Academic literature on the topic 'Telomere protection'
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Journal articles on the topic "Telomere protection"
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Hsu, Joseph K., Tao Lin, and Robert Y. L. Tsai. "Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1." Journal of Cell Biology 197, no. 5 (May 28, 2012): 613–24. http://dx.doi.org/10.1083/jcb.201109038.
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Continuously dividing cells must be protected from telomeric and nontelomeric DNA damage in order to maintain their proliferative potential. Here, we report a novel telomere-protecting mechanism regulated by nucleostemin (NS). NS depletion increased the number of telomere damage foci in both telomerase-active (TA+) and alternative lengthening of telomere (ALT) cells and decreased the percentage of damaged telomeres associated with ALT-associated PML bodies (APB) and the number of APB in ALT cells. Mechanistically, NS could promote the recruitment of PML-IV to SUMOylated TRF1 in TA+ and ALT cells. This event was stimulated by DNA damage. Supporting the importance of NS and PML-IV in telomere protection, we demonstrate that loss of NS or PML-IV increased the frequency of telomere damage and aberration, reduced telomeric length, and perturbed the TRF2ΔBΔM-induced telomeric recruitment of RAD51. Conversely, overexpression of either NS or PML-IV protected ALT and TA+ cells from telomere damage. This work reveals a novel mechanism in telomere protection.
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Bunch, Jeremy T., Nancy S. Bae, Jessica Leonardi, and Peter Baumann. "Distinct Requirements for Pot1 in Limiting Telomere Length and Maintaining Chromosome Stability." Molecular and Cellular Biology 25, no. 13 (July 1, 2005): 5567–78. http://dx.doi.org/10.1128/mcb.25.13.5567-5578.2005.
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ABSTRACT The fission yeast Pot1 (protection of telomeres) protein binds to the single-stranded extensions at the ends of telomeres, where its presence is critical for the maintenance of linear chromosomes. Homologs of Pot1 have been identified in a wide variety of eukaryotes, including plants, animals, and humans. We now show that Pot1 plays dual roles in telomere length regulation and chromosome end protection. Using a series of Pot1 truncation mutants, we have defined distinct areas of the protein required for chromosome stability and for limiting access to telomere ends by telomerase. We provide evidence that a large portion of Pot1, including the N-terminal DNA binding domain and amino acids close to the C terminus, is essential for its protective function. C-terminal Pot1 fragments were found to exert a dominant-negative effect by displacing endogenous Pot1 from telomeres. Reducing telomere-bound Pot1 in this manner resulted in dramatic lengthening of the telomere tract. Upon further reduction of Pot1 at telomeres, the opposite phenotype was observed: loss of telomeric DNA and chromosome end fusions. Our results demonstrate that cells must carefully regulate the amount of telomere-bound Pot1 to differentiate between allowing access to telomerase and catastrophic loss of telomeres.
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Mattern, Karin A., Susan J. J. Swiggers, Alex L. Nigg, Bob Löwenberg, Adriaan B. Houtsmuller, and J. Mark J. M. Zijlmans. "Dynamics of Protein Binding to Telomeres in Living Cells: Implications for Telomere Structure and Function." Molecular and Cellular Biology 24, no. 12 (June 15, 2004): 5587–94. http://dx.doi.org/10.1128/mcb.24.12.5587-5594.2004.
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ABSTRACT Telomeric proteins have an essential role in the regulation of the length of the telomeric DNA tract and in protection against end-to-end chromosome fusion. Telomere organization and how individual proteins are involved in different telomere functions in living cells is largely unknown. By using green fluorescent protein tagging and photobleaching, we investigated in vivo interactions of human telomeric DNA-binding proteins with telomeric DNA. Our results show that telomeric proteins interact with telomeres in a complex dynamic fashion: TRF2, which has a dual role in chromosome end protection and telomere length homeostasis, resides at telomeres in two distinct pools. One fraction (∼73%) has binding dynamics similar to TRF1 (residence time of ∼44 s). Interestingly, the other fraction of TRF2 binds with similar dynamics as the putative end-protecting factor hPOT1 (residence time of ∼11 min). Our data support a dynamic model of telomeres in which chromosome end-protection and telomere length homeostasis are governed by differential binding of telomeric proteins to telomeric DNA.
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Kelleher, Colleen, Isabel Kurth, and Joachim Lingner. "Human Protection of Telomeres 1 (POT1) Is a Negative Regulator of Telomerase Activity In Vitro." Molecular and Cellular Biology 25, no. 2 (January 15, 2005): 808–18. http://dx.doi.org/10.1128/mcb.25.2.808-818.2005.
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ABSTRACT The telomeric single-strand DNA binding protein protection of telomeres 1 (POT1) protects telomeres from rapid degradation in Schizosaccharomyces pombe and has been implicated in positive and negative telomere length regulation in humans. Human POT1 appears to interact with telomeres both through direct binding to the 3′ overhanging G-strand DNA and through interaction with the TRF1 duplex telomere DNA binding complex. The influence of POT1 on telomerase activity has not been studied at the molecular level. We show here that POT1 negatively effects telomerase activity in vitro. We find that the DNA binding activity of POT1 is required for telomerase inhibition. Furthermore, POT1 is incapable of inhibiting telomeric repeat addition to substrate primers that are defective for POT1 binding, suggesting that in vivo, POT1 likely affects substrate access to telomerase.
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Smogorzewska, Agata, Bas van Steensel, Alessandro Bianchi, Stefan Oelmann, Matthias R. Schaefer, Gisela Schnapp, and Titia de Lange. "Control of Human Telomere Length by TRF1 and TRF2." Molecular and Cellular Biology 20, no. 5 (March 1, 2000): 1659–68. http://dx.doi.org/10.1128/mcb.20.5.1659-1668.2000.
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ABSTRACT Telomere length in human cells is controlled by a homeostasis mechanism that involves telomerase and the negative regulator of telomere length, TRF1 (TTAGGG repeat binding factor 1). Here we report that TRF2, a TRF1-related protein previously implicated in protection of chromosome ends, is a second negative regulator of telomere length. Overexpression of TRF2 results in the progressive shortening of telomere length, similar to the phenotype observed with TRF1. However, while induction of TRF1 could be maintained over more than 300 population doublings and resulted in stable, short telomeres, the expression of exogenous TRF2 was extinguished and the telomeres eventually regained their original length. Consistent with their role in measuring telomere length, indirect immunofluorescence indicated that both TRF1 and TRF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts. Neither TRF1 nor TRF2 affected the expression level of telomerase. Furthermore, the presence of TRF1 or TRF2 on a short linear telomerase substrate did not inhibit the enzymatic activity of telomerase in vitro. These findings are consistent with the recently proposed t loop model of telomere length homeostasis in which telomerase-dependent telomere elongation is blocked by sequestration of the 3′ telomere terminus in TRF1- and TRF2-induced telomeric loops.
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Kibe, Tatsuya, Yuuki Ono, Koichiro Sato, and Masaru Ueno. "Fission Yeast Taz1 and RPA Are Synergistically Required to Prevent Rapid Telomere Loss." Molecular Biology of the Cell 18, no. 6 (June 2007): 2378–87. http://dx.doi.org/10.1091/mbc.e06-12-1084.
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The telomere complex must allow nucleases and helicases to process chromosome ends to make them substrates for telomerase, while preventing these same activities from disrupting chromosome end-protection. Replication protein A (RPA) binds to single-stranded DNA and is required for DNA replication, recombination, repair, and telomere maintenance. In fission yeast, the telomere binding protein Taz1 protects telomeres and negatively regulates telomerase. Here, we show that taz1-d rad11-D223Y double mutants lose their telomeric DNA, indicating that RPA (Rad11) and Taz1 are synergistically required to prevent telomere loss. Telomere loss in the taz1-d rad11-D223Y double mutants was suppressed by additional mutation of the helicase domain in a RecQ helicase (Rqh1), or by overexpression of Pot1, a single-strand telomere binding protein that is essential for protection of chromosome ends. From our results, we propose that in the absence of Taz1 and functional RPA, Pot1 cannot function properly and the helicase activity of Rqh1 promotes telomere loss. Our results suggest that controlling the activity of Rqh1 at telomeres is critical for the prevention of genomic instability.
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Fernandes, Stina George, Rebecca Dsouza, Gouri Pandya, Anuradha Kirtonia, Vinay Tergaonkar, Sook Y. Lee, Manoj Garg, and Ekta Khattar. "Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential." Cancers 12, no. 7 (July 14, 2020): 1901. http://dx.doi.org/10.3390/cancers12071901.
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Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects them from being identified as DNA damage sites. Telomeres are transcribed by RNA polymerase II, and generate a long noncoding RNA called telomeric repeat-containing RNA (TERRA), which plays a key role in regulating subtelomeric gene expression. Replicative immortality and genome instability are hallmarks of cancer and to attain them cancer cells exploit telomere maintenance and telomere protection mechanisms. Thus, understanding the role of telomeres and their associated proteins in cancer initiation, progression and treatment is very important. The present review highlights the critical role of various telomeric components with recently established functions in cancer. Further, current strategies to target various telomeric components including human telomerase reverse transcriptase (hTERT) as a therapeutic approach in human malignancies are discussed.
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Donate, Luis E., and Maria A. Blasco. "Telomeres in cancer and ageing." Philosophical Transactions of the Royal Society B: Biological Sciences 366, no. 1561 (January 12, 2011): 76–84. http://dx.doi.org/10.1098/rstb.2010.0291.
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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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Calado, Rodrigo T. "Telomeres and marrow failure." Hematology 2009, no. 1 (January 1, 2009): 338–43. http://dx.doi.org/10.1182/asheducation-2009.1.338.
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AbstractTelomeres, repeat sequences at the ends of chromosomes, are protective chromosomal structures highly conserved from primitive organisms to humans. Telomeres inevitably shorten with every cell cycle, and telomere attrition has been hypothesized to be fundamental to normal senescence of cells, tissues, and organisms. Molecular mechanisms have evolved to maintain their length and protective function; telomerase (TERT) is a reverse transcriptase enzyme that uses an RNA molecule (TERC) as the template to elongate the 3′ ends of telomeres. Shelterin is a collection of DNA-binding proteins that cover and protect telomeres. The recent discovery of inherited mutations in genes that function to repair telomeres as etiologic in a range of human diseases, which have clinical manifestations in diverse tissues, including the hematopoietic tissue, suggests that defects in telomere repair and protection can cause organ failure. Dyskeratosis congenita is the prototype of telomere diseases; it is characterized by bone marrow failure, mucocutaneous abnormalities, pulmonary fibrosis, liver cirrhosis, and increased susceptibility to cancer, including acute myeloid leukemia. Aplastic anemia, acute myeloid leukemia, and idiopathic pulmonary fibrosis also are associated with inherited mutations in telomere repair or protection genes. Additionally, telomere defects associate with predisposition to hematologic malignancy and epithelial tumors. Telomere erosion is abnormally rapid in patients with mutations in telomerase genes but also after hematopoietic stem cell transplant, and telomeres are naturally shorter in older individuals—all conditions associated with higher rates of malignant diseases. In human tissue culture, short telomeres produce end-to-end chromosome fusion, nonreciprocal translocations, and aneuploidy.
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Maddar, Haggar, Nir Ratzkovsky, and Anat Krauskopf. "Role for Telomere Cap Structure in Meiosis." Molecular Biology of the Cell 12, no. 10 (October 2001): 3191–203. http://dx.doi.org/10.1091/mbc.12.10.3191.
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Telomeres, the natural ends of eukaryotic chromosomes, are essential for the protection of chromosomes from end-to-end fusions, recombination, and shortening. Here we explore their role in the process of meiotic division in the budding yeast, Kluyveromyces lactis. Telomerase RNA mutants that cause unusually long telomeres with deregulated structure led to severely defective meiosis. The severity of the meiotic phenotype of two mutants correlated with the degree of loss of binding of the telomere binding protein Rap1p. We show that telomere size and the extent of potential Rap1p binding to the entire telomere are irrelevant to the process of meiosis. Moreover, we demonstrate that extreme difference in telomere size between two homologous chromosomes is compatible with the normal function of telomeres during meiosis. In contrast, the structure of the most terminal telomeric repeats is critical for normal meiosis. Our results demonstrate that telomeres play a critical role during meiotic division and that their terminal cap structure is essential for this role.
Dissertations / Theses on the topic "Telomere protection"
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Karpov, Victor. "A study on telomere protection and telomerase-and-cap-independent mechanisms of telomere maintenance in yeast Saccharomyces cerevisiae." Mémoire, Université de Sherbrooke, 2008. http://savoirs.usherbrooke.ca/handle/11143/3940.
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An SGA approach to discover cdc13-1ts supressors. Telomeres, the DNA-protein complexes at the end of eukaryotic chromosomes, are essential for chromosomal stability. In yeast, the telomeric single-strand binding protein Cdc13p has multiple important roles related to telomere maintenance: (1) telomeric"capping"--protection of telomeres by forming complexes with yKu70/80 and with Stn1p/Ten1p; (2) positive regulation of telomere replication via interaction with Est1p, which is a part of telomerase; (3) negative regulation of telomerase by the recruitment of telomere elongation suppressors Stn1p and Ten1p. In an attempt to identify genes that are involved in the deleterious outcome of an absence of Cdc13p, we screened the yeast gene knock-out library for genes that could suppress the growth defect of cdc13-1 cells at 33ê C. For this purpose, we performed an SGA array experiment. We scored for the ability of double mutant haploids to grow at 33ê C. Eventually, we hoped to find the elusive genes involved in telomere 5'-end processing (exonucleases). Based on the comparative analysis of growth properties of the strains (23ê C vs 33ê C), the initial screen identified up to 111 genes that displayed an apparent growth at 33ê C. In order to verify these results, diploids were regenerated, sporulated, microdissected, and haploid double mutants cdc13-1 yfg[deletion] were isolated from 38 potential cdc13-1 suppressors. Unfortunately, this verification failed to reproduce a suppression of the growth defect by any of the selected genes at any temperature. While disappointing, the results reemphasize that careful re-examination of large scale SGA approaches are indispensable before going on to more involved experimentation. Similarities and differences between adaptation to DNA double-strand break and to telomere uncapping in yeast Saccharomyces cerevisiae. It was previously shown that a certain proportion of telomerase negative survivor cells (both type I and type II cells) is able to survive in the absence of the telomere capping protein Cdc13p. These strains (named [deletion]13s) were characterized in great detail and one of their discovered features was a striking ability to continuously inactivate DNA-damage checkpoints. Based on structural similarities between DNA double strand breaks (DSB) and unprotected telomeres, we attempted to verify if the molecular mechanisms regulating adaptation to a single irreparable DSB also regulate adaptation to a loss of Cdc13p. For this purpose we created three tlc1[deletion] cdc13[deletion] strains also harboring DSB adaptation related mutations tid1[deletion], ptc2[deletion] and rfa1-t11. After deprotection of their telomeres, mutant survivor cells showed similar cell cycle progression patterns as compared to the cells where a single irreparable DSB was introduced. Adaptation defective mutants tid1[deletion] and ptc2[deletion] demonstrated an inability to adapt to telomere uncapping and to resume cell cycle. Interestingly, cells harboring the rfa1-t11 allele, which was reported to suppress adaptation defects of other mutations, did not show any distinguishable phenotype in terms of initial adaptation to telomere deprotection; i.e. rfa1-t11 mutant survivors do escape the G2/M arrest and re-enter the cell cycle. However, all three mutant survivor strains failed to produce viable [deletion]13 capping independent cells, which is consistent with the hypothesis that adaptation to loss of Cdc13p depends on the same pathway as the previously reported adaptation phenomenon. Finally, we report the surprising finding that if cells had once experienced an adapted [deletion]13 state, they will re-produce capping negative survivors much more readily. Thus, while a culture of type II survivor cells generates [deletion]13s at a rate of about 1×10 -5 events per division, cells that had been [deletion]13s and re-transformed with a Cdc13p carrying plasmid will produce capping independent cells at about 1×10-2 events per division. We are currently examining why these cells re-generate [deletion]13 cell lines more readily and suspect structural differences in telomere terminal sequence arrangements.
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Perera, Yatawarage Omesha Nalindri. "A non-canonical function of human telomerase reverse transcriptase in telomere protection." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14963.
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Telomerase is a ribonucleoprotein complex with a well-established role in telomere maintenance. There is growing evidence of non-canonical functions of telomerase that promote tumorigenesis. Here we have demonstrated that hTERT can mediate telomere protection independent of its canonical function in telomere maintenance, potentially enhancing positive feedback pathways that may facilitate oncogenesis. hTERT mediated telomere protection was found to be independent of catalytic activity and telomere recruitment, required nuclear export of hTERT, and required an intact N-terminal portion of hTERT. We have further shown that hTERT appears to regulate two seemingly independent pathways, with mutual requirement of both NFκB and Hsp70 to exert telomere protection. hTERT over-expression resulted in an increased localization of Hsp70 at the telomeric protein TRF2. This increase was dependent on the presence of the shelterin accessory protein Apollo, suggesting that Apollo acts as the bridge between Hsp70 and TRF2, facilitating the stabilization of TRF2 to form a fully capped telomere. Conversely, depletion of hTERT down-regulated NFκB signaling, with a concomitant increase in telomeric DNA damage and consequential G1 arrest. These two pathways may intersect physiologically through Hsp70 regulation of the NFκB pathway, further enforcing the feed-forward mechanism between hTERT and its transcriptional targets to promote oncogenesis.
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Xu, Mengyuan. "The Role of Shelterin Proteins in Telomere DNA Protection and Regulation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1585760345643995.
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ANBALAGAN, SAVANI. "Role of saccharomyces cerevisiae Rif1 and Rif2 proteins in protection of telomeres." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/43717.
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Eukaryotic cells distinguish their chromosome ends from accidental DNA double-strand breaks (DSBs) by packaging them into protective structures called telomeres that prevent DNA repair/recombination activities. In this work, we investigated the role of key telomeric proteins in protecting Saccharomyces cerevisiae telomeres from degradation. We show that the shelterin-like proteins Rif1, Rif2, and Rap1 inhibit nucleolytic processing at both de novo and native telomeres during G1 and G2 cell cycle phases, with Rif2 and Rap1 showing the strongest effects. Also Yku prevents telomere resection in G1, independently of its role in non-homologous end joining. Yku and the shelterin-like proteins have additive effects in inhibiting DNA degradation at G1 de novo telomeres. In particular, while Yku plays the major role in preventing initiation, Rif2 and Rap1 act primarily by limiting extensive resection. Finally, Rap1 and Rif2 prevent telomere degradation by inhibiting MRX access to telomeres, which are also protected from the Exo1 nuclease by Yku. Thus, chromosome end degradation is controlled by telomeric proteins that specifically inhibit the action of different nucleases.
Since Rif1 plays a very minor role in protecting wild type telomeres from degradation, we further investigated whether Rif1 participates in telomere protection in combination with other capping activities, like those exerted by the CST complex (Cdc13-Stn1-Ten1). We found that, unlike RIF2 deletion, the lack of RIF1 is lethal for stn1ΔC cells and causes a dramatic reduction in viability of cdc13-1 and cdc13-5 mutants. Both cdc13-1 rif1Δ and cdc13-5 rif1Δ cells display very high amounts of telomeric single-stranded DNA and DNA damage checkpoint activation, indicating that severe defects in telomere integrity cause their loss of viability. In agreement with this hypothesis, lethality in cdc13 rif1Δ cells is partially counteracted by the lack of the Exo1 nuclease, which is involved in telomeric single-stranded DNA generation. Like CDC13, RIF1 also genetically interacts with the Polα-primase complex, which is involved in the fill-in of the telomeric complementary strand. Thus, these data highlight a novel role for Rif1 in assisting the essential telomere protection function of the CST complex.
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Ye, Ying. "The role of Apollo (DCLRE1B) in telomere protection during replication." Lyon, École normale supérieure (sciences), 2009. http://www.theses.fr/2009ENSL0512.
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Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes to maintain the integrity of chromosome ends. In human cells, telomeres are protected by a complex of six proteins bound to telomeric DNA, named shelterin. As a crucial component of shelterin, the human telomeric capping protein TRF2 is required for telomere stabilization and function. Recently, TRF2 was shown to form a complex with Apollo, a 5' -exonuclease of the metallo-beta-lactamase family. In this thesis, biochjemical, genetic, and cellular approaches were combined to understand the mechanism of 5' -exonuclease of Apollo in the telomere protection. First, in vitro evidence shows that TRF2 plays a dual role in controlling Apollo nuclease activity. TRF2 stimulates the nuclease activity of Apollo on TRF2-free DNA ends and inhibits it when it is bound proximately to the 5' end. This stimulatory effect of Apollo nuclease depends on the basic domain of TRF2. Second, the specific coupling between the Apollo nuclease activity and the dynamics of TRF2 DNA binding shows in vivo that TRF2 and Apollo are not only involved in the protection of the very-terminal structure of telomeres but also of the inner part of telomere repeat tracts, which is required for telomere integrity during S-phase. Moreover TRF2 and Apollo protect from DNA damage telomere repeat tracts inserted far away from chromosome ends, furthze indicating that TRF2 couples the exonuclease activity of Apollo to protect telomere during fork progression. Third, exonuclease activity of Apollo, which is required for the telomere protection, is directly regulated by TRF2. These data are consistent with a new model of telomere protection in with TRF2 couples the exonuclease activity of Apollo to replication in order to eliminate clastogenic and recombinogenic structures. The work in my thesis suggest that replicative senescence in human cells may not only be caused by loss of the terminal cap integrity but also by replication-linked DNA breakages and recombinations within the inner part of telomeres.
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Oikemus, Sarah R. "Epigenetic Telomere Protection by Drosophila DNA Damage Response Pathways: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/229.
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Several aspects of Drosophila telomere biology indicate that telomere protection can be regulated by an epigenetic mechanism. First, terminally deleted chromosomes can be stably inherited and do not induce damage responses such as apoptosis or cell cycle arrest. Second, the telomere protection proteins HP1 and HOAP localize normally to these chromosomes and protect them from fusions. Third, unprotected telomeres still contain HeT-A sequences at sites of fusions. Taken together these observations support a model in which an epigenetic mechanism mediated by DNA damage response proteins protects Drosophilatelomeres from fusion.
Work presented in this thesis demonstrates that the Drosophila proteins ATM and Nbs are required for the regulation of DNA damage responses similar to their yeast and mammalian counterparts. This work also establishes a role for the ATM and ATR DNA damage response pathways in the protection of both normal and terminally deleted chromosomes. Mutations that disrupt both pathways result in a severe telomere fusion phenotype, similar to HP1 and HOAP mutants. Consistent with this phenotype, HOAP localization at atm,atr double mutant telomeres is completely eliminated. Furthermore, telomeric sequences are still present, even at the sites of fusions. These results support a model in which an epigenetic mechanism mediated by DNA damage response proteins protects Drosophila telomeres from fusion.
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Khan, Sheik Jamaludin. "Functions of TRF2: From Telomere Protection to DNA Damage Signaling and Vascular Remodeling." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/123.
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TTAGGG repeat factor 2 (TRF2) is a protein that plays an important role in capping telomere ends from DNA damage responses. Telomere DNA consists of double strand repeats of the TTAGGG sequence ending with a 3'single-stranded overhang of the guanine strand (the G-strand overhang). TRF2 protects telomeres from being recognized as double-stranded breaks. It is thought that this protection is performed through the formation of T-loop structures and recruitment of proteins into a complex called shelterin. The exact mechanism of T-loop formation is unknown. I show with in vitro biochemical studies that TRF2 specifically interacts with telomeric ss/ds DNA junctions and binding is sensitive to the sequence of the G-strand overhang and double-stranded DNA sequence at the junction. Binding assays with TRF2 truncation mutants suggest that TRF2 interacts with both the double-stranded DNA through the C-terminal DNA binding domain and the G-strand overhang through the N-terminus. Mobility shifts and atomic force microscopy with truncation mutants bound to telomeric DNA also show that a previously uncharacterized "linker" region within TRF2 is involved in DNA-specific TRF2 oligomerization. From these observations, I suggest that TRF2 forms protective loops by oligomerizing through both a previously characterized dimerization domain and the linker region. I propose that loop formation involving the telomere ends is accomplished through direct interactions between TRF2 and the G-strand overhang. In addition to DNA protection, a new role has emerged for TRF2 in sensing DNA damage. TRF2 can be phosphorylated within its dimerization domain by ATM and recruited to DNA damage foci in cells. The inhibition of TRF2 function alone has been shown to induce senescence and apoptosis in vascular endothelial cells. Since the common stimuli for a senescence phenotype is activation of a DNA damage response, I studied the relationship between DNA damage and TRF2 phosphorylation. Ex-vivo characterization of DNA damage-induced changes in vascular smooth muscle cells (VSMC) was undertaken. VSMC treated with H202 induced an increase in reactive oxygen species (ROS), and 8-oxo-guanine accumulation resulting in cell cycle arrest, chromatin condensation and a senescent phenotype. Interestingly phosphorylated TRF2 and ATM were also up regulated. Balloon injury was used to test the connection between phosphorylated TRF2 and senescence during vascular remodeling in rat arteries. Vascular remodeling as judged by neointima formation was associated with accumulation of 8-oxo-guanine, DNA damage signaling, including phosphorylated TRF2, an increase in cell cycle inhibitors and senescence. These events were exaggerated in aged animals and are consistent with a role in telomere dysfunction, and age related diseases.
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Khurana, Jaspreet S. "Drosophila piRNA Function in Genome Maintenance, Telomere Protection and Genome Evolution: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/518.
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Upon fertilization, the early embryo sustains most of the cellular processes using the maternally deposited reserves in the egg itself until the zygotic gene expression takes charge. Among the plethora of essential components provided by the mother are small non-coding RNAs called PIWI-interacting RNAs (piRNAs), which provide immunity to the zygote against transposon challenge. In this thesis, I have presented three different functions of piRNAs in Drosophila melanogaster- in maintenance of genomic integrity, telomere protection and their role as an adaptive immune system against genomic parasites.
In Chapter 2, I have described the phenotypic effects of the loss of piRNA function in early embryos. The mutations affecting the piRNA pathway are known to cause embryonic lethality. To describe this lethality in detail, I have shown that all the characterized piRNA mutants show compromised zygotic genomic integrity during early embryogenesis. In addition, two piRNA pathway components, Aubergine (Aub) and Armitage (Armi) are also required for telomere resolution during early embryogenesis. Aub and Armi recruit telomeric protection complex proteins, HOAP and HP1, to the telomeric ends and thus avoid activation of the Non-homologous end joining (NHEJ) DNA repair pathway at the telomeres.
There are about 120 transposon families in Drosophila melanogaster and piRNA pathway mutations cause activation of many of the resident transposons in the genome. In Chapter 3, I have described the effects of infection by a single transposon, P-element, in naïve strains by introduction through the zygote. Activation of the P-element leads to desilencing of unrelated transposons, causing accumulation of germline DNA damage which is linked to severely reduced fertility in the hybrid females. However, there is partial restoration of fertility as the hybrid progeny age, which correlates with P-element piRNA production and thus P-element silencing.
Additionally, a number of transposons mobilize into piRNA generating heterochromatic clusters in the genome, and these insertions are stably inherited in the progeny. Collectively our data shows that piRNA production can be triggered in the adults in an absence of maternal contribution and that piRNAs serve as an adaptive immune system which helps resolve an internal genetic conflict between the host and the parasite.
In an effort to understand the phenotypic effects of piRNA dysfunction in Drosophila, we have uncovered new exciting roles for piRNAs in development and presented evidence how transposons can act as architects in restructuring the host genome.
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Arora, Amit, Mark A. Beilstein, and Dorothy E. Shippen. "Evolution of Arabidopsis protection of telomeres 1 alters nucleic acid recognition and telomerase regulation." OXFORD UNIV PRESS, 2016. http://hdl.handle.net/10150/622915.
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Protection of telomeres (POT1) binds chromosome ends, recognizing single-strand telomeric DNA via two oligonucleotide/oligosaccharide binding folds (OB-folds). The Arabidopsis thaliana POT1a and POT1b paralogs are atypical: they do not exhibit telomeric DNA binding, and they have opposing roles in regulating telomerase activity. AtPOT1a stimulates repeat addition processivity of the canonical telomerase enzyme, while AtPOT1b interacts with a regulatory lncRNA that represses telomerase activity. Here, we show that OB1 of POT1a, but not POT1b, has an intrinsic affinity for telomeric DNA. DNA binding was dependent upon a highly conserved Phe residue (F65) that in human POT1 directly contacts telomeric DNA. F65Amutation of POT1aOB1 abolished DNA binding and diminished telomerase repeat addition processivity. Conversely, AtPOT1b and other POT1b homologs from Brassicaceae and its sister family, Cleomaceae, naturally bear a non-aromatic amino acid at this position. By swapping Val (V63) with Phe, AtPOT1bOB1 gained the capacity to bind telomeric DNA and to stimulate telomerase repeat addition processivity. We conclude that, in the context of DNA binding, variation at a single amino acid position promotes divergence of the AtPOT1b paralog from the ancestral POT1 protein.
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MENIN, LUCA. "Role of Tel1/ATM in protecting and signaling abnormal replication forks and short telomeres." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241165.
Full textAbstract:
Le cellule eucariotiche prevengono l’instabilità genomica attivando un complesso sistema biochimico chiamato Risposta ai Danni al DNA (DDR). Le proteine chinasi Mec1 e Tel1 di S. cerevisiae, ortologhe di ATR ed ATM umane, giocano un ruolo centrale nella DDR. Queste proteine attivano il checkpoint da danni al DNA il quale coordina la riparazione dei danni al DNA con la progressione del ciclo cellulare. Il ruolo della proteina Tel1 è particolarmente evidente in presenza di rotture a doppia elica del DNA (DSB). I DSB possono essere riparati tramite ricombinazione omologa la quale richiede la degradazione dell’estremità 5’ della rottura (resection). Tel1 contribuisce alla riparazione dei DSB promuovendo l’inizio della resection. Nonostante le funzioni di Tel1 nella DDR, l’assenza di Tel1 conferisce alle cellule di lievito solo una moderata sensibilità alla camptotecina (CPT), un inibitore delle topoisomerasi di tipo I. Dato che derivati della CPT sono attualmente usati in chemioterapia, comprendere il ruolo di Tel1 in risposta alla CPT è rilevante per lo sviluppo di nuove terapie anticancro.
Oltre a ciò, Tel1 è importante per il mantenimento dei telomeri, i quali vengono replicati grazie ad una trascrittasi inversa chiamata telomerasi. In particolare, Tel1 promuove il reclutamento della telomerasi e quindi l’omeostasi dei telomeri. La telomerasi è inattivata nella maggior parte dei tessuti umani che di conseguenza sono soggetti ad un progressivo accorciamento dei telomeri. Quando i telomeri divengono criticamente corti, si ha il blocco della divisione cellulare in un processo noto come senescenza replicativa che limita la proliferazione cellulare agendo da meccanismo oncosoppressore. La senescenza è innescata dall’attivazione del checkpoint da danni al DNA governato da Mec1/ATR e Tel1/ATM. In particolare, il meccanismo attraverso il quale Tel1/ATM induce la senescenza è ancora ignoto.
Durante il mio dottorato ho quindi seguito due distinti progetti allo scopo di far luce sui meccanismi molecolari che coinvolgono Tel1 in risposta alla CPT e nell’induzione della senescenza. Riguardo al primo progetto, sia in lievito che in mammifero la CPT induce la reversione delle forche replicative. Cellule tel1∆ sono caratterizzate da un ridotto livello di forche regresse indotte dalla CPT rispetto a cellule selvatiche. In risposta alla CPT, l’assenza dell’attività nucleasica di Mre11 ripristina livelli normali di forche regresse in cellule tel1∆. Inoltre, l’inattivazione della proteina Mrc1 mitiga la sensibilità a CPT di cellule tel1∆ e previene la reversione delle forche in cellule selvatiche, in cellule tel1∆ e in cellule senza l’attività nucleasica di Mre11. Nel loro insieme questi risultati indicano che Tel1 stabilizza le forche regresse generate da Mrc1 in presenza della CPT inibendo l’attività nucleasica di Mre11 a livello di queste strutture di DNA.
Riguardo al secondo progetto, per studiare il ruolo di Tel1 nell’induzione della senescenza ho sfruttato cellule di lievito senza telomerasi e l’allele mutante TEL1-hy184 identificato precedentemente come soppressore dei difetti di checkpoint di cellule mec1∆. Subito dopo l’inattivazione della telomerasi la variante Tel1-hy184 accelera la senescenza rispetto a cellule che esprimono la forma selvatica di Tel1. L’aumentata senescenza indotta da Tel1-hy184 è causata dall’attivazione di un checkpoint completamente dipendente dalla proteina Rad9 e solo in parte dipendente da Mec1. Inoltre, Tel1-hy184 non sembra aumentare il livello di ssDNA alle estremità di DNA. Ciò suggerisce che Tel1 induce la senescenza replicativa contribuendo direttamente all’attivazione del checkpoint in presenza di telomeri disfunzionali.
Nel complesso, i risultati che ho ottenuto durante il mio dottorato permettono di comprendere meglio le funzioni di Tel1/ATM nel mantenimento della stabilità genomica.Eukaryotic cells prevent genomic instability by activating a complex network of safeguard pathways called DNA Damage Response (DDR). S. cerevisiae Mec1 and Tel1 protein kinases, orthologs of human ATR and ATM, play a central role in the DDR. These proteins activate a checkpoint cascade which coordinates DNA damage repair with cell cycle progression. The role of Tel1 is particularly evident in the presence of DNA Double-Strand Breaks (DSBs), one of the most cytotoxic forms of DNA lesions. DSBs can be repaired by Homologous Recombination (HR), which requires the degradation of 5’-ended strands of the break (resection). Tel1 contributes to DSB repair by promoting resection initiation. Despite Tel1 functions in DDR, the absence of Tel1 confers a moderate sensitivity to camptothecin (CPT), an inhibitor of type I DNA topoisomerases. Since CPT derivatives are currently used in chemotherapy, understanding the molecular basis of tel1Δ mutant sensitivity to CPT is relevant for the development of anti-cancer therapies based on combined treatments with CPT derivatives and ATM inhibitors. In addition, Tel1 is important for the maintenance of telomeres, which are replicated by a reverse transcriptase called telomerase. In particular, Tel1 promotes the recruitment of telomerase and therefore telomere homeostasis. Telomerase is inactivated in most human tissues, which undergo progressive telomere shortening. When telomeres become critically short, a block of cell division, known as replicative senescence, limits cell proliferation, thus acting as a cancer-suppressor mechanism. Senescence is triggered by the activation of a checkpoint response governed by Mec1/ATR and Tel1/ATM. While Mec1/ATR is known to block cell division in the presence of extended ssDNA, the molecular mechanism by which Tel1/ATM triggers senescence is still unclear. During my PhD I have managed two different projects with the aim to shed light into the molecular mechanisms that involve Tel1 in response to CPT and in the induction of replicative senescence. Regarding the first project, in both yeast and mammals, CPT induces replication fork reversal, which has been proposed to stabilize stalled replication forks, thus providing time for the repair of CPT-induced lesions and supporting replication restart. tel1∆ cells have a reduced amount of CPT-induced reversed forks compared to wild type cells. The lack of Mre11 nuclease activity restores wild-type levels of reversed forks in CPT-treated tel1Δ cells, without affecting fork reversal in wild-type cells. Moreover, Mrc1 inactivation prevents fork reversal in wild-type, tel1Δ, and mre11 nuclease-deficient cells and relieves the hypersensitivity of tel1Δ cells to CPT. Altogether, these data indicate that Tel1 stabilizes Mrc1-dependent reversed forks generated in the presence of CPT by counteracting Mre11 nucleolytic activity at these structures. Regarding the second project, to studying the role of Tel1/ATM in the induction of senescence, I took advantage of telomerase-deficient yeast cells, which are considered a reliable model of replicative senescence, and the TEL1-hy184 allele, previously identified because it was able to suppress the checkpoint defects of Mec1-deficient cells. Upon telomerase inactivation, Tel1-hy184 accelerates senescence compared to wild type Tel1, while the lack of Tel1 was found to delay senescence. The enhanced senescence in telomerase-negative TEL1-hy184 cells depends on the activation of a checkpoint that is completely Rad9-dependent and only partially dependent on Mec1. Furthermore, Tel1-hy184 does not appear to increase ssDNA at DNA ends, suggesting that Tel1 induces replicative senescence by directly contributing to checkpoint signaling at dysfunctional telomeres. Taken together, the results that I have obtained during my PhD allow to better understand the functions of Tel1/ATM in the maintenance of genome stability.
Book chapters on the topic "Telomere protection"
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Schneider, Michael D. "Dual Roles of Telomerase in Cardiac Protection and Repair." In Novartis Foundation Symposia, 260–71. Chichester, UK: John Wiley & Sons, Ltd, 2008. http://dx.doi.org/10.1002/0470029331.ch16.
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"Telomeres and cancer protection." In Dynamics of Cancer, 375–401. WORLD SCIENTIFIC, 2014. http://dx.doi.org/10.1142/9789814566377_0020.
Full textConference papers on the topic "Telomere protection"
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Chow, Tracy T., and Elizabeth H. Blackburn. "Abstract LB-161: Exploiting non-canonical heterochromatin-mediated telomere protection mechanisms in human cells." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-lb-161.
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Muthumalage, T., I. K. Sundar, and I. Rahman. "Telomere Protection Protein 1 (TPP1) Deletion in Lung Epithelial Cells Augments Cigarette Smoke-Induced Lung Inflammation." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a1231.
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Muthumalage, T., and I. Rahman. "Selective Ablation of Telomere Protection Protein 1 (TPP1) in Lung Epithelium Induce an Age-Dependent Augmentation of the Inflammatory Response by Tobacco Smoke Exposure." In American Thoracic Society 2021 International Conference, May 14-19, 2021 - San Diego, CA. American Thoracic Society, 2021. http://dx.doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4295.
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Muthumalage, T., and I. Rahman. "Conditional Knockout of Telomere Protection Protein 1 (TPP1) in Lung Epithelium Triggers Senescence-Associated Lung Diseases and Increases Cancer Risk Upon Cigarette Smoke Exposure." In American Thoracic Society 2022 International Conference, May 13-18, 2022 - San Francisco, CA. American Thoracic Society, 2022. http://dx.doi.org/10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a3902.
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Zou, Jiang, Ru Sun, Jingruo Xia, Dan Xiao, Chang Liu, Hebin Liao, Lei Xu, et al. "Abstract 341: The role of telomere protective protein TPP1 in hepatocellular carcinoma." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-341.
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Baribault, Michelle E., Mark J. Swanson, and Nancy S. Bae. "Abstract 2261: Natural redistribution of end-protection proteins in aging cells as telomeres shorten." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-2261.
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Mashtalyar, D. V., S. V. Gnedenkov, S. L. Sinebryukhov, K. V. Nadaraia, D. P. Kiryukhin, P. P. Kushch, G. A. Kichigina, and V. M. Buznik. "Formation of protective composite coatings with the use of solution of TFE telomers." In ADVANCES IN ELECTRICAL AND ELECTRONIC ENGINEERING: FROM THEORY TO APPLICATIONS: Proceedings of the International Conference on Electrical and Electronic Engineering (IC3E 2017). Author(s), 2017. http://dx.doi.org/10.1063/1.4998101.
Full textReports on the topic "Telomere protection"
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Cervantes, Rachel. The Role of the Telomere End Protection Complex in Telomere Main. Fort Belvoir, VA: Defense Technical Information Center, June 2003. http://dx.doi.org/10.21236/ada437895.
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Cervantes, Rachel B. The Role of the Telomere End Protection Complex in Telomere Maintenance. Fort Belvoir, VA: Defense Technical Information Center, June 2003. http://dx.doi.org/10.21236/ada417832.
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