata Smogorzewska, Titia De LangeAbstract:Programmed Telomere shortening in human somatic cells is thought to act as a tumor suppressor pathway, limiting the replicative potential of developing tumor cells. Critically short human Telomeres induce senescence either by activating p53 or by inducing the p16/RB pathway, and suppression of both pathways is required to suppress senescence of aged human cells. Here we report that removal of TRF2 from human Telomeres and the ensuing de-protection of chromosome ends induced immediate premature senescence. Although the telomeric tracts remained intact, the TRF2ΔBΔM-induced premature senescence was indistinguishable from replicative senescence and could be mediated by either the p53 or the p16/RB pathway. Telomere de-protection also induced a growth arrest and senescent morphology in mouse cells. However, in this setting the loss of p53 function was sufficient to completely abrogate the arrest, indicating that the p16/RB response to Telomere dysfunction is not active in mouse cells. These findings reveal a fundamental difference in Telomere damage signaling in human and mouse cells that bears on the use of mouse models for the Telomere tumor suppressor pathway.
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senescence induced by altered Telomere state not Telomere loss
Science, 2002Co-Authors: Jan Karlseder, Agata Smogorzewska, Titia De LangeAbstract:Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed Telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of Telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as Telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short Telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened Telomeres rather than by a complete loss of telomeric DNA.
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Protection of mammalian Telomeres
Oncogene, 2002Co-Authors: Titia De LangeAbstract:Telomeres allow cells to distinguish natural chromosome ends from damaged DNA. When Telomere function is disrupted, a potentially lethal DNA damage response can ensue, DNA repair activities threaten the integrity of chromosome ends, and extensive genome instability can arise. It is not clear exactly how the structure of Telomere ends diers from sites of DNA damage and how Telomeres protect chromosome ends from DNA repair activities. What are the de®ning structural features of Telomeres and through which mechanisms do they ensure chromosome end protection? What is the molecular basis of the telomeric cap and how does it act to sequester the chromosome end? Here I discuss data gathered in the last few years, suggesting that the protection of human chromosome ends primarily depends on the telomeric protein TRF2 and that Telomere capping involves the formation of a higher order structure, the telomeric loop or t-loop.
João F. Passos - One of the best experts on this subject based on the ideXlab platform.
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Aging and Telomeres
Reference Module in Biomedical Sciences, 2014Co-Authors: T. Von Zglinicki, Gabriele Saretzki, João F. PassosAbstract:Telomeres protect the ends of all linear chromosomes against DNA loss and faulty recombination. They shorten during replication and also in response to external stress and damage. Telomerase counteracts Telomere shortening but has nontelomeric functions as well. Shortened or otherwise uncapped Telomeres are recognized by the cell's DNA damage response machinery and induce apoptosis or cell senescence, thus contributing to functional decline during aging. In humans and many other animals, Telomeres in somatic tissues shorten with age. Telomere length in such tissues is associated with aging but currently lacks the diagnostic precision needed for it to be a reliable biomarker. Telomeres and telomerase, however, are promising targets for interventions to limit tumor growth and possibly to slow down age-related functional decline.
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Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence
Nature Communications, 2012Co-Authors: Graeme Hewitt, Clara Correia-melo, Rhys Anderson, Francisco D M Marques, Timothy Hardy, Agata Gackowska, Morgan Taschuk, Jelena Mann, Diana Jurk, João F. PassosAbstract:Telomeres are specialized nucleoprotein structures, which protect chromosome ends and have been implicated in the ageing process. Telomere shortening has been shown to contribute to a persistent DNA damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells. Similarly, persistent DDR foci can be found in stress-induced senescence, although their nature is not understood. Here we show, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress-induced senescence are located at Telomeres irrespective of telomerase activity. Moreover, live-cell imaging experiments reveal that all persistent foci are associated with Telomeres. Finally, we report an age-dependent increase in frequencies of Telomere-associated foci in gut and liver of mice, occurring irrespectively of Telomere length. We conclude that Telomeres are important targets for stress in vitro and in vivo and this has important consequences for the ageing process.
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DNA damage in Telomeres and mitochondria during cellular senescence: Is there a connection?
Nucleic Acids Research, 2007Co-Authors: João F. Passos, Gabriele Saretzki, Thomas Von ZglinickiAbstract:Cellular senescence is the ultimate and irreversible loss of replicative capacity occurring in primary somatic cell culture. It is triggered as a stereotypic response to unrepaired nuclear DNA damage or to uncapped Telomeres. In addition to a direct role of nuclear DNA double-strand breaks as inducer of a DNA damage response, two more subtle types of DNA damage induced by physiological levels of reactive oxygen species (ROS) can have a significant impact on cellular senescence: Firstly, it has been established that Telomere shortening, which is the major contributor to Telomere uncapping, is stress dependent and largely caused by a Telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence. Improvement of mitochondrial function results in less telomeric damage and slower Telomere shortening, while Telomere-dependent growth arrest is associated with increased mitochondrial dysfunction. Moreover, telomerase, the enzyme complex that is known to re-elongate shortened Telomeres, also appears to have functions independent of Telomeres that protect against oxidative stress. Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence.
Maria A Blasco - One of the best experts on this subject based on the ideXlab platform.
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Telomere-driven diseases and Telomere-targeting therapies.
Journal of Cell Biology, 2017Co-Authors: Paula Martinez, Maria A BlascoAbstract:Telomeres, the protective ends of linear chromosomes, shorten throughout an individual’s lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short Telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in Telomere maintenance genes are associated with pathologies referred to as Telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in Telomere length maintenance genes and in shelterin components, the protein complex that protects Telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent Telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying Telomere-driven diseases and highlight recent advances in the preclinical development of Telomere-targeted therapies using mouse models.
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Telomere length and telomerase activity impact the UV sensitivity syndrome xeroderma pigmentosum C
Cancer Research, 2013Co-Authors: Gerdine J. Stout, Maria A BlascoAbstract:Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with Telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional Telomeres, including mice deficient for telomerase (Terc(-/-) mice). Thus, we investigated a hypothesized role for telomerase and Telomere dysfunction in the pathobiology of XP by comparing Xpc(-/-)-mutant mice and Xpc(-/-)G1-G3Terc(-/-) double-mutant mice and exposed them to UV radiation. Chronically UV-exposed Xpc(-/-) skin displayed shorter Telomeres on an average compared with wild-type skin. Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long Telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of Telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc(-/-)G1-G3Terc(-/-) mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in Telomere stability, particularly upon UV exposure. In absence of telomerase, critically short Telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of Telomere lengthening.
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Telomeres in cancer and ageing
Philosophical Transactions of the Royal Society B: Biological Sciences, 2011Co-Authors: Luis Enrique Donate, Maria A BlascoAbstract:Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are heterochromatic domains composed of repetitive DNA (TTAGGG repeats) bound to an array of specialized proteins. The length of Telomere repeats and the integrity of Telomere-binding proteins are both important for Telomere protection. Furthermore, Telomere length and integrity are regulated by a number of epigenetic modifications, thus pointing to higher order control of Telomere function. In this regard, we have recently discovered that Telomeres are transcribed generating long, non-coding RNAs, which remain associated with the telomeric chromatin and are likely to have important roles in Telomere regulation. In the past, we showed that Telomere length and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of stem cells. These effects of telomerase and Telomere length on stem cell behaviour anticipate the premature ageing and cancer phenotypes of telomerase mutant mice. Recently, we have demonstrated the anti-ageing activity of telomerase by forcing telomerase expression in mice with augmented cancer resistance. Shelterin is the major protein complex bound to mammalian Telomeres; however, its potential relevance for cancer and ageing remained unaddressed to date. To this end, we have generated mice conditionally deleted for the shelterin proteins TRF1, TPP1 and Rap1. The study of these mice demonstrates that Telomere dysfunction, even if Telomeres are of a normal length, is sufficient to produce premature tissue degeneration, acquisition of chromosomal aberrations and initiation of neoplastic lesions. These new mouse models, together with the telomerase-deficient mouse model, are valuable tools for understanding human pathologies produced by Telomere dysfunction.
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A ‘higher order’ of Telomere regulation: Telomere heterochromatin and telomeric RNAs
The EMBO Journal, 2009Co-Authors: Stefan Schoeftner, Maria A BlascoAbstract:Protection of chromosome ends from DNA repair and degradation activities is mediated by specialized protein complexes bound to Telomere repeats. Recently, it has become apparent that epigenetic regulation of the telomric chromatin template critically impacts on Telomere function and Telomere-length homeostasis from yeast to man. Across all species, telomeric repeats as well as the adjacent subtelomeric regions carry features of repressive chromatin. Disruption of this silent chromatin environment results in loss of Telomere-length control and increased Telomere recombination. In turn, progressive Telomere loss reduces chromatin compaction at telomeric and subtelomeric domains. The recent discoveries of Telomere chromatin regulation during early mammalian development, as well as during nuclear reprogramming, further highlights a central role of Telomere chromatin changes in ontogenesis. In addition, Telomeres were recently shown to generate long, non-coding RNAs that remain associated to telomeric chromatin and will provide new insights into the regulation of Telomere length and Telomere chromatin. In this review, we will discuss the epigenetic regulation of Telomeres across species, with special emphasis on mammalian Telomeres. We will also discuss the links between epigenetic alterations at mammalian Telomeres and Telomere-associated diseases.
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Suv4-20h deficiency results in Telomere elongation and derepression of Telomere recombination
Journal of Cell Biology, 2007Co-Authors: Roberta Benetti, Isabel Jaco, Susana Gonzalo, Gunnar Schotta, Peter Klatt, Thomas Jenuwein, Maria A BlascoAbstract:Mammalian Telomeres have heterochromatic features, including trimethylated histone H3 at lysine 9 (H3K9me3) and trimethylated histone H4 at lysine 20 (H4K20me3). In addition, subtelomeric DNA is hypermethylated. The enzymatic activities responsible for these modifications at Telomeres are beginning to be characterized. In particular, H4K20me3 at Telomeres could be catalyzed by the novel Suv4-20h1 and Suv4-20h2 histone methyltransferases (HMTases). In this study, we demonstrate that the Suv4-20h enzymes are responsible for this histone modification at Telomeres. Cells deficient for Suv4-20h2 or for both Suv4-20h1 and Suv4-20h2 show decreased levels of H4K20me3 at Telomeres and subTelomeres in the absence of changes in H3K9me3. These epigenetic alterations are accompanied by Telomere elongation, indicating a role for Suv4-20h HMTases in Telomere length control. Finally, cells lacking either the Suv4-20h or Suv39h HMTases show increased frequencies of Telomere recombination in the absence of changes in subtelomeric DNA methylation. These results demonstrate the importance of chromatin architecture in the maintenance of Telomere length homeostasis and reveal a novel role for histone lysine methylation in controlling Telomere recombination.
Thomas Von Zglinicki - One of the best experts on this subject based on the ideXlab platform.
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DNA damage in Telomeres and mitochondria during cellular senescence: Is there a connection?
Nucleic Acids Research, 2007Co-Authors: João F. Passos, Gabriele Saretzki, Thomas Von ZglinickiAbstract:Cellular senescence is the ultimate and irreversible loss of replicative capacity occurring in primary somatic cell culture. It is triggered as a stereotypic response to unrepaired nuclear DNA damage or to uncapped Telomeres. In addition to a direct role of nuclear DNA double-strand breaks as inducer of a DNA damage response, two more subtle types of DNA damage induced by physiological levels of reactive oxygen species (ROS) can have a significant impact on cellular senescence: Firstly, it has been established that Telomere shortening, which is the major contributor to Telomere uncapping, is stress dependent and largely caused by a Telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence. Improvement of mitochondrial function results in less telomeric damage and slower Telomere shortening, while Telomere-dependent growth arrest is associated with increased mitochondrial dysfunction. Moreover, telomerase, the enzyme complex that is known to re-elongate shortened Telomeres, also appears to have functions independent of Telomeres that protect against oxidative stress. Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence.
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Telomeres, cell senescence and human ageing
Signal Transduction, 2005Co-Authors: Thomas Von Zglinicki, Carmen M. Martin-ruiz, Gabriele SaretzkiAbstract:Telomeres in most human cell types shorten during DNA replication in vitro because of various factors including the inability of DNA polymerases to fully copy the lagging strand, DNA end processing and random damage, often caused by oxidative stress. Short, uncapped Telomeres activate replicative senescence, an irreversible cell cycle arrest and are thus a major cause of cell ageing in vitro. We will review how uncapped Telomeres initiate a signalling cascade toward senescence, and why oxidative stress is a major cause of Telomere shortening. Telomeres in most human cells shorten during ageing in vivo as well, suggesting two distinct possibilities. (1) Telomere shortening could be among the causes for ageing in vivo: Short Telomeres might lead to senescence of (stem) cells in a tissue-specific fashion, and this might contribute to age-related functional attenuation in this tissue and even to systemic effects. Evidence for this is mostly indirect. (2) Telomere length could be a biomarker of ageing and age-related morbidity: Short Telomeres might indicate a history of high stress and damage in the individual and could thus act as risk markers for age-related disease residing in a completely different tissue. There is evidence to support this possibility, although it is mostly correlative and is often derived from underpowered studies.
Jan Karlseder - One of the best experts on this subject based on the ideXlab platform.
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tzap a Telomere associated protein involved in Telomere length control
Science, 2017Co-Authors: Julia Su Zhou Li, Javier Miralles Fuste, Tatevik Simavorian, Cristina Bartocci, Jill Tsai, Jan Karlseder, Eros Lazzerini DenchiAbstract:Telomeres are found at the end of chromosomes and are important for chromosome stability. Here we describe a specific Telomere-associated protein: TZAP (telomeric zinc finger–associated protein). TZAP binds preferentially to long Telomeres that have a low concentration of shelterin complex, competing with the telomeric-repeat binding factors TRF1 and TRF2. When localized at Telomeres, TZAP triggers a process known as Telomere trimming, which results in the rapid deletion of telomeric repeats. On the basis of these results, we propose a model for Telomere length regulation in mammalian cells: The reduced concentration of the shelterin complex at long Telomeres results in TZAP binding and initiation of Telomere trimming. Binding of TZAP to long Telomeres represents the switch that triggers Telomere trimming, setting the upper limit of Telomere length.
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functional human Telomeres are recognized as dna damage in g2 of the cell cycle
Molecular Cell, 2005Co-Authors: Ramiro E Verdun, Laure Crabbe, Candy Haggblom, Jan KarlsederAbstract:Summary Telomeres have to be distinguished from DNA breaks that initiate a DNA damage response. Proteins involved in the DNA damage response have previously been found at Telomeres in transformed cells; however, the importance of these factors for Telomere function has not been understood. Here, we show that Telomeres of telomerase-negative primary cells recruit Mre11, phosphorylated NBS1, and ATM in every G2 phase of the cell cycle. This recruitment correlates with a partial release of telomeric POT1; moreover, Telomeres were found to be accessible to modifying enzymes at this time in the cell cycle, suggesting that they are unprotected. Degradation of the MRN complex, as well as inhibition of ATM, led to Telomere dysfunction. Consequentially, we propose that a localized DNA damage response at Telomeres after replication is essential for recruiting the processing machinery that promotes formation of a chromosome end protection complex.
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defective Telomere lagging strand synthesis in cells lacking wrn helicase activity
Science, 2004Co-Authors: Laure Crabbe, Ramiro E Verdun, Candy Haggblom, Jan KarlsederAbstract:Cells from Werner syndrome patients are characterized by slow growth rates, premature senescence, accelerated Telomere shortening rates, and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here we report that cells lacking WRN exhibit deletion of Telomeres from single sister chromatids. Only Telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual Telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. We propose that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing Telomere dysfunction and consequent genomic instability.
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senescence induced by altered Telomere state not Telomere loss
Science, 2002Co-Authors: Jan Karlseder, Agata Smogorzewska, Titia De LangeAbstract:Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed Telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of Telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as Telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short Telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened Telomeres rather than by a complete loss of telomeric DNA.
