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Showing 1 to 6 of 6 (0.073 seconds)Spelling suggestions: "subject:"telomere maintenance"" "subject:"elomere maintenance""
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Characterization of the telomeric repeat binding factor 2 (TRF2) in the UV-induced DNA damage response and telomere maintenanceGlenfield, Kimberly 09 1900 (has links)
TRF2 is an essential telomeric protein involved in preventing the telomere ends
from being recognized as DNA breaks. I have shown that TRF2 does not appear to play
a major role in the UV -induced DNA damage response in IMR90, Cockayne syndrome or
XPC deficient cells. TRF2 binds telomeric DNA via its Myb domain and also contains an
N-terminal basic domain. Expression of TRF2MMM causes telomere fusions, whereas
TRF2^(ΔB) causes rapid deletion of telomeric DNA, as both phenotypes result in senescence.
These phenotypes are dependant upon recombination events. Thus, the basic domain of
TRF2 may be essential to suppress recombination events at telomeres. However, it is not
fully understood what amino acid residues in the basic domain of TRF2 are indispensable
to maintain its function. By creating mutations in the arginine residues in the basic
domain of TRF2, I have shown that the positive charge of the basic domain alone is not
sufficient to maintain its protective function. By expressing these TRF2 mutants in the
presence or absence of the Myb domain in HT1080 and BJ/hTERT cells, I have been able
to recapitulate the TRF2^(ΔB) and TRF2^(ΔBΔM) decreased proliferation and senescence
phenotypes. Furthermore, by analyzing anaphase and metaphase chromosomes and
performing Southern blotting, I have shed light on the molecular mechanisms responsible
for the deleterious phenotypes observed in the TRF2 mutants. Amino acid changes from
arginines to lysines introduced into the basic domain of TRF2 results in a significant
increase in telomere doublets. However, when these TRF2 mutants are expressed in the
absence of the Myb domain, a significant increase in telomere fusions events occur.
Collectively, my results indicate that more than one arginine residue in the basic domain is essential to maintain the protective function of TRF2, as these arginine residues may
act as substrates for protein arginine methyltransferases. / Thesis / Master of Science (MSc)
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Variant requirements for DNA repair proteins in cancer cell lines that use alternative lengthening of telomere mechanisms of elongationMartinez, Alaina R. January 2016 (has links)
No description available.
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Mechanisms of alternative telomere elongation in human cancer cellsGocha, April Renee Sandy 18 December 2012 (has links)
No description available.
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Telomere Maintenance Pathway Activity Analysis Enables Tissue- and Gene-Level InferencesNersisyan, Lilit, Simonyan, Arman, Binder, Hans, Arakelyan, Arsen 24 March 2023 (has links)
Telomere maintenance is one of the mechanisms ensuring indefinite divisions of cancer
and stem cells. Good understanding of telomere maintenance mechanisms (TMM) is
important for studying cancers and designing therapies. However, molecular factors
triggering selective activation of either the telomerase dependent (TEL) or the alternative
lengthening of telomeres (ALT) pathway are poorly understood. In addition, more
accurate and easy-to-use methodologies are required for TMM phenotyping. In this
study, we have performed literature based reconstruction of signaling pathways for the
ALT and TEL TMMs. Gene expression data were used for computational assessment
of TMM pathway activities and compared with experimental assays for TEL and
ALT. Explicit consideration of pathway topology makes bioinformatics analysis more
informative compared to computational methods based on simple summary measures
of gene expression. Application to healthy human tissues showed high ALT and TEL
pathway activities in testis, and identified genes and pathways that may trigger TMM
activation. Our approach offers a novel option for systematic investigation of TMM
activation patterns across cancers and healthy tissues for dissecting pathway-based
molecular markers with diagnostic impact.
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Fyziologická podstata dlouhověkosti králů a královen termitů - souvisí dlouhověkost termitů s aktivací telomerázového mechanismu? / Physiological basis of extended longevity in termite kings and queens - is activation of telomerase mechanism linked with extended longevity of termites?Pangrácová, Marie January 2018 (has links)
- Extended longevity and high fecundity are two phenomena typical for reproductive castes (queens, eventually kings) of eusocial insects. In my thesis, we explore the hypothesis that the longevity of reproductives in the termite Prorhinotermes simplex is linked with the activation of the telomerase enzyme complex. Telomerase is well known for its life-extension functions, due especially to its capacity to prolong the telomeric ends of chromosomes. Therefore, we studied here the gene expression of: (1) the gene TERT coding for the catalytic subunit of the telomerase and (2) the genes of the main endocrine regulatory pathways, known to be responsible for the control of reproduction and longevity in insects. Expression dynamics of these genes were measured in sterile and reproductive castes of P. simplex during their development and sexual maturation. Based on our results obtained from the TERT expression analyses and their comparison with telomerase enzyme activities, we assume that the telomerase action in the long-lived reproductive individuals is regulated at a post-transcription level. Furthermore, we observed in reproductive castes a simultaneous upregulation of some transcription variants of vitellogenin and the genes for insulin signalling pathways. We can, therefore, conclude that in...
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Cis-regulation and genetic control of gene expression in neuroblastomaBurkert, Christian Martin 28 June 2021 (has links)
Genregulation beeinflusst Phänotypen im Kontext von Gesundheit und Krankheit. In Krebszellen regulieren genetische und epigenetische Faktoren die Genexpression in cis. Das Neuroblastom ist eine Krebserkrankung, die häufig im Kindesalter auftritt. Es ist gekennzeichnet durch eine geringe Anzahl exonischer Mutationen und durch häufige Veränderungen der somatischen Kopienzahl, einschließlich Genamplifikationen auf extrachromosomaler zirkulärer DNA. Bisher ist wenig darüber bekannt, wie lokale genetische und epigenetische Faktoren Gene im Neuroblastom regulieren. In dieser Arbeit kombiniere ich die allelspezifische Analyse ganzer Genome (WGS), Transkriptome und zirkulärer DNA von Neuroblastom-Patienten, um genetische und cis-regulatorische Effekte zu charakterisieren. Ich zeige, dass somatische Dosis-Effekte der Kopienzahl andere lokale genetische Effekte dominieren und wichtige Signalwege regulieren. Genamplifikationen zeigen starke Dosis-Effekte und befinden sich häufig auf großen extrachromosomalen zirkulären DNAs. Die vorgestellte Analyse zeigt, dass der Verlust von 11q zu einer Hochregulation von Histonvarianten H3.3 und H2A in Tumoren mit alternativer Verlängerung der Telomere (ALT) führt, und dass erhöhte somatische Kopienzahl die Expression der TERT Gens verstärken können. Weitere Erkenntnisse sind, dass 17p-Ungleichgewichte und die damit verbundene Herunterregulierung neuronaler Gene sowie die Hochregulierung des genomisch geprägten Gens RTL1 durch Kopienzahl-unabhängige allelische Dosis-Effekte mit einer ungünstigen Prognose verbunden sind. Die cis-QTL-Analyse bestätigt eine zuvor beschriebene Regulation des LMO1 Gens durch einen Enhancer-Polymorphismus und charakterisiert das regulatorische Potenzial weiterer GWAS-Risiko-Loci. Die Arbeit unterstreicht die Bedeutung von Dosis-Effekten im Neuroblastom und liefert eine detaillierte Übersicht regulatorischer Varianten, die in dieser Krankheit aktiv sind. / Gene regulation controls phenotypes in health and disease. In cancer, the interplay between germline variation, genetic aberrations and epigenetic factors modulate gene expression in cis. The childhood cancer neuroblastoma originates from progenitor cells of the sympathetic nervous system. It is characterized by a sparsity of recurrent exonic mutations but frequent somatic copy-number alterations, including gene amplifications on extrachromosomal circular DNA. So far, little is known on how local genetic and epigenetic factors regulate genes in neuroblastoma to establish disease phenotypes. I here combine allele-specific analysis of whole genomes, transcriptomes and circular DNA from neuroblastoma patients to characterize genetic and cis-regulatory effects, and prioritize germline regulatory variants by cis-QTLs mapping and chromatin profiles. The results show that somatic copy-number dosage dominates local genetic effects and regulates pathways involved in telomere maintenance, genomic stability and neuronal processes. Gene amplifications show strong dosage effects and are frequently located on large but not small extrachromosomal circular DNAs. My analysis implicates 11q loss in the upregulation of histone variants H3.3 and H2A in tumors with alternative lengthening of telomeres and cooperative effects of somatic rearrangements and somatic copy-number gains in the upregulation of TERT. Both 17p copy-number imbalances and associated downregulation of neuronal genes as well as upregulation of the imprinted gene RTL1 by copy-number-independent allelic dosage effects is associated with an unfavorable prognosis. cis-QTL analysis confirms the previously reported regulation of the LMO1 gene by a super-enhancer risk polymorphism and characterizes the regulatory potential of additional GWAS risk loci. My work highlights the importance of dosage effects in neuroblastoma and provides a detailed map of regulatory variation active in this disease.
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