Tesis sobre el tema "Telomeres"
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Shakirov, Yevgeniy Vitalievich. "Telomeres and telomere binding proteins in Arabidopsis thaliana". Diss., Texas A&M University, 2004. http://hdl.handle.net/1969.1/422.
Texto completoMaddison, Rachelle Louise. "Telomeres in the absence of telomerase in Saccharomyces cerevisiae". Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/30365.
Texto completoMoye, Aaron Lavel. "Understanding the relationship between telomeres, telomerase, and DNA G-quadruplexes". Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17713.
Texto completoLee, Joyce Hiu Yan. "Detection of Alternative Lengthening of Telomeres in Telomerase-Positive Cancers". Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17252.
Texto completoLee, Michael. "Next Generation Sequencing Strategies to Investigate Telomeres in Cancer". Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21844.
Texto completoSherwood, Rebecca. "The Effect of the Copy Number of the Telomerase RNA Gene on the Elongation of Telomeres in Saccharomyces cerevisiae". Thesis, Boston College, 2008. http://hdl.handle.net/2345/532.
Texto completoTelomeres are repeated sequences at the ends of chromosomes, which promote chromosome stability by preventing the loss of necessary nucleotides from the DNA with successive rounds of replication. Telomeres are elongated by the enzyme telomerase, which has both a protein component and an RNA component. In the yeast Saccharomyces cerevisiae, the TLC1 gene encodes the RNA component of the enzyme. Telomerase RNA interacts with several proteins to perform its function, including the Ku protein, which binds to the end of the DNA and helps to recruit telomerase to the chromosome thereby facilitating the lengthening of chromosome ends. Ku interacts with telomerase RNA at the site of a 48-nucleotide stem-loop on the RNA's structure. Previous experiments have shown that yeast strains engineered to carry two copies of the TLCI gene exhibit higher levels of telomerase RNA than those that have only one copy of the gene. Also, a yeast strain carrying a copy of the mutant tlc1Δ48 gene, which contains a deletion of the 48-nucleotide stem-loop, contains lower levels of telomerase RNA than a strain with the wild type TLC1 gene. This series of experiments is investigating whether the copy number of the telomerase RNA gene affects the elongation of telomeres in S. cerevisiae. In order to determine this effect, the de novo telomere addition of four strains was examined, as were the native telomere lengths of these strains. The assay indicated that the efficiency of telomere elongation was unchanged by increasing the copy number of the wild type gene but was increased upon increasing the copy number of the mutant gene. Analysis of the native telomere lengths showed that increasing the copy number of either the wild type or the mutant gene allowed the cells to maintain their telomeres at a longer length
Thesis (BS) — Boston College, 2008
Submitted to: Boston College. College of Arts and Sciences
Discipline: Biology
Discipline: College Honors Program
Schuller, Christine Children's Cancer Institute Australia for Medical Research Faculty of Medicine UNSW. "Telomeres and telomerase in haematopoietic progenitors and bone marrow endothelial cells". Publisher:University of New South Wales. Children's Cancer Institute Australia for Medical Research, 2008. http://handle.unsw.edu.au/1959.4/41098.
Texto completoHenson, Jeremy D. "The role of Alternative Lengthening of Telomeres in human cancer". Thesis, The University of Sydney, 2006. http://hdl.handle.net/2123/1533.
Texto completoHenson, Jeremy D. "The role of Alternative Lengthening of Telomeres in human cancer". University of Sydney, 2006. http://hdl.handle.net/2123/1533.
Texto completoActivation of a telomere maintenance mechanism is a vital step in the development of most cancers and provides a target for the selective killing of cancer cells. Cancers can use either telomerase or Alternative Lengthening of Telomeres (ALT) to maintain their telomeres and inhibition of either telomere maintenance mechanism can cause cancer cells to undergo senescence or apoptosis. Although telomerase inhibitors are undergoing clinical trials, on commencing this study very little was known about the role of ALT in cancer, what proteins were involved in its mechanism and regulation and how it could be targeted clinically. The primary aim of this thesis was to develop an assay for ALT suitable for examining archived tumour specimens and to begin using it to examine the prevalence and clinical significance of ALT in cancer. This assay and gene expression analysis was also used to identify genes that are involved in or associated with the activation of the ALT mechanism, to contribute towards the overall goal of an ALT cancer therapy. The ALT mechanism involves recombination mediated replication and ALT cells have a marked increase in a range of recombinational events specifically at their telomeres. Presumably, as a consequence of this the telomere lengths of ALT cells are very heterogeneous and on average long. This can be detected by terminal restriction fragment (TRF) Southern analysis, which has been used previously as the definitive test for ALT activity. However, TRF analysis requires intact genomic DNA and is unsuitable for tumour specimens which are commonly archived by paraffin embedding. Another hallmark of ALT is ALT-associated PML bodies (APBs) which are the subset of PML bodies that contain telomeric DNA. Work done in this study to consolidate APBs as a hallmark of ALT, combined with published data, showed 29/31 ALT[+], 3/31 telomerase[+] and 0/10 mortal cell lines/strains are APB[+]. The three APB[+]/telomerase[+] cell lines identified here had an order of magnitude lower frequency of APB[+] nuclei than the ALT[+] cell lines. APBs may be functionally linked to the ALT mechanism and contain the recombination proteins that are thought to be involved in the ALT mechanism. This study, in collaboration with Dr W-Q Jiang, strengthened this functional link by demonstrating that loss of ALT activity (as determined by TRF analysis) coincided with the disruption of APBs. The detection of APBs was developed into a robust assay for ALT in archived tumour specimens using a technique of combined immunofluorescence and telomere fluorescence in situ hybridisation. It was demonstrated that the APB assay concurred exactly with the standard assay for ALT (TRF analysis) in 60 tumours for which TRF analysis gave unequivocal results. The APB assay may be a more appropriate technique in the case of tumour specimen heterogeneity, which may explain why the APB assay was able to give definitive results when TRF analysis was equivocal. We demonstrated that intratumoral heterogeneity for ALT does exist and this could explain why about 3% of tumours in this study were APB[+] but with more than a ten-fold reduction in the frequency of APB[+] nuclei. This study also made the novel discovery of single stranded C-rich telomeric DNA inside APBs which potentially could be used to make the APB assay more suitable for routine pathology laboratory use. The APB assay was used to show that ALT is a significant concern for oncology. ALT was utilised in approximately one quarter of glioblastoma multiforme (GBM), one third of soft tissue sarcomas (STS) including three quarters of malignant fibrous histiocytomas (MFH), half of osteosarcomas and one tenth of non-small cell lung carcinomas (NSCLC). Furthermore, the patients with these ALT[+] tumours had poor survival; median survivals were 2 years for ALT[+] GBM, 4 years for ALT[+] STS including 3.5 years for ALT[+] MFH and 5 years for ALT[+] osteosarcoma. ALT[+] STS and osteosarcomas were also just as aggressive as their ALT[-] counterparts in terms of grade and patient outcome. ALT status was not found to be associated with response to chemotherapy in osteosarcomas or survival in STS. ALT was however, less prevalent in metastatic STS. The APB assay was a prognostic indicator for GBM and was correlated with three fold increased median survival in GBM (although this survival was still poor). ALT was more common in lower grade astrocytomas (88% ALT[+]) than GBM (24% ALT[+]) and ALT[+] GBM had an identical median age at diagnosis to that reported for secondary GBM. It is discussed that these data indicate that ALT was indirectly associated with secondary GBM and is possibly an early event in its progression from lower grade astrocytoma. This is relevant because secondary GBM have distinct genetic alterations that may facilitate activation of the ALT mechanism. Putative repressors of ALT could explain why this study found that ALT varied among the different STS subtypes. ALT was common in MFH (77%), leiomyosarcoma (62%) and liposarcoma (33%) but rare in rhabdomyosarcoma (6%) and synovial sarcoma (9%). ALT was not found in colorectal carcinoma (0/31) or thyroid papillary carcinoma (0/17) which have a high prevalence of telomerase activity and a reduced need for a telomere maintenance mechanism (low cell turnover), respectively. A yeast model of ALT predicts that one of the five human RecQ helicases may be required for ALT. Using the APB assay to test for the presence of ALT in tumours from patients with known mutations in either WRN or RECQL4 it was demonstrated that neither of these RecQ helicases is essential for ALT. Although p53 and mismatch repair (MMR) proteins have been suggested to be possible repressors of ALT, there was no apparent increase in the frequency of ALT in tumours from patients with a germline mutation in p53 codon 273 or in colorectal carcinomas that had microsatellite instability and thus MMR deficiency. Also contrary to being a repressor of ALT but consistent with its ability to interact with a protein involved in the ALT mechanism, the MMR protein MLH1, was demonstrated to be present in the APBs of an ALT[+] cell line. To further test for genes that may be involved in the ALT mechanism or associated with its activation, RNA microarray was used to compare the gene expression of 12 ALT[+] with 12 matched telomerase[+] cell lines; 240 genes were identified that were significantly differentially expressed (p<0.005) between the ALT[+] and telomerase[+] cell lines. Only DRG2 and SFNX4 were significantly differentially expressed after adjusting for the estimated false positive rate. Overall, DRG2, MGMT and SATB1 were identified as most likely to be relevant to the ALT[+] tumours and Western analysis indicated that DRG2 and MGMT levels were down-regulated after activation of ALT and up-regulated after activation of telomerase, whereas SATB1 protein levels appeared to be up-regulated after immortalisation but to a higher degree with activation of ALT compared to telomerase. Since lack of MGMT is known to be a determinant of temozolomide sensitivity in GBM, the possibility that ALT and the APB assay could be used to predict temozolomide sensitivity is discussed. The microarray data was consistent with MGMT expression being suppressed by EGF (p < 0.05), indicating that caution may be needed with combining EGFR inhibitors with temozolomide in ALT cancers. One ALT[+] cell line which did not express MGMT had TTAA sequence in its telomeres. This could possibly have resulted from mutations due to lack of MGMT expression and a possible role for MGMT in the ALT mechanism is discussed. Further analysis of the microarray data identified two groups of co-regulated genes (p < 5x10-5): CEBPA, TACC2, SFXN4, HNRPK and MGMT, and SIGIRR, LEF1, NSBP1 and SATB1. Two thirds of differentially expressed genes were down-regulated in ALT. Chromosomes 10 and 15 had a bias towards genes with lower expression in ALT while chromosomes 1, 4, 14 and X had a bias towards genes with higher expression levels in ALT. This work has developed a robust assay for ALT in tumour specimens which was then used to show the significance of ALT in sarcomas, astrocytomas and NSCLC. It has also identified genes that could possibly be molecular targets for the treatment of ALT[+] cancers.
Dagg, Rebecca Ann. "The extensive proliferation of human cancer cells with ever-shorter telomeres". Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17341.
Texto completoKartawinata, Maria Melissa. "Regulation of the recruitment of telomerase to telomeres in human cancer cells". Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17128.
Texto completoSchulze, Franziska. "Die Telomerlänge als Prognosefaktor in MYCN nicht-amplifizierten Neuroblastomen". Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-200943.
Texto completoHidalgo, Bravo Alberto. "Human telomeres and recombination". Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/27809.
Texto completoBruneau, Julie. "Hemopathies spontanément regressives : exemples de la matocytose et de la papulose lymphomatoide". Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-00980884.
Texto completoAlotaibi, Mohammad Kdaimes H. "Genes required to maintain telomeres in the absence of telomerase in Saccharomyces cerevisiae". Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12589/.
Texto completoElizalde, Violeta Serra. "Modulation of telomere length by oxidative stress in vitro and in vivo". Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366579.
Texto completoBaldassarri, Enrico Junior. "Effetto dei controioni sul processo di autoassemblaggio di molecole di guanosina: uno studio strutturale". Doctoral thesis, Università Politecnica delle Marche, 2014. http://hdl.handle.net/11566/242740.
Texto completoMy PhD project described in this thesis concerns the study of supramolecular aggregation of guanosine molecules. The project starts from the more ambitious idea of studying the behavior, stability and supramolecular aggregation of single strands DNA that lead to the formation of unusual structures called G-Quadruplexes. G-Quadruplexes are noncanonical forms of DNA and the interest for these structures origins from an article of Gellert et.al. in 1962, when these helical structures formed by guanylic acid were identified for the first time. G-Quadruplexes were then correlated with the Telomeres rich in guanosine at the end of chromosomes. Telomeres are tightly bound to Telomerase, the enzyme that replicates the tandem repeated sequences (TRs) in chromosome, and is expressed at very low levels in somatic cells of di↵erent organisms but is present in high amounts in cancer cells (allowing them to replicate indefinitely and bringing to an immortalization condition that due the carcinogenesis process). Therefore, the interest in G-Quadruplexes is linked with the several hypotheses on possible anti-cancer activities. In this thesis I present an extended study on the self-assembly process and behavior of Guanosine 5’-monophosphate under di↵erent physical conditions. I performed several experiments at Di.S.V.A. Laboratories and at di↵erent European Large Scale Facilities (LSF) using various techniques such as Small Angle Scattering (SAS), X-ray Di↵raction (XRD), obtaining information on the structural parameters, stability, counter-ion e↵ects and interactions between telomeres using a simple model based on G-quadruplex formation by Guanosine molecules.
Brouilette, Scott Wayne. "Telomeres and coronary heart disease". Thesis, University of Leicester, 2004. http://hdl.handle.net/2381/29899.
Texto completoArora, Amit, Mark A. Beilstein y 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.
Texto completoXin, Xing. "Effects of polychlorinated biphenyls (PCBs) on telomere maintenance in hematopoietic stem cells and progenitor cells". Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/2026.
Texto completoWestin, Erik R. "Characterization of telomeric defects and signal transduction pathways in Dyskeratosis Congenita cells". Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/1276.
Texto completoGarg, Aggarwal Mansi. "Characterization of the role of SUMO in telomere length homeostasis and overhang processing at yeast telomeres". Thesis, University of Sussex, 2017. http://sro.sussex.ac.uk/id/eprint/68661/.
Texto completoLu, Robert. "The FANCM-BLM-TOP3A-RMI1/2 complex suppresses telomere replication stress and Alternative Lengthening of Telomeres". Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23414.
Texto completoBrault, Marie Eve. "Telomeres and telomerase: role in human cancer, the premature aging syndrome dyskeratosis congenita and frailty". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=117043.
Texto completoLes télomeres et la télomérase se rencontrent à la jonction de processus cellulaires qui régulent le vieillissement, le cancer et certaines maladies. Plusieurs maladies de vieillissement précoce ou maladies associées au vieillissement sont caractérisées par la présence de courts télomères, qui compromettent la viabilité et la fonction de la cellule, alors que les cellules cancéreuses sont capables de réactiver la télomérase ou un mécanisme alternatif d'élongation des télomères (ALT) pour maintenir leurs télomères et devenir immortelles. Les télomères et la télomérase représentent des cibles très attrayantes pour le développement de thérapies anti-cancer. Il existe toutefois certaines possibilités que ces thérapies conduisent au développement d'une résistance chez la cellule. Ces mécanismes de résistance peuvent inclure la réactivation de l'enzyme télomérase ou réactivation du mécanisme ALT dans les cellules télomérase-positives. Nous démontrons que la recombination des télomères peut être induite par une dysfonction des télomères, une stratégie anti-cancer présentement en développement, et cela malgré la présence de télomérase dans la cellule. Nos résultats mettent l'emphase sur un mécanisme potentiel de résistance, et pourraient aussi permettre de mieux comprendre comment le mécanisme ALT et la télomérase sont régulés dans la cellule. Un maintien déficient des télomères est associé aux maladies de vieillissement précoce ou accéléré. Des mutations dans la majorité des composants de l'enzyme télomérase ont été retrouvées chez des patients atteints de Dyskératose congénitale (DC), révélant l'importance d'une télomérase fonctionnelle pour la fonction des cellules souches et le potentiel réplicatif des cellules. Nous avons identifié que la protéine dyskérine est sumoylée sur des lysines hautement conservées et que la présence de protéines mutantes dans la cellule imite les phénotypes associés à la maladie DC. Nos résultats démontrent qu'un défaut de modifications post-traductionnelles peut conduire à la maladie DC mais surtout, identifient de nouvelles possibilités pour le traitement des patients atteints de DC. Finalement, nous avons investigué la relation complexe qui existe entre le maintien des télomères, la fragilité et les maladies cardiovasculaires. Nous avons examiné le potentiel de mesurer les télomères pour prédire la mortalité et morbidité chez des patients âgés sur le point de subir une chirurgie cardiaque. Nos résultats préliminaires indiquent que la taille des télomères ne peut servir à prédire l'issue d'une chirurgie cardiaque. Nos résultats suggèrent que l'utilisation de la taille des télomères comme marqueur dans un contexte épidémiologique ou clinique doit être étudiée et interprétée avec précaution.
DUCRAY, CAROLINE. "Dynamique de la taille des telomeres, activite telomerase et instabilite chromosomique dans des cellules humaines". Paris 6, 1999. http://www.theses.fr/1999PA066166.
Texto completoAGUADO, PEREZ JULIO. "THE ROLE OF TELOMERIC RNA AT DYSFUNCTIONAL TELOMERES AND ITS IMPACT ON SENESCENCE AND AGING". Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/556299.
Texto completoMarzec, Paulina. "NR2C/F telomeric association drives telomere-genome rearrangements in ALT cells". Thesis, Montpellier 2, 2013. http://www.theses.fr/2013MON20179.
Texto completoCellular immortality is always accompanied by the activation of telomere maintenance mechanism. In most human cancers this role is fulfilled by the telomerase enzyme. However in 15% of tumors, telomerase is not activated and telomeres are maintained by an Alternative Lengthening of Telomeres (ALT) pathway that involves telomere-telomere recombination. Interestingly ALT is more prevalent in tumors originating from mesenchymal tissues (sarcomas), where it is present in 40-60% of cases, than in epithelial tumors. Understanding ALT maintenance is critical since inhibiting telomerase in tumors leads to the activation of ALT. The ALT pathway is operationally defined by typical telomere hallmarks. In ALT cells, aberrant DNA transactions are not restricted to telomeres since genomes are often highly rearranged. Whether these abnormal genomic features are linked to atypical telomere maintenance is not known, but genome instability is certainly contributing to transformation. We have previously shown that orphan receptors of the NR2C/F families were enriched at telomeres in ALT cell lines. We proposed that these factors could be recruited to telomeres through direct binding to the GGGTCA variant repeat, a high affinity binding site for these proteins. My project is aimed at understanding (i) their mechanism of binding and (ii) their role, if any, in the ALT process.We show that in human primary sarcomas, ALT telomeres are often bound by orphan nuclear receptors of the NR2C/F subfamilies, particularly in more advanced-stage tumors. This suggests an active role for these factors in ALT tumor progression. Using ChIP-sequencing, we show that NR2C/F proteins bind to an amplified direct repeat (DR0) at telomeres, and not significantly to any other GGGTCA motif combination. We also analyzed the genome wide distribution of NR2C2/F2 and TRF2, a telomere binding protein, in ALT(-) and in ALT(+) cells. While there are only few genomic sites bound by TRF2 in ALT(-) cells, we were surprised to identify several hundred regions bound by TRF2 in ALT(+) cells. More surprisingly, the great majority of these ALT specific TRF2 regions overlap with endogenous NR2C2/F2 sites. Since these sites usually do not contain telomere repeats, TRF2 is likely indirectly recruited. Consistent with this interpretation, we show that NR2C/F factors drive locus proximity. Moreover, a subset of these unique genomic regions harbor heterogeneous ALT telomere sequence additions, not only suggesting a telomere recruitment role for NR2C/F proteins but also a recombination targeting function in the genome. Consistently, we find these telomere/genome rearrangements are located close to endogenous GGGTCA motifs. Next, we wanted to evaluate a role of these rearrangements in formation of complex karyotype which characterize approximately 50% of sarcomas. We found by spectral karyotyping that interstitial telomeric sites are frequently located at translocation/ rearrangements sites between two or more chromosomes, which we could also observe in our ChIPseq data. Furthermore, we demonstrate that addition of interstitial telomeric sites to the genome is enhanced by DNA damage and specific for ALT genome. Therefore we conclude that NR2C/F factors target telomere proximity to defined NR2C/F regions which enables telomere-genome rearrangements under DNA damage condition. This contributes not only to efficient telomere recombination, but also it drives further genomic instability at selected NR2C/F sites.We believe we identified a new mechanism of telomere dysfunction potentially driving targeted genome instability and mediated by NR2C/F proteins in ALT cells which probably underlie complexity of sarcomas genome. Understanding the ALT mechanism allows designing NR2C/F-targeted therapies in treatment of ALT tumors and therapies for patients treated with anti-telomerase drugs to prevent ALT appearance
Sousa, Rute Inês Silva e. 1983. "The Epigenetic regulation of Drosophila telomeres". Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/96908.
Texto completoEl manteniment dels telòmers de Drosophila depèn de la transposició especialitzada de tres retrotransposons, HeT-A, TART i TAHRE (HTT). El control de l’activació i la repressió d’aquests elements és crucial a l’hora de mantenir la llargada telomèrica sense comprometre l’estabilitat genòmica. En aquesta tesi jo he pogut identificar el paper de diferents proteïnes cromosòmiques involucrades en crear un estat de la cromatina adient per mantenir la longitud i l’estabilitat telomèrica. JIL-1 juntament amb HP1a i Z4 ajuden a crear el llindar entre la frontera dels domini telomèric i subtelomèric. L’actuació conjunta d’aquestes proteïnes aconsegueix un estat d’equilibri activació/repressió dels retrotransposons telomèrics. A més a més, he contribuït a la descoberta de la implicació de la proteïna HeT-A Gag en el reclutament de diferents complexes proteics als telomèrs de Drosophila per poder garantir l’estabilitat telomèrica. També he pogut demostrar que altres membres dels complexes on participa Z4, com ara: DREF, TRF2 i KEN, estan també implicats en el silenciament dels retrotransposons telomèrics segurament per mitjà de la remodelació de la cromatina. Finalment he pogut demostrar que el domini subtelomèric del telòmer 4R, té una estructura cromatínica diferent a la resta dels dominis subtelomèrics dels altres cromosomes i he pogut demostrar que les proteïnes SETDB1, HP1a i POF estan implicades en la regulació de l’HTT del cromosoma 4. Els resultats d’aquesta tesi ajuden de manera substancial a comprendre com els retrotransposons telomèrics estan orquestrats per tal de poder fer una funció anàloga als telòmers de telomerasa en altres eucariotes.
Wang, Zhuo. "Extracellular Inflammatory Signaling from Dysfunctional Telomeres". Thesis, University of the Sciences in Philadelphia, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10692989.
Texto completoTelomere dysfunction describes the catastrophic damage at telomeres, which often leads to genomic instability at the cellular level. There is rising evidence showing that telomere dysfunction also influences the extracellular environment with the inflammatory response. However, little is known about the molecular mechanism of this dysfunctional telomere-associated inflammation. In this dissertation, we identified extracellular forms of Telomeric repeat-containing RNA (TERRA), and demonstrated it might play a role in mediating the crosstalk of telomere dysfunction and inflammation. We found this cell-free TERRA (cfTERRA) is present in mouse tumor and embryonic brain tissue, as well as in human tissue culture cell lines using RNA in situ hybridization. RNA-seq analyses revealed TERRA to be among the most highly represented transcripts in extracellular fractions derived from both normal and cancer patient blood plasma. By characterizing extracellular fractions of the human lymphoblastoid cell line (LCL) culture media, cfTERRA is shown as a shorter form (∼200 nt) of cellular TERRA and co-purifies with CD63- and CD81-positive exosome vesicles that could be visualized by cryo-electron microscopy. Mass spectrometry and extracellular chromatin immunoprecipitation (ChIP) assays revealed that regular cfTERRA was physically interacting with histones and telomeric DNA. Incubation of cfTERRA-containing exosomes with peripheral blood mononuclear cells (PBMCs) stimulated transcription of several inflammatory cytokine genes, including TNFα, IL6, and C-X-C chemokine 10 (CXCL10). Exosomes engineered with elevated TERRA or liposomes with synthetic TERRA further stimulated inflammatory cytokines, suggesting that exosome-associated TERRA augments innate immune signaling. The levels of cfTERRA and DNA damage marker γH2AX were increasingly incorporated into the exosomes during telomere dysfunction. These dysfunctional telomere-derived exosomes activated a more robust transcription of inflammatory cytokines in PBMCs. These findings imply a previously unknown extrinsic function of TERRA and a potentially molecular mechanism of communication between telomeres and innate immune signaling in tissue and tumor microenvironments.
Cross, Sally H. "Isolation and characterisation of human telomeres". Thesis, University of Edinburgh, 1989. http://hdl.handle.net/1842/13500.
Texto completoORRU', FEDERICA. "Role of Telomeres in Onco-Hematology". Doctoral thesis, Università degli Studi di Cagliari, 2017. http://hdl.handle.net/11584/249705.
Texto completoElchinova, Elena Georgieva. "Analysis of the levels of monocyte subsets in patients with heart failure". Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667760.
Texto completoHeart failure is a disorder characterized by different clinical signs and symptoms due to a structural or functional anomaly of the heart. It is the most predominant heart disease in developed countries, both from epidemiological point of view and clinical implications. Indeed, it is a growing medical problem related to major hospitalization needs and high mortality, with significant economic and population burden worldwide. Established prognostic factors, such as age, sex, aetiology, comorbidities, New York Heart Association functional class, left ventricle ejection fraction, and routine laboratory markers might fail to completely and individually predict disease progression and mortality. A good risk stratification strategy is crucial as risk might be refined using several biological biomarkers of different pathophysiological processes that the former mortality risk factors do not necessarily directly reflect. That is why efficient and reliable new prognostic predictor markers are of upmost importance and relevance for the future management of the disease. Monocytes are a heterogeneous population of effector cells with key roles in the maintenance and restoration of tissue integrity. Three distinct human monocyte subsets can be identified by flow cytometry: classical (CD14++/CD16–), intermediate (CD14++/CD16+) and non-classical (CD14–/CD16+). Little is known about the importance, relationship between the levels of the circulating monocytes and their distribution in heart failure, even less if these parameters could be used as a predictor markers for the progression of the disease. The main objective of the current project was to assess the relationship between the levels and distribution of the different circulating monocyte subsets and the length of its telomeres in outpatients with heart failure with adverse events, namely mortality and heart failure hospitalizations. Three cohorts of respectively 28, 400 and 101 ambulatory patients, consecutively treated at a multidisciplinary heart failure Clinic from December 2013 to May 2015 were included in the studies described in this doctoral thesis, independently of the data of their entry into the heart failure Clinic program. All study procedures were performed in accordance with all ethical standards and all participants provided written informed consent. Peripheral blood samples of all patients were extracted for subsequent analysis by flow cytometry. The samples were incubated directly by means of monoclonal antibodies with fluorocromes against monocyte specific surface antigens, type CD86 (or HLA -DR), CD14 and CD 16 and in parallel (in 100 samples) genetic markers (telomeres) were subsequently analyzed by flow cytometer (BD LSRFortessa) in the Department of Citolatry of the IGTP. The percentage distribution of each monocyte subset was analyzed and their absolute cell count (U/mL) was also determined quantitatively. We were able to establish an innovating, accurate and much less expensive method than established ones for simultaneously measuring the different monocyte subsets and the its relative telomere length. In our study, the intermediate subset was independently associated with all-cause death and the composite end-point of all-cause death or heart failure hospitalization, in multivariable analyses. The quantitative determination of the absolute cell count of each monocyte subset expressed by U/mL was superior from the prognostic point of view than the percentage of these monocyte subsets in outpatients with Heart failure. We observed about 22% reduction in telomere length over 1 year in the monocytes of our patients, being the baseline telomere length and change in telomere length not significantly associated with outcomes. Therefore, the change in telomere length is not likely to be a useful biomarker of heart failure progression. The monocytes and monocyte subsets could be used not only as a predictor factor but also might be taken into consideration as part of an immuno-modulation therapy in the future for the heart failure patients.
Roberts, Amity Rondalyne. "Studies on the Control of Telomere Length and the Effects of Shorter Telomeres on Gene Expression in the Mouse". Thesis, Griffith University, 2013. http://hdl.handle.net/10072/366153.
Texto completoThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
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Sridhar, Akila. "The role of Tel1 at short telomeres". Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=203802.
Texto completoMarkiewicz-Potoczny, Marta. "Responding to different types of damaged telomeres". Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3745.
Texto completoWalsh, Monica Eve. "The role of SUV methyltransferases at telomeres". Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16620.
Texto completoÖstlund-Lagerström, Lina. "Effect of long-term ultra-endurance training on telomere length and telomere regulatory protein expressions in vastus lateralis of healthy humans". Thesis, Örebro universitet, Hälsoakademin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-15859.
Texto completoViviescas, Maldonado Maria Alejandra. "Análise Estrutural do Componente Telomerase Transcriptase Reversa de Leihmania major". Botucatu, 2018. http://hdl.handle.net/11449/154850.
Texto completoResumo: Os parasitos do gênero Leishmania são protozoários primitivos entre os quais estão os causadores de um espectro de doenças conhecidas como leishmaniose, as quais afetam milhões de pessoas no mundo inteiro, sendo o Brasil um dos países que apresenta maior número de casos por ano. Os tratamentos e vacinas disponíveis para a leishmaniose apresentam problemas como toxicidade, alto custo e baixa eficiência, tornando importante a busca por novos alvos terapêuticos. Dada sua importância para a estabilidade genômica e proliferação celular, os telômeros têm sido considerados como alvos terapêuticos potenciais no tratamento da leishmaniose. Os telômeros são as extremidades físicas dos cromossomos lineares compostos por complexos ribonucleoproteicos que envolvem a interação entre proteínas, DNA e RNA. A maioria dos eucariotos mantêm o tamanho dos telômeros pela ação do complexo telomerase, que é minimamente composto por uma proteína (TERT, Telomerase Reverse Transcriptase) e um RNA longo não codificador (TER, Telomerase RNA). Os dois componentes do complexo telomerase em Leishmania sp. foram identificados, porém não há informação disponível sobre suas estruturas. O objetivo principal deste estudo foi a caracterização estrutural do componente TERT de Leishmania major. Utilizando alinhamentos múltiplos de sequências, foi possível verificar que os quatro domínios estruturais das telomerases canônicas estão presentes no componente TERT em Leishmania sp. Três destes domínios foram estudados ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Parasites of the Leishmania genus are primitive protozoa and among them are the causative agents of a spectrum of diseases called leishmaniasis, which affect millions of people in tropical countries worldwide, being Brazil one of the countries with higher number of cases each year. The drugs or vaccines available to treat leishmaniasis present problems such as toxicity, excessive cost a low efficiency, so it is important to search for new potential therapeutic targets. Due to their importance in genome stability and cell proliferation, telomeres have been considered a potential therapeutic target against leishmaniasis. Telomeres are the ends of linear chromosomes composed by ribonucleoproteic complexes that involve the interaction between proteins, DNA and RNA. Most eukaryotes maintain their telomere length by the action of the telomerase complex, minimally composed by a protein (TERT, Telomerase Reverse Transcriptase) and a long non-coding RNA (TER, Telomerase RNA). Both components of the Leishmania sp. telomerase complex have already been identified, however, little is known about their structure. This study had the aim to characterize the structure of the Leishmania major TERT component. Using multiple sequence alignments, we were able to verify that the four structural domains of canonical telomerases are present in Leishmania sp. Using different bioinformatic approaches three of these domains were independently studied. The TEN (Telomerase essential N-terminal) domain is... (Complete abstract click electronic access below)
Doutor
Giardini, Miriam Aparecida. "Caracterização bioquimica e molecular do componente transcriptase reversa da telomerase de Leishmania spp". [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317096.
Texto completoTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Telômeros são complexos DNA-proteínas que protegem os cromossomos eucarióticos da degradação, garantindo estabilidade genômica. As seqüências teloméricas são ricas em G e apresentam uma protrusão 3¿ simples-fita que se estende em direção ao terminal cromossômico. Em Leishmania, os telômeros são compostos pela seqüência repetida 5¿-TTAGGG-3¿ e são replicados pela telomerase, a principal responsável pela manutenção dos terminais cromossômicos em eucariotos. Além de replicar os telômeros, o complexo holoenzimático da telomerase, composto pela transcriptase reversa da telomerase (TERT), pelo RNA da telomerase (TER) e por proteínas associadas, também atua como parte de um complexo de ordem maior que protege os terminais teloméricos. O entendimento do mecanismo de regulação da manutenção telomérica será de grande valor científico e poderá levar ao descobrimento de algum alvo potencial para o desenvolvimento de novas drogas anti-leishmania. Com esse objetivo, identificamos, clonamos e caracterizamos o gene que codifica o componente TERT em Leishmania spp.. O alinhamento múltiplo das seqüências através do programa ClustalW demonstrou que as telomerases de Leishmania apresentam muito mais homologia entre si do que com as proteínas de outros kinetoplastídeos e eucariotos. Experimentos de caracterização indicaram que a seqüência putativa do gene da telomerase de Leishmania localiza-se provavelmente em cópia única nos maiores cromossomos. Um único transcrito de RNA mensageiro foi encontrado nos promastigotas. Análises filogenéticas sugeriram que a telomerase de Leishmania pode representar uma ligação entre os mais antigos e os mais novos ramos das telomerases. Além disso, proteínas recombinantes foram expressas em sistema bacteriano, tornando possível a produção de anticorpos policlonais em coelhos. Experimentos de ¿Western blotting¿ e imunoprecipitação de cromatina indicaram que o anticorpo foi capaz de reconhecer a proteína nativa e que a telomerase de L. amazonensis interage in vivo com a seqüência telomérica rica em G. A atividade de telomerase de L. amazonensis foi purificada utilizando-se uma combinação de colunas cromatográficas. Testou-se a atividade enzimática em cada passo da purificação utilizando-se o ensaio ¿Two-tube TRAP¿. Os resultados mostraram que a atividade enzimática é encontrada nas frações purificadas pelas cromatografias de troca iônica, de afinidade por Heparina e de gel filtração. A atividade foi altamente enriquecida após a purificação por afinidade utilizando um oligonucleotídeo de DNA telomérico rico em G. Quando foi utilizado um oligorribonucleotídeo 2¿O-metil complementar à putativa seqüência molde do TER de Leishmania como ligante na cromatografia de afinidade, pouca ou nenhuma atividade enzimática foi eluída da resina, sugerindo que a interação entre a telomerase de L. amazonensis e este oligorribonucleotídeo é tão forte que não permite sua dissociação nas condições de eluição gentis necessárias para manter a atividade enzimática. Formas procíclicas de Trypanosoma brucei foram utilizadas para a construção do sistema ¿PTP-tagging¿, no intuito de futuramente purificar o complexo holoenzimático da telomerase. Em paralelo, ensaios de ¿primer extension¿ foram padronizados e identificou-se uma seqüência candidata ao gene do RNA da telomerase de T. brucei. Também foi identificada e clonada em L. amazonensis, uma seqüência homóloga à PinX1 humana, descrita como uma proteína que interage diretamente com a TERT humana e considerada um inibidor natural da atividade de telomerase
Abstract: Telomeres are protein-DNA complexes that protect linear chromosomes from degradation, providing genomic stability. The telomeric sequences are G-rich and contain a 3¿ single-stranded region that protrudes toward the chromosome end. In Leishmania, the telomeric DNA is composed by the conserved 5¿-TTAGGG-3¿ repeated sequence and it is replicated by telomerase. Telomerase is responsible for maintaining chromosome ends in most eucaryotes by adding new telomeric sequences to the G-rich strand. Besides replicating telomeres, the telomerase holoenzyme complex, composed by the reverse transcriptase component (TERT), the telomerase RNA (TER) and associated proteins, also works as part of the higher order complex that protects telomeric ends. Understanding the regulation of the telomeric maintainance mechanism may allow the discovery of potential targets to the development of new antileishmania drugs. Therefore, we identified, cloned and characterized the TERT gene in Leishmania spp.. A ClustalW multiple-sequence alignment demonstrated that the Leishmania telomerases show greater homology with each other than with the proteins of other kinetoplastids and eukaryotes. Characterization experiments indicated that the putative Leishmania TERT gene was probably located in single copy at the largest chromosomes. A single messenger RNA transcript was found in promastigotes. Phylogenetic analysis suggested that Leishmania telomerase might represent a liaison between the oldest and the newest branches of telomerases. Besides that, recombinant proteins were expressed in bacterial system, allowing production of anti-LaTERT polyclonal serum in rabbits. Western blotting and chromatin immunoprecipitation assays indicated that the anti-LaTERT serum was able to recognize a native protein in nuclear and total extracts of the parasite and that L. amazonensis telomerase interacts in vivo with the G-richtelomeric sequence. We have also purified the L. amazonensis telomerase activity in order to better understand its biochemical features. Protein extracts of L. amazonensis containing telomerase activity were purified using combined chromatographic columns. Enzyme activity was tested in each purification step using the ¿Two-tube TRAP¿ assay. The results showed that enzyme activity is found in fractions purified by ion exchange (DEAE), Heparin affinity and gel filtration chromatographic methods. The activity was greatly enriched after affinity purification using a G rich telomeric DNA oligonucleotide as the ligand. When a 2¿O-methyl oligoribonucleotide complementary to the putative L. amazonensis TER template was used as a ligand in the affinity purification, little or no enzyme activity was eluted from resin, suggesting that the interaction between L. amazonensis telomerase and this oligoribonucleotide is too strong that disables its dissociation under the gentle elution conditions necessary to maintain enzyme activity. In order to identify the telomerase holoenzyme components, procyclic forms of Trypanosoma brucei were used to construct the PTP-tagging system. ¿Primer extension¿ reactions were also done in order to isolate and sequence an RNA candidate for the telomerase RNA gene in T. brucei. In addition, we have cloned a L. amazonensis homologue of the human PinX1 protein, previously known as a hTERT-interacting factor and as a potent telomerase inhibitor
Doutorado
Genetica de Microorganismos
Doutor em Genetica e Biologia Molecular
Lee, Hyemin [Verfasser]. "mEst1A (mouse ever shorter telomeres 1A) regulates telomere length and RNA quality control in murine stem cells / Hyemin Lee". Ulm : Universität Ulm. Fakultät für Naturwissenschaften, 2012. http://d-nb.info/1024534235/34.
Texto completoPerrem, Kilian Thomas. "Molecular Studies of an alternative lengthening of telomeres (ALT) mechanism". Thesis, The University of Sydney, 2001. http://hdl.handle.net/2123/793.
Texto completoPerrem, Kilian Thomas. "Molecular Studies of an alternative lengthening of telomeres (ALT) mechanism". University of Sydney. Children's Medical Research Institute, 2001. http://hdl.handle.net/2123/793.
Texto completoIdol, Rachel A. "Telomeres and their associated factors in Arabidopsis thaliana". Texas A&M University, 2005. http://hdl.handle.net/1969.1/4141.
Texto completoColeman, Joanna. "The analysis of variation at human autosomal telomeres". Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/30306.
Texto completoVaziri, Homayoun. "Telomeres, DNA damage signaling molecules and cellular aging". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0020/NQ45836.pdf.
Texto completoTsolou, Avgi. "Cellular responses to uncapped telomeres in eukaryotic cells". Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442349.
Texto completoWhite, Elizabeth W. "Selective Recognition of Quadruplex DNA by Small Molecules". Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/chemistry_diss/10.
Texto completoAbbou, Scarlette. "Exploration préliminaire du rôle de la jonction à trois branches de la sous-unité ARN de la télomérase chez Saccharomyces cerevisiae dans le maintien de la longueur des télomères et dans la viabilité des cellules". Mémoire, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/10647.
Texto completoAbstract : Telomerase is essential for telomere maintenance. It compensates for the End-replication problem by adding DNA sequences to the ends of chromosomes. In humans, telomerase is very active in the early stages of development (embryos, foetus). Later, its activity is repressed, and in most cells its activity becomes undetectable. This leads to telomere shortening, a deprotection of chromosome ends and to an arrest of cellular divisions, a highly regulated process also called cellular senescence. However, in cancer cells of 90% of all subtypes, telomerase is up-regulated. Hence, this enzyme promotes the proliferative capacity of cancer cells and their immortalization. The budding yeast Saccharomyces cerevisiae is our organism of study. In addition to its ease of access, telomerase is constitutively expressed in this yeast, which makes it a useful and inexpensive model of cancer cells. My master’s project aims at studying one of the telomerase components in S. cerevisiae, namely the RNA subunit Tlc1, and more specifically a part of this RNA, forming a Three-Way Junction (TWJ). So far, this structure was considered as non-essential for cell viability. However, this structure is highly conserved among species, and in diverse species it was shown to be crucial for telomerase assembly and activity. My project hence consisted in trying to determine whether or not this structure plays a role in telomerase assembly or activity. The requirements on this structure were explored by creating mutations and by analyzing their effects on cell growth and telomere length. Of all the mutants, a specific nucleotide substitution, Adenine 119 in the TWJ, leads to shortened telomeres, and this shortening is stable during further outgrowth. Furthermore, a telomere shortening of up to 100 base pairs is observed when a part or the complete TWJ structure is deleted. This shortening is quite significant as it represents about one third of the normal length of telomeres. Moreover, expressing these mutants of the TWJ in cells with short telomeres creates a synthetic lethal effect.
VENTURINI, LORENZA. "TELOMERE MAINTENANCE MECHANISMS IN TUMOR OF MESENCHYMAL ORIGIN: EVALUATION OF PROGNOSTIC SIGNIFICANCE AND CHARACTERIZATION OF RELEVANT MOLECULAR PATHWAYS". Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/171334.
Texto completoKvaloey, Kirsti. "The long arm telomeres of the human sex chromosomes". Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358686.
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