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1
Bryan, Tracy M. "G-Quadruplexes at Telomeres: Friend or Foe?" Molecules 25, no. 16 (August 13, 2020): 3686. http://dx.doi.org/10.3390/molecules25163686.
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Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures.
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Harrington, Lea, and Fabio Pucci. "In medio stat virtus : unanticipated consequences of telomere dysequilibrium." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1741 (January 15, 2018): 20160444. http://dx.doi.org/10.1098/rstb.2016.0444.
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The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones. Although the catastrophic consequences of full telomere de-protection are well described, recent evidence points to other, less obvious perturbations that arise when telomere length equilibrium is altered. For example, critically short telomeres also perturb DNA methylation and histone post-translational modifications at distal sites throughout the genome. In murine stem cells for example, this dysregulated chromatin leads to inappropriate suppression of pluripotency regulator factors such as Nanog . This review summarizes these recent findings, with an emphasis on how these genome-wide, telomere-induced perturbations can have profound consequences on cell function and fate. This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
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Bettin, Nicole, Claudio Oss Pegorar, and Emilio Cusanelli. "The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability." Cells 8, no. 3 (March 15, 2019): 246. http://dx.doi.org/10.3390/cells8030246.
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The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response and DNA repair pathways. Chromosome end protection is achieved by the activity of specific proteins that associate with chromosome ends, forming telomeres. Telomeres need to be constantly maintained as they are in a heterochromatic state and fold into specific structures (T-loops), which may hamper DNA replication. In addition, in the absence of maintenance mechanisms, chromosome ends shorten at every cell division due to limitations in the DNA replication machinery, which is unable to fully replicate the extremities of chromosomes. Altered telomere structure or critically short chromosome ends generate dysfunctional telomeres, ultimately leading to replicative senescence or chromosome instability. Telomere biology is thus implicated in multiple human diseases, including cancer. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for “TElomeric Repeat-containing RNA,” actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the molecular details of TERRA activities remain to be elucidated. In this review, we discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases.
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López-Fernández, C., E. Pradillo, M. Zabal-Aguirre, J. L. Fernández, C. García de la Vega, and J. Gosálvez. "Telomeric and interstitial telomeric-like DNA sequences in Orthoptera genomes." Genome 47, no. 4 (August 1, 2004): 757–63. http://dx.doi.org/10.1139/g03-143.
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A (TTAGG)n-specific telomeric DNA probe was hybridized to 11 orthopteroid insect genomes by fluorescence in situ hybridization. Nine different genera, mainly distributed within two evolutionary branches with male chromosome numbers 2n = 23 and 2n = 17 were included in the analysis. Telomere sequences yielded positive signals in every telomere and there was a considerable number of interstitial telomeric-like sequences, mainly located at the distal end of some, but not all, subterminal chromosome regions. One of the species, Pyrgomorpha conica, showed massive hybridization signals associated with constitutive heterochromatin. The results are discussed along two lines: (i) the chromosomal evolutionary trends within this group of insects and (ii) the putative role that ITs may play in a genome when they are considered telomere-derived, but not telomere-functional, DNA sequences.Key words: telomere, insect chromosomes, karyotype evolution, fluorescence in situ hybridization.
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Pal, Jagannath, Jie Ding, Subodh Kumar, Zachary Hunter, Teresa Calimeri, Jianhong Lin, Maria Gkotzamanidou, et al. "Telomerase Contributes To Repair Of DNA Breaks In Myeloma Cells By Incorporating “TTAGGG” Sequences Within Genome: Biological and Translational Significance." Blood 122, no. 21 (November 15, 2013): 1249. http://dx.doi.org/10.1182/blood.v122.21.1249.1249.
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Abstract We previously reported that telomerase activity is elevated in multiple myeloma (MM), and its inhibition induces telomere shortening and growth arrest in cancer cells. We have now gone on to study the role of telomerase in DNA break repair and genome maintenance in MM cells. To demonstrate the role of telomerase in DNA break repair: 1) We used g-H2AX staining (marker for DNA breaks) and comet assay, a gel-based technique for detection of DNA breaks in individual cells, and observed that telomerase inhibition leads to significantly increased DNA breaks in MM cells; 2) We have confirmed the repair and re-circularization of a linearized plasmid by telomerase in MM cell extracts; and 3) Demonstrated increased genomic instability, especially deletions, upon telomerase inhibition in MM cells. This does not necessarily suggest role of telomerase in DNA repair as telomerase inhibition with attrition of telomeres can also lead to increased instability. To confirm the direct role of telomerase in DNA repair in MM, we now present the evidence and mechanism of DNA break repair by telomerase by demonstrating: 1) The presence of “TTAGGG” repeats at non-telomeric sites at higher frequency in cancer vs normal cells; and 2) Decline in “TTAGGG” insertions at non-telomeric sites in MM cells following suppression of telomerase. To evaluate rare telomeric insertions in the cancer genome, we created libraries of genomic DNA fragments enriched for “TTAGGG” sequences from primary MM and matching normal PBMCs derived from the same patient. The libraries were sequenced using Illumina platform and reads containing 4 or more telomeric repeats were filtered for further analysis. Telomeric insertion sites were located from unique genomic sequences immediately following TTAGGG at one end of each read. By subtracting telomeric insertions detected in normal cells, from MM cells of same patent, we identified 94 unique loci with telomeric insertion in the primary MM cells. To investigate if telomerase inserts new “TTAGGG” repeats within cancer genome following DNA breaks, UV-treated RPMI cells were incubated with and without telomerase inhibitor for 4 days, cultured without telomerase inhibition for another 6 days, harvested and DNA libraries prepared and enriched for telomeric fragments and subjected to sequencing. DNA from cells preserved before UV treatment (day 0) was used as baseline control and their telomeric insertions were subtracted from UV-treated control and telomerase-inhibited cells. Following induction of DNA breaks by UV, 21 and 3 new telomeric insertions were detected in control and telomerase-inhibited MM cells, respectively, indicating 86% reduction of telomeric insertions within MM cell genome upon telomerase inhibition. Analyses of flanking sequences indicated that 71% of the new telomeric insertions in the UV-treated control cells occurred at sites which did not have any pre-existing “TTAGGG” repeats. Similarly in primary MM cells, 67%, 29% and 4% of the new insertions were observed at positions containing 0, 1 and 2 copies of “TTAGGG” repeats, respectively, indicating that telomerase could use both telomeric as well as non-telomeric DNA as substrate for interstitial telomeric sequence insertions. Evaluation of a few telomeric insertions by Q-PCR confirmed the sequencing data. For an insertion on chr16 (q24.1), a 9.2-fold increase in telomeric signal in UV-treated control relative to background (day 0) cells was observed, whereas the same locus in telomerase-inhibited sample showed near background amplification. We also looked for somatic telomere insertions in 55 largely untreated patients with Waldenström’s macroglobulinemia for whom whole genome sequencing data was available. The absolute number of telomere insertions correlated with the number of somatic structural variants (translocation, inversions, and large deletions) per genome (tau = 0.3 p=0.001) indicating a possible role in DNA double stranded break repair. Thus telomerase contributes to survival of MM and other cancer cells, not only by preventing telomere attrition, but also the repair of DNA breaks which involves the insertion of telomeric repeats within genome. Inhibition of telomerase therefore, may increase the efficacy of chemotherapeutic agents targeting DNA repair. Evaluating interstitial telomeric insertion pattern in cancer could also be a potentially useful tool to study tumor progression or evolution upon treatment. Disclosures: No relevant conflicts of interest to declare.
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Stroik, Susanna, Kevin Kurtz, and Eric A. Hendrickson. "CtIP is essential for telomere replication." Nucleic Acids Research 47, no. 17 (August 5, 2019): 8927–40. http://dx.doi.org/10.1093/nar/gkz652.
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Abstract The maintenance of telomere length is critical to longevity and survival. Specifically, the failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and, in turn, genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, we describe a novel role for CtIP. We show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. Our findings demonstrate a new role for CtIP as a protector of human telomere integrity.
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Vinayagamurthy, Soujanya, Akansha Ganguly, and Shantanu Chowdhury. "Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness." Journal of Biological Chemistry 295, no. 30 (May 22, 2020): 10245–54. http://dx.doi.org/10.1074/jbc.rev119.009710.
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Telomeres comprise specialized nucleic acid–protein complexes that help protect chromosome ends from DNA damage. Moreover, telomeres associate with subtelomeric regions through looping. This results in altered expression of subtelomeric genes. Recent observations further reveal telomere length–dependent gene regulation and epigenetic modifications at sites spread across the genome and distant from telomeres. This regulation is mediated through the telomere-binding protein telomeric repeat–binding factor 2 (TRF2). These observations suggest a role of telomeres in extra-telomeric functions. Most notably, telomeres have a broad impact on pluripotency and differentiation. For example, cardiomyocytes differentiate with higher efficacy from induced pluripotent stem cells having long telomeres, and differentiated cells obtained from human embryonic stem cells with relatively long telomeres have a longer lifespan. Here, we first highlight reports on these two seemingly distinct research areas: the extra-telomeric role of telomere-binding factors and the role of telomeres in pluripotency/stemness. On the basis of the observations reported in these studies, we draw attention to potential molecular connections between extra-telomeric biology and pluripotency. Finally, in the context of the nonlocal influence of telomeres on pluripotency and stemness, we discuss major opportunities for progress in molecular understanding of aging-related disorders and neurodegenerative diseases.
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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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Cohn, Marita, Ahu Karademir Andersson, Raquel Quintilla Mateo, and Mirja Carlsson Möller. "Alternative Lengthening of Telomeres in the Budding Yeast Naumovozyma castellii." G3: Genes|Genomes|Genetics 9, no. 10 (August 19, 2019): 3345–58. http://dx.doi.org/10.1534/g3.119.400428.
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The enzyme telomerase ensures the integrity of linear chromosomes by maintaining telomere length. As a hallmark of cancer, cell immortalization and unlimited proliferation is gained by reactivation of telomerase. However, a significant fraction of cancer cells instead uses alternative telomere lengthening mechanisms to ensure telomere function, collectively known as Alternative Lengthening of Telomeres (ALT). Although the budding yeast Naumovozyma castellii (Saccharomyces castellii) has a proficient telomerase activity, we demonstrate here that telomeres in N. castellii are efficiently maintained by a novel ALT mechanism after telomerase knockout. Remarkably, telomerase-negative cells proliferate indefinitely without any major growth crisis and display wild-type colony morphology. Moreover, ALT cells maintain linear chromosomes and preserve a wild-type DNA organization at the chromosome termini, including a short stretch of terminal telomeric sequence. Notably, ALT telomeres are elongated by the addition of ∼275 bp repeats containing a short telomeric sequence and the subtelomeric DNA located just internally (TelKO element). Although telomeres may be elongated by several TelKO repeats, no dramatic genome-wide amplification occurs, thus indicating that the repeat addition may be regulated. Intriguingly, a short interstitial telomeric sequence (ITS) functions as the initiation point for the addition of the TelKO element. This implies that N. castellii telomeres are structurally predisposed to efficiently switch to the ALT mechanism as a response to telomerase dysfunction.
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Rassoulzadegan, Minoo, Ali Sharifi-Zarchi, and Leila Kianmehr. "DNA-RNA Hybrid (R-Loop): From a Unified Picture of the Mammalian Telomere to the Genome-Wide Profile." Cells 10, no. 6 (June 19, 2021): 1556. http://dx.doi.org/10.3390/cells10061556.
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Local three-stranded DNA/RNA hybrid regions of genomes (R-loops) have been detected either by binding of a monoclonal antibody (DRIP assay) or by enzymatic recognition by RNaseH. Such a structure has been postulated for mouse and human telomeres, clearly suggested by the identification of the complementary RNA Telomeric repeat-containing RNA “TERRA”. However, the tremendous disparity in the information obtained with antibody-based technology drove us to investigate a new strategy. Based on the observation that DNA/RNA hybrids in a triplex complex genome co-purify with the double-stranded chromosomal DNA fraction, we developed a direct preparative approach from total protein-free cellular extract without antibody that allows their physical isolation and determination of their RNA nucleotide sequence. We then define in the normal mouse and human sperm genomes the notion of stable DNA associated RNA terminal R-loop complexes, including TERRA molecules synthesized from local promoters of every chromosome. Furthermore, the first strong evidence of all telomeric structures, applied additionally to the whole murine sperm genome compared to the testes, showed reproducible R-loop complexes of the whole genome and suggesting a defined profile in the sperm genome for the next generation.
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Nakamura, Mirai, Akira Nabetani, Takeshi Mizuno, Fumio Hanaoka, and Fuyuki Ishikawa. "Alterations of DNA and Chromatin Structures at Telomeres and Genetic Instability in Mouse Cells Defective in DNA Polymerase α." Molecular and Cellular Biology 25, no. 24 (December 15, 2005): 11073–88. http://dx.doi.org/10.1128/mcb.25.24.11073-11088.2005.
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ABSTRACT Telomere length is controlled by a homeostatic mechanism that involves telomerase, telomere-associated proteins, and conventional replication machinery. Specifically, the coordinated actions of the lagging strand synthesis and telomerase have been argued. Although DNA polymerase α, an enzyme important for the lagging strand synthesis, has been indicated to function in telomere metabolism in yeasts and ciliates, it has not been characterized in higher eukaryotes. Here, we investigated the impact of compromised polymerase α activity on telomeres, using tsFT20 mouse mutant cells harboring a temperature-sensitive polymerase α mutant allele. When polymerase α was temperature-inducibly inactivated, we observed sequential events that included an initial extension of the G-tail followed by a marked increase in the overall telomere length occurring in telomerase-independent and -dependent manners, respectively. These alterations of telomeric DNA were accompanied by alterations of telomeric chromatin structures as revealed by quantitative chromatin immunoprecipitation and immunofluorescence analyses of TRF1 and POT1. Unexpectedly, polymerase α inhibition resulted in a significantly high incidence of Robertsonian chromosome fusions without noticeable increases in other types of chromosomal aberrations. These results indicate that although DNA polymerase α is essential for genome-wide DNA replication, hypomorphic activity leads to a rather specific spectrum of chromosomal abnormality.
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DA SILVEIRA, RITA DE CÁSSIA VIVEIROS, MARCELO SANTOS DA SILVA, VINÍCIUS SANTANA NUNES, ARINA MARINA PEREZ, and MARIA ISABEL NOGUEIRA CANO. "The natural absence of RPA1N domain did not impair Leishmania amazonensis RPA-1 participation in DNA damage response and telomere protection." Parasitology 140, no. 4 (February 7, 2013): 547–59. http://dx.doi.org/10.1017/s0031182012002028.
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SUMMARYWe have previously shown that the subunit 1 of Leishmania amazonensis RPA (LaRPA-1) alone binds the G-rich telomeric strand and is structurally different from other RPA-1. It is analogous to telomere end-binding proteins described in model eukaryotes whose homologues were not identified in the protozoan´s genome. Here we show that LaRPA-1 is involved with damage response and telomere protection although it lacks the RPA1N domain involved with the binding with multiple checkpoint proteins. We induced DNA double-strand breaks (DSBs) in Leishmania using phleomycin. Damage was confirmed by TUNEL-positive nuclei and triggered a G1/S cell cycle arrest that was accompanied by nuclear accumulation of LaRPA-1 and RAD51 in the S phase of hydroxyurea-synchronized parasites. DSBs also increased the levels of RAD51 in non-synchronized parasites and of LaRPA-1 and RAD51 in the S phase of synchronized cells. More LaRPA-1 appeared immunoprecipitating telomeres in vivo and associated in a complex containing RAD51, although this interaction needs more investigation. RAD51 apparently co-localized with few telomeric clusters but it did not immunoprecipitate telomeric DNA. These findings suggest that LaRPA-1 and RAD51 work together in response to DNA DSBs and at telomeres, upon damage, LaRPA-1 works probably to prevent loss of single-stranded DNA and to assume a capping function.
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Longhese, Maria Pia, Vera Paciotti, Holger Neecke, and Giovanna Lucchini. "Checkpoint Proteins Influence Telomeric Silencing and Length Maintenance in Budding Yeast." Genetics 155, no. 4 (August 1, 2000): 1577–91. http://dx.doi.org/10.1093/genetics/155.4.1577.
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AbstractA complex network of surveillance mechanisms, called checkpoints, interrupts cell cycle progression when damage to the genome is detected or when cells fail to complete DNA replication, thus ensuring genetic integrity. In budding yeast, components of the DNA damage checkpoint regulatory network include the RAD9, RAD17, RAD24, MEC3, DDC1, RAD53, and MEC1 genes that are proposed to be involved in different aspects of DNA metabolism. We provide evidence that some DNA damage checkpoint components play a role in maintaining telomere integrity. In fact, rad53 mutants specifically enhance repression of telomere-proximal transcription via the Sir-mediated pathway, suggesting that Rad53 might be required for proper chromatin structure at telomeres. Moreover, Rad53, Mec1, Ddc1, and Rad17 are necessary for telomere length maintenance, since mutations in all of these genes cause a decrease in telomere size. The telomeric shortening in rad53 and mec1 mutants is further enhanced in the absence of SIR genes, suggesting that Rad53/Mec1 and Sir proteins contribute to chromosome end protection by different pathways. The finding that telomere shortening, but not increased telomeric repression of gene expression in rad53 mutants, can be suppressed by increasing dNTP synthetic capacity in these strains suggests that transcriptional silencing and telomere integrity involve separable functions of Rad53.
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Calado, Rodrigo T., Solomon A. Graf, and Neal S. Young. "Telomeric Recombination in Lymphocytes Implicates ALT, an Alternative Mechanism for Telomere Length Maintenance, in Normal Human Hematopoietic Cells." Blood 110, no. 11 (November 16, 2007): 1332. http://dx.doi.org/10.1182/blood.v110.11.1332.1332.
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Abstract Telomeres are the very ends of chromosomes and protect the genome from recombination, end-to-end-fusion, and recognition as damaged DNA. Telomeres are eroded with each cell division, eventually reaching such critically short length as to cause cell cycle arrest, apoptosis, or genomic instability. In most highly proliferative cells, including hematopoietic stem cells and T lymphocytes, telomere attrition is countered by telomere extension by telomerase reverse transcriptase complex. The majority of cancer cells also express telomerase, which maintains telomere length and allows indefinite cell proliferation. However, about 10% of tumors maintain telomere length in the absence of telomerase by mechanisms collectively termed alternative lengthening of telomeres (ALT). ALT mainly acts through asymmetrical exchange of telomeric material between chromosomes or sister chromatids, producing one daughter-cell with short telomeres and a limited life-span and its sister with long telomeres and higher proliferative capacity. To date, ALT has only been reported in cancer cells or through genetic engineering of mammalian cells. Here we investigated whether ALT mechanisms were active in hematopoietic cells using chromosome orientation fluorescent in situ hybridization (CO-FISH). In standard FISH, a telomeric probe produces fours signals per chromosome, one at each end of the two chromatids. Using CO-FISH, the newly synthesized DNA strand is fragmented by BrdU incorporation and UV light exposure and then digested by exonucleases. In CO-FISH, a telomeric probe produces two signals only, one at each end of the chromosome; in the presence of telomeric recombination, the telomeric signal is split, generating more than two signals per chromosome. Peripheral blood lymphocytes from three healthy volunteers, normal human fibroblasts, K562 cells, telomerase-positive HeLa cells (known to be negative for ALT),and telomerase-negative VA13 cells (known to be positive for ALT) were investigated for telomeric sister chromatid exchange (t-SCE); at least 20 metaphases per cell type were examined. Cultured peripheral blood lymphocytes and VA13 cells both showed increased levels of telomeric sister chromatid exchange in comparison to the other cells (P=0.0001): telomeric probe generated 2.62±0.11 telomeric signals/chromosome in lymphocytes; 2.23±0.04 in VA13 cells; 2.09±0.01 in HeLa cells; 2.02±0.01 in K562 cells; and 2.02±0.01 in human skin fibroblasts. Staining incorporated-BrdU over 24 hours and evaluation of “harlequin” chromosomes point to a similar rate of genomic sister chromatid exchange in lymphocytes, VA13 cells, and HeLa cells, suggesting that high chromatid exchange is confined to the telomeric region. A physical association between promyelocytic leukemia protein (PML) and telomeres is characteristic of some ALT-positive cells, but confocal microscopy failed to co-localize the telomeric probe and anti-PML monoclonal antibody in peripheral blood lymphocytes, suggesting that t-SCE in lymphocytes is not mediated by PML. This is the first demonstration of ALT activation in normal mammalian cells. ALT may be activated in peripheral blood lymphocytes as a complementary mechanism to maintain telomere length, and may explain the differences in age-related telomere shortening observed between lymphocytes and granulocytes.
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Baird, Duncan M. "Telomeres and genomic evolution." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1741 (January 15, 2018): 20160437. http://dx.doi.org/10.1098/rstb.2016.0437.
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The terminal regions of eukaryotic chromosomes, composed of telomere repeat sequences and sub-telomeric sequences, represent some of the most variable and rapidly evolving regions of the genome. The sub-telomeric regions are characterized by segmentally duplicated repetitive DNA elements, interstitial telomere repeat sequences and families of variable genes. Sub-telomeric repeat sequence families are shared among multiple chromosome ends, often rendering detailed sequence characterization difficult. These regions are composed of constitutive heterochromatin and are subjected to high levels of meiotic recombination. Dysfunction within telomere repeat arrays, either due to disruption in the chromatin structure or because of telomere shortening, can lead to chromosomal fusion and the generation of large-scale genomic rearrangements across the genome. The dynamic nature of telomeric regions, therefore, provides functionally useful variation to create genetic diversity, but also provides a mechanism for rapid genomic evolution that can lead to reproductive isolation and speciation. This article is part of the theme issue ‘Understanding diversity in telomere dynamics'. This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
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Palacios, Jose A., Daniel Herranz, Maria Luigia De Bonis, Susana Velasco, Manuel Serrano, and Maria A. Blasco. "SIRT1 contributes to telomere maintenance and augments global homologous recombination." Journal of Cell Biology 191, no. 7 (December 27, 2010): 1299–313. http://dx.doi.org/10.1083/jcb.201005160.
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Yeast Sir2 deacetylase is a component of the silent information regulator (SIR) complex encompassing Sir2/Sir3/Sir4. Sir2 is recruited to telomeres through Rap1, and this complex spreads into subtelomeric DNA via histone deacetylation. However, potential functions at telomeres for SIRT1, the mammalian orthologue of yeast Sir2, are less clear. We studied both loss of function (SIRT1 deficient) and gain of function (SIRT1super) mouse models. Our results indicate that SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity. Using chromatin immunoprecipitation assays, we find that SIRT1 interacts with telomeric repeats in vivo. In addition, SIRT1 overexpression increases homologous recombination throughout the entire genome, including telomeres, centromeres, and chromosome arms. These findings link SIRT1 to telomere biology and global DNA repair and provide new mechanistic explanations for the known functions of SIRT1 in protection from DNA damage and some age-associated pathologies.
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Kaufer, Benedikt B., Keith W. Jarosinski, and Nikolaus Osterrieder. "Herpesvirus telomeric repeats facilitate genomic integration into host telomeres and mobilization of viral DNA during reactivation." Journal of Experimental Medicine 208, no. 3 (March 7, 2011): 605–15. http://dx.doi.org/10.1084/jem.20101402.
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Some herpesviruses, particularly lymphotropic viruses such as Marek’s disease virus (MDV) and human herpesvirus 6 (HHV-6), integrate their DNA into host chromosomes. MDV and HHV-6, among other herpesviruses, harbor telomeric repeats (TMRs) identical to host telomeres at either end of their linear genomes. Using MDV as a natural virus-host model, we show that herpesvirus TMRs facilitate viral genome integration into host telomeres and that integration is important for establishment of latency and lymphoma formation. Integration into host telomeres also aids in reactivation from the quiescent state of infection. Our results and the presence of TMRs in many herpesviruses suggest that integration mediated by viral TMRs is a conserved mechanism, which ensures faithful virus genome maintenance in host cells during cell division and allows efficient mobilization of dormant viral genomes. This finding is of particular importance as reactivation is critical for virus spread between susceptible individuals and is necessary for continued herpesvirus evolution and survival.
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Osterhage, Jennifer L., and Katherine L. Friedman. "Chromosome End Maintenance by Telomerase." Journal of Biological Chemistry 284, no. 24 (March 12, 2009): 16061–65. http://dx.doi.org/10.1074/jbc.r900011200.
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Telomeres, protein-DNA complexes at the ends of eukaryotic linear chromosomes, are essential for genome stability. The accumulation of chromosomal abnormalities in the absence of proper telomere function is implicated in human aging and cancer. Repetitive telomeric sequences are maintained by telomerase, a ribonucleoprotein complex containing a reverse transcriptase subunit, a template RNA, and accessory components. Telomere elongation is regulated at multiple levels, including assembly of the telomerase holoenzyme, recruitment of telomerase to the chromosome terminus, and telomere accessibility. This minireview provides an overview of telomerase structure, function, and regulation and the role of telomerase in human disease.
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Royle, Nicola J., Aarón Méndez-Bermúdez, Athanasia Gravani, Clara Novo, Jenny Foxon, Jonathan Williams, Victoria Cotton, and Alberto Hidalgo. "The role of recombination in telomere length maintenance." Biochemical Society Transactions 37, no. 3 (May 20, 2009): 589–95. http://dx.doi.org/10.1042/bst0370589.
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Human telomeres shorten during each cell division, predominantly because of incomplete DNA replication. This eventually results in short uncapped telomeres that elicit a DNA-damage response, leading to cellular senescence. However, evasion of senescence results in continued cell division and telomere erosion ultimately results in genome instability. In the long term, this genome instability is not sustainable, and cancer cells activate a TMM (telomere maintenance mechanism), either expression of telomerase or activation of the ALT (alternative lengthening of telomeres) pathway. Activation of the ALT mechanism results in deregulation of recombination-based activities at telomeres. Thus ALT+ cells show elevated T-SCE (telomere sister-chromatid exchange), misprocessing of t-loops that cap chromosomes and recombination-based processes between telomeres or between telomeres and ECTRs (extrachromosomal telomeric repeats). Some or all of these processes underlie the chaotic telomere length maintenance that allows cells in ALT+ tumours unlimited replicative capacity. ALT activation is also associated with destabilization of a minisatellite, MS32. The connection between the minisatellite instability and the deregulation of recombination-based activity at telomeres is not understood, but analysis of the minisatellite can be used as a marker for ALT. It is known that telomere length maintenance in ALT+ cells is dependent on the MRN [MRE11 (meiotic recombination 11)–Rad50–NBS1 (Nijmegen breakage syndrome 1)] complex, but knowledge of the role of other genes, including the Werner's (WRN) and Bloom's (BLM) syndrome DNA helicase genes, is still limited.
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Aksenova, Anna Y., and Sergei M. Mirkin. "At the Beginning of the End and in the Middle of the Beginning: Structure and Maintenance of Telomeric DNA Repeats and Interstitial Telomeric Sequences." Genes 10, no. 2 (February 5, 2019): 118. http://dx.doi.org/10.3390/genes10020118.
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Tandem DNA repeats derived from the ancestral (TTAGGG)n run were first detected at chromosome ends of the majority of living organisms, hence the name telomeric DNA repeats. Subsequently, it has become clear that telomeric motifs are also present within chromosomes, and they were suitably called interstitial telomeric sequences (ITSs). It is well known that telomeric DNA repeats play a key role in chromosome stability, preventing end-to-end fusions and precluding the recurrent DNA loss during replication. Recent data suggest that ITSs are also important genomic elements as they confer its karyotype plasticity. In fact, ITSs appeared to be among the most unstable microsatellite sequences as they are highly length polymorphic and can trigger chromosomal fragility and gross chromosomal rearrangements. Importantly, mechanisms responsible for their instability appear to be similar to the mechanisms that maintain the length of genuine telomeres. This review compares the mechanisms of maintenance and dynamic properties of telomeric repeats and ITSs and discusses the implications of these dynamics on genome stability.
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Cooley, Carol, Katie M. Baird, Virginie Faure, Thomas Wenner, Jillian L. Stewart, Sonie Modino, Predrag Slijepcevic, Christine J. Farr, and Ciaran G. Morrison. "Trf1 Is Not Required for Proliferation or Functional Telomere Maintenance in Chicken DT40 Cells." Molecular Biology of the Cell 20, no. 10 (May 15, 2009): 2563–71. http://dx.doi.org/10.1091/mbc.e08-10-1019.
Full textAbstract:
The telomere end-protection complex prevents the ends of linear eukaryotic chromosomes from degradation or inappropriate DNA repair. The homodimeric double-stranded DNA-binding protein, Trf1, is a component of this complex and is essential for mouse embryonic development. To define the requirement for Trf1 in somatic cells, we deleted Trf1 in chicken DT40 cells by gene targeting. Trf1-deficient cells proliferated as rapidly as control cells and showed telomeric localization of Trf2, Rap1, and Pot1. Telomeric G-strand overhang lengths were increased in late-passage Trf1-deficient cells, although telomere lengths were unaffected by Trf1 deficiency, as determined by denaturing Southern and quantitative FISH analysis. Although we observed some clonal variation in terminal telomere fragment lengths, this did not correlate with cellular Trf1 levels. Trf1 was not required for telomere seeding, indicating that de novo telomere formation can proceed without Trf1. The Pin2 isoform and a novel exon 4, 5–deleted isoform localized to telomeres in Trf1-deficient cells. Trf1-deficient cells were sensitive to DNA damage induced by ionizing radiation. Our data demonstrate that chicken DT40 B cells do not require Trf1 for functional telomere structure and suggest that Trf1 may have additional, nontelomeric roles involved in maintaining genome stability.
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Kim, Eunkyeong, Jun Kim, Chuna Kim, and Junho Lee. "Long-read sequencing and de novo genome assemblies reveal complex chromosome end structures caused by telomere dysfunction at the single nucleotide level." Nucleic Acids Research 49, no. 6 (March 8, 2021): 3338–53. http://dx.doi.org/10.1093/nar/gkab141.
Full textAbstract:
Abstract Karyotype change and subsequent evolution is triggered by chromosome fusion and rearrangement events, which often occur when telomeres become dysfunctional. Telomeres protect linear chromosome ends from DNA damage responses (DDRs), and telomere dysfunction may result in genome instability. However, the complex chromosome end structures and the other possible consequences of telomere dysfunction have rarely been resolved at the nucleotide level due to the lack of the high-throughput methods needed to analyse these highly repetitive regions. Here we applied long-read sequencing technology to Caenorhabditis elegans survivor lines that emerged after telomere dysfunction. The survivors have preserved traces of DDRs in their genomes and our data revealed that variants generated by telomere dysfunction are accumulated along all chromosomes. The reconstruction of the chromosome end structures through de novo genome assemblies revealed diverse types of telomere damage processing at the nucleotide level. When telomeric repeats were totally eroded by telomere dysfunction, DDRs were mostly terminated by chromosome fusion events. We also partially reconstructed the most complex end structure and its DDR signatures, which would have been accumulated via multiple cell divisions. These finely resolved chromosome end structures suggest possible mechanisms regarding the repair processes after telomere dysfunction, providing insights into chromosome evolution in nature.
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Mitchell, Meghan T., Jasmine S. Smith, Mark Mason, Sandy Harper, David W. Speicher, F. Brad Johnson, and Emmanuel Skordalakes. "Cdc13 N-Terminal Dimerization, DNA Binding, and Telomere Length Regulation." Molecular and Cellular Biology 30, no. 22 (September 13, 2010): 5325–34. http://dx.doi.org/10.1128/mcb.00515-10.
Full textAbstract:
ABSTRACT The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single-stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres.
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Dobrzanska, Marta, Elzbieta Kraszewska, Maria Bucholc, and Glyn Jenkins. "Molecular cytogenetic analysis of DNA sequences with flanking telomeric repeats inTriticum aestivumcv. Begra." Genome 44, no. 1 (February 1, 2001): 133–36. http://dx.doi.org/10.1139/g00-093.
Full textAbstract:
A cloned genomic DNA fragment (pTa241) formerly derived from a DNA fraction obtained from isolated nuclei of embryos of a Polish cultivar of wheat (Triticum aestivum cv. Begra) comprises a tandem repeat of the telomeric array CCCTAAA, and hybridizes in situ exclusively to the telomeres of all chromosome arms of the somatic chromosome complement of wheat. A second cloned fragment (pTa637) derived from the same fraction is 637 bp long, flanked by 28 bp of the same telomeric repeat unit, and hybridizes in situ to the entire lengths of all the chromosomes of the complement. The same pattern of hybridization was observed when the flanking telomeric sequences were removed. A third DNA fragment (pTa1439), derived from unfractionated genomic DNA and flanked with 62 bp of the same telomeric unit, showed the same patterns of distribution. Together with additional evidence from Southern analysis, these observations were interpreted to mean that these sequences are associated with mobile DNA elements and are distributed widely throughout the genome. The chromosomal distribution of the non-telomeric parts of the clones is consistent with the dispersed genomic distribution characteristic of transposons and retroelements.Key words: wheat, Triticum aestivum cv. Begra, mobile elements, telomeric DNA sequence, FISH.
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Craven, Rolf J., Patricia W. Greenwell, Margaret Dominska, and Thomas D. Petes. "Regulation of Genome Stability by TEL1 and MEC1, Yeast Homologs of the Mammalian ATM and ATR Genes." Genetics 161, no. 2 (June 1, 2002): 493–507. http://dx.doi.org/10.1093/genetics/161.2.493.
Full textAbstract:
Abstract In eukaryotes, a family of related protein kinases (the ATM family) is involved in regulating cellular responses to DNA damage and telomere length. In the yeast Saccharomyces cerevisiae, two members of this family, TEL1 and MEC1, have functionally redundant roles in both DNA damage repair and telomere length regulation. Strains with mutations in both genes are very sensitive to DNA damaging agents, have very short telomeres, and undergo cellular senescence. We find that strains with the double mutant genotype also have ∼80-fold increased rates of mitotic recombination and chromosome loss. In addition, the tel1 mec1 strains have high rates of telomeric fusions, resulting in translocations, dicentrics, and circular chromosomes. Similar chromosome rearrangements have been detected in mammalian cells with mutations in ATM (related to TEL1) and ATR (related to MEC1) and in mammalian cells that approach cell crisis.
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Matsumoto, T., K. Fukui, O. Niwa, N. Sugawara, J. W. Szostak, and M. Yanagida. "Identification of healed terminal DNA fragments in linear minichromosomes of Schizosaccharomyces pombe." Molecular and Cellular Biology 7, no. 12 (December 1987): 4424–30. http://dx.doi.org/10.1128/mcb.7.12.4424.
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The minichromosome Ch16 of the fission yeast Schizosaccharomyces pombe is derived from the centromeric region of chromosome III. We show that Ch16 and a shorter derivative, Ch12, made by gamma-ray cleavage, are linear molecules of 530 and 280 kilobases, respectively. Each minichromosome has two novel telomeres, as shown by genomic Southern hybridization with an S. pombe telomere probe. Comparison by hybridization of the minichromosomes and their chromosomal counterparts showed no signs of gross rearrangement. Cosmid clones covering the ends of the long arms of Ch16 and Ch12 were isolated, and subcloned fragments that contained the breakage sites were identified. They are apparently unique in the genome. By hybridization and Bal 31 digestion, the ends appear to consist of the broken-end sequences directly associated with short stretches (about 300 base pairs) of new DNA that hybridizes to a cloned S. pombe telomere. They do not contain the telomere-adjacent repeated sequences that are present in the normal chromosomes. The sizes of the short telomeric stretches are roughly the same as those of the normal chromosomes. Our results show that broken chromosomal ends in S. pombe can be healed by the de novo addition of the short telomeric repeats. The formation of Ch16 must have required two breakage-healing events, whereas a single cleavage-healing event in the long arm of Ch16 yielded Ch12.
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Matsumoto, T., K. Fukui, O. Niwa, N. Sugawara, J. W. Szostak, and M. Yanagida. "Identification of healed terminal DNA fragments in linear minichromosomes of Schizosaccharomyces pombe." Molecular and Cellular Biology 7, no. 12 (December 1987): 4424–30. http://dx.doi.org/10.1128/mcb.7.12.4424-4430.1987.
Full textAbstract:
The minichromosome Ch16 of the fission yeast Schizosaccharomyces pombe is derived from the centromeric region of chromosome III. We show that Ch16 and a shorter derivative, Ch12, made by gamma-ray cleavage, are linear molecules of 530 and 280 kilobases, respectively. Each minichromosome has two novel telomeres, as shown by genomic Southern hybridization with an S. pombe telomere probe. Comparison by hybridization of the minichromosomes and their chromosomal counterparts showed no signs of gross rearrangement. Cosmid clones covering the ends of the long arms of Ch16 and Ch12 were isolated, and subcloned fragments that contained the breakage sites were identified. They are apparently unique in the genome. By hybridization and Bal 31 digestion, the ends appear to consist of the broken-end sequences directly associated with short stretches (about 300 base pairs) of new DNA that hybridizes to a cloned S. pombe telomere. They do not contain the telomere-adjacent repeated sequences that are present in the normal chromosomes. The sizes of the short telomeric stretches are roughly the same as those of the normal chromosomes. Our results show that broken chromosomal ends in S. pombe can be healed by the de novo addition of the short telomeric repeats. The formation of Ch16 must have required two breakage-healing events, whereas a single cleavage-healing event in the long arm of Ch16 yielded Ch12.
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Płucienniczak, G., and A. Płucienniczak. "Fragments of LINE-1 retrotransposons flanked by inverted telomeric repeats are present in the bovine genome. Homology with human LINE-1 elements." Acta Biochimica Polonica 46, no. 4 (December 31, 1999): 873–78. http://dx.doi.org/10.18388/abp.1999_4108.
Full textAbstract:
In the bovine genome we found two intrachromosomal DNA fragments flanked by inverted telomeric repeats (GenBank Accession Nos. AF136741 and AF136742). The internal parts of the fragments are homologous exclusively to the human sequences and to the consensus sequence of the L1MC4 subfamily of LINE-1 retrotransposons which are widespread among mammalian genomes. We found that distribution of homologous human sequences within our fragments is not random, reflecting a complicated pattern of insertion mechanisms of and maintenance of retrotransposons in mammalian genomes. One of the possible explanations of the origin of LINE-1 truncated elements flanked by inverted telomeric repeats in the bovine genome is that extrachromosomal DNA fragments may be modified by telomerase and subsequently, transferred into chromosomal DNA.
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Weipoltshammer, Klara, Christian Schöfer, Marlene Almeder, Vlada V. Philimonenko, Klemens Frei, Franz Wachtler, and Pavel Hozák. "Intranuclear Anchoring of Repetitive DNA Sequences." Journal of Cell Biology 147, no. 7 (December 27, 1999): 1409–18. http://dx.doi.org/10.1083/jcb.147.7.1409.
Full textAbstract:
Centromeres, telomeres, and ribosomal gene clusters consist of repetitive DNA sequences. To assess their contributions to the spatial organization of the interphase genome, their interactions with the nucleoskeleton were examined in quiescent and activated human lymphocytes. The nucleoskeletons were prepared using “physiological” conditions. The resulting structures were probed for specific DNA sequences of centromeres, telomeres, and ribosomal genes by in situ hybridization; the electroeluted DNA fractions were examined by blot hybridization. In both nonstimulated and stimulated lymphocytes, centromeric alpha-satellite repeats were almost exclusively found in the eluted fraction, while telomeric sequences remained attached to the nucleoskeleton. Ribosomal genes showed a transcription-dependent attachment pattern: in unstimulated lymphocytes, transcriptionally inactive ribosomal genes located outside the nucleolus were eluted completely. When comparing transcription unit and intergenic spacer, significantly more of the intergenic spacer was removed. In activated lymphocytes, considerable but similar amounts of both rDNA fragments were eluted. The results demonstrate that: (a) the various repetitive DNA sequences differ significantly in their intranuclear anchoring, (b) telomeric rather than centromeric DNA sequences form stable attachments to the nucleoskeleton, and (c) different attachment mechanisms might be responsible for the interaction of ribosomal genes with the nucleoskeleton.
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Vaughan, H. E., J. S. Heslop-Harrison, and G. M. Hewitt. "The localization of mitochondrial sequences to chromosomal DNA in orthopterans." Genome 42, no. 5 (October 1, 1999): 874–80. http://dx.doi.org/10.1139/g99-020.
Full textAbstract:
There is growing evidence that the integration of mitochondrial DNA sequences into nuclear and chloroplast genomes of higher organisms may be widespread rather than exceptional. We report the localization of 18S-25S rDNA and mitochondrial DNA sequences to meiotic chromosomes of several orthopteran species using in situ hybridisation. The cytochrome oxidase I (COI) sequence localizes to the centromeric and two telomeric regions of the eight bivalents of Chorthippus parallelus, the telomeric regions in Schistocerca gregaria and is present throughout the genome of Italopodisma sp. (Orthoptera: Acrididae). The control region of the mitochondrion and COI localize to similar chromosomal regions in S. gregaria. These data explain sequencing data that are inconsistent with the COI sequence being solely mitochondrial. The different nuclear locations of mtDNA in the different genera studied suggest that grasshopper mtDNA-like sequences have been inserted into the nuclear genome more than once in Acridid history, and there may have been different mechanisms involved when these events occurred in each of these species.Key words: Schistocerca gregaria, Italopodisma spp., Chorthippus parallelus, in situ hybridisation, mitochondrial DNA, genome organization.
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Lisaingo, Kathleen, Evert-Jan Uringa, and Peter M. Lansdorp. "Resolution of telomere associations by TRF1 cleavage in mouse embryonic stem cells." Molecular Biology of the Cell 25, no. 13 (July 2014): 1958–68. http://dx.doi.org/10.1091/mbc.e13-10-0564.
Full textAbstract:
Telomere associations have been observed during key cellular processes such as mitosis, meiosis, and carcinogenesis and must be resolved before cell division to prevent genome instability. Here we establish that telomeric repeat-binding factor 1 (TRF1), a core component of the telomere protein complex, is a mediator of telomere associations in mammalian cells. Using live-cell imaging, we show that expression of TRF1 or yellow fluorescent protein (YFP)-TRF1 fusion protein above endogenous levels prevents proper telomere resolution during mitosis. TRF1 overexpression results in telomere anaphase bridges and aggregates containing TRF1 protein and telomeric DNA. Site-specific protein cleavage of YFP-TRF1 by tobacco etch virus protease resolves telomere aggregates, indicating that telomere associations are mediated by TRF1. This study provides novel insight into the formation and resolution of telomere associations.
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Lian, Hui-Yong, E. Douglas Robertson, Shin-ichiro Hiraga, Gina M. Alvino, David Collingwood, Heather J. McCune, Akila Sridhar, Bonita J. Brewer, M. K. Raghuraman, and Anne D. Donaldson. "The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation." Molecular Biology of the Cell 22, no. 10 (May 15, 2011): 1753–65. http://dx.doi.org/10.1091/mbc.e10-06-0549.
Full textAbstract:
DNA replication in Saccharomyces cerevisiae proceeds according to a temporal program. We have investigated the role of the telomere-binding Ku complex in specifying late replication of telomere-proximal sequences. Genome-wide analysis shows that regions extending up to 80 kb from telomeres replicate abnormally early in a yku70 mutant. We find that Ku does not appear to regulate replication time by binding replication origins directly, nor is its effect on telomere replication timing mediated by histone tail acetylation. We show that Ku instead regulates replication timing through its effect on telomere length, because deletion of the telomerase regulator Pif1 largely reverses the short telomere defect of a yku70 mutant and simultaneously rescues its replication timing defect. Consistent with this conclusion, deleting the genome integrity component Elg1 partially rescued both length and replication timing of yku70 telomeres. Telomere length–mediated control of replication timing requires the TG1–3 repeat-counting component Rif1, because a rif1 mutant replicates telomeric regions early, despite having extended TG1–3 tracts. Overall, our results suggest that the effect of Ku on telomere replication timing results from its impact on TG1–3 repeat length and support a model in which Rif1 measures telomere repeat length to ensure that telomere replication timing is correctly programmed.
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Lin, Jiangguo, Preston Countryman, Noah Buncher, Parminder Kaur, Longjiang E, Yiyun Zhang, Greg Gibson, et al. "TRF1 and TRF2 use different mechanisms to find telomeric DNA but share a novel mechanism to search for protein partners at telomeres." Nucleic Acids Research 42, no. 4 (November 22, 2013): 2493–504. http://dx.doi.org/10.1093/nar/gkt1132.
Full textAbstract:
Abstract Human telomeres are maintained by the shelterin protein complex in which TRF1 and TRF2 bind directly to duplex telomeric DNA. How these proteins find telomeric sequences among a genome of billions of base pairs and how they find protein partners to form the shelterin complex remains uncertain. Using single-molecule fluorescence imaging of quantum dot-labeled TRF1 and TRF2, we study how these proteins locate TTAGGG repeats on DNA tightropes. By virtue of its basic domain TRF2 performs an extensive 1D search on nontelomeric DNA, whereas TRF1’s 1D search is limited. Unlike the stable and static associations observed for other proteins at specific binding sites, TRF proteins possess reduced binding stability marked by transient binding (∼9–17 s) and slow 1D diffusion on specific telomeric regions. These slow diffusion constants yield activation energy barriers to sliding ∼2.8–3.6 κBT greater than those for nontelomeric DNA. We propose that the TRF proteins use 1D sliding to find protein partners and assemble the shelterin complex, which in turn stabilizes the interaction with specific telomeric DNA. This ‘tag-team proofreading’ represents a more general mechanism to ensure a specific set of proteins interact with each other on long repetitive specific DNA sequences without requiring external energy sources.
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Chen, Lianxiang, Xiaowei Zhu, Yaru Zou, Jun Xing, Eric Gilson, Yiming Lu, and Jing Ye. "The topoisomerase II catalytic inhibitor ICRF-193 preferentially targets telomeres that are capped by TRF2." American Journal of Physiology-Cell Physiology 308, no. 5 (March 1, 2015): C372—C377. http://dx.doi.org/10.1152/ajpcell.00321.2014.
Full textAbstract:
The increased level of chromosome instability in cancer cells is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies kill cells by inducing a nontolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplastic drugs. In the present study, HT1080 cell lines compromised for either telomere repeats binding factor 2 (TRF2) or POT1 were treated with ICRF-193 (3 μM, 24 h) or bleomycin (1 μM, 24 h). DNA damage was assayed by combining telomeric DNA staining of a (CCCTAA)n PNA probe with immunofluorescence of 53BP1 to score the rate of telomere colocalization with 53BP1 foci. We found that ICRF-193, but not bleomycin, leads to DNA damage preferentially at telomeres, which can be rescued by TRF2 inhibition. POT1 inhibition exacerbates telomere dysfunction induced by ICRF-193. Thus, ICRF-193 induces damage at telomeres properly capped by TRF2 but not by POT1. These findings are expected to broaden our view on the mechanism by which conventional therapeutic molecules act to eliminate cancer cells and how to use TRF2 and POT1 levels as surrogate markers for anti-topoisomerase II sensitivity.
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Kondratieva, Yu A., and L. P. Mendeleeva. "Characteristics of telomere length in patients with hematological diseases (literature review)." Oncohematology 16, no. 1 (April 14, 2021): 23–30. http://dx.doi.org/10.17650/1818-8346-2021-16-1-23-30.
Full textAbstract:
Telomeres are protein structures that regulate the process of cellular aging and play the role of a protective “cap” on the end sections of chromosomes. The telomeres of nucleated cells undergo permanent shortening during their lifetime as a result of multiple cycles of DNA replication. The enzyme that provides completion of the missing telomeric repeats at the ends of chromosomes is called “telomerase”. However, recovery of critically short telomeres by telomerase or recombination in somatic cells is limited due to the presence of a large accumulation of unclosed telomeres, which triggers apoptosis. The death of stem cells due to telomere depletion ensures the selection of abnormal cells in which the genome instability contributes to malignant progression. During carcinogenesis, cells acquire mechanisms for maintaining telomeres in order to avoid programmed death. In addition, tumor cells are able to support the telomere's DNA, counteracting its shortening and premature death. Activation of telomere length maintenance mechanisms is a hallmark of most types of cancers. In the modern world, there is an increasing interest in studying the biological characteristics of telomeres. The development of new methods for measuring telomere length has provided numerous studies to understand the relationship between telomere length of human nucleated cells and cancer. Perhaps maintaining telomere length will be an important step, determining the course and prognosis of the disease. The purpose of this review is to provide an analysis of published data of the role and significance of telomere length in patients with hematological malignancies.
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DeMasi, Joseph, Shan Du, David Lennon, and Paula Traktman. "Vaccinia Virus Telomeres: Interaction with the Viral I1, I6, and K4 Proteins." Journal of Virology 75, no. 21 (November 1, 2001): 10090–105. http://dx.doi.org/10.1128/jvi.75.21.10090-10105.2001.
Full textAbstract:
ABSTRACT The 192-kb linear DNA genome of vaccinia virus has covalently closed hairpin termini that are extremely AT rich and contain 12 extrahelical bases. Vaccinia virus telomeres have previously been implicated in the initiation of viral genome replication; therefore, we sought to determine whether the telomeres form specific protein-DNA complexes. Using an electrophoretic mobility shift assay, we found that extracts prepared from virions and from the cytoplasm of infected cells contain telomere binding activity. Four shifted complexes were detected using hairpin probes representing the viral termini, two of which represent an interaction with the “flip” isoform and two with the “flop” isoform. All of the specificity for protein binding lies within the terminal 65-bp hairpin sequence. Viral hairpins lacking extrahelical bases cannot form the shifted complexes, suggesting that DNA structure is crucial for complex formation. Using an affinity purification protocol, we purified the proteins responsible for hairpin-protein complex formation. The vaccinia virus I1 protein was identified as being necessary and sufficient for the formation of the upper doublet of shifted complexes, and the vaccinia virus I6 protein was shown to form the lower doublet of shifted complexes. Competition and challenge experiments confirmed that the previously uncharacterized I6 protein binds tightly and with great specificity to the hairpin form of the viral telomeric sequence. Incubation of viral hairpins with extracts from infected cells also generates a smaller DNA fragment that is likely to reflect specific nicking at the apex of the hairpin; we show that the vaccinia virus K4 protein is necessary and sufficient for this reaction. We hypothesize that these telomere binding proteins may play a role in the initiation of vaccinia virus genome replication and/or genome encapsidation.
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Prangishvili, D., and R. A. Garrett. "Exceptionally diverse morphotypes and genomes of crenarchaeal hyperthermophilic viruses." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 204–8. http://dx.doi.org/10.1042/bst0320204.
Full textAbstract:
The remarkable diversity of the morphologies of viruses found in terrestrial hydrothermal environments with temperatures >80°C is unprecedented for aquatic ecosystems. The best-studied viruses from these habitats have been assigned to novel viral families: Fuselloviridae, Lipothrixviridae and Rudiviridae. They all have double-stranded DNA genomes and infect hyperthermophilic crenarchaea of the orders Sulfolobales and Thermoproteales. Representatives of the different viral families share a few homologous ORFs (open reading frames). However, about 90% of all ORFs in the seven sequenced genomes show no significant matches to sequences in public databases. This suggests that these hyperthermophilic viruses have exceptional biochemical solutions for biological functions. Specific features of genome organization, as well as strategies for DNA replication, suggest that phylogenetic relationships exist between crenarchaeal rudiviruses and the large eukaryal DNA viruses: poxviruses, the African swine fever virus and Chlorella viruses. Sequence patterns at the ends of the linear genome of the lipothrixvirus AFV1 are reminiscent of the telomeric ends of linear eukaryal chromosomes and suggest that a primitive telomeric mechanism operates in this virus.
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Roach, Ruby J., Miguel Garavís, Carlos González, Geoffrey B. Jameson, Vyacheslav V. Filichev, and Tracy K. Hale. "Heterochromatin protein 1α interacts with parallel RNA and DNA G-quadruplexes." Nucleic Acids Research 48, no. 2 (December 4, 2019): 682–93. http://dx.doi.org/10.1093/nar/gkz1138.
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Abstract The eukaryotic genome is functionally organized into domains of transcriptionally active euchromatin and domains of highly compact transcriptionally silent heterochromatin. Heterochromatin is constitutively assembled at repetitive elements that include the telomeres and centromeres. The histone code model proposes that HP1α forms and maintains these domains of heterochromatin through the interaction of its chromodomain with trimethylated lysine 9 of histone 3, although this interaction is not the sole determinant. We show here that the unstructured hinge domain, necessary for the targeting of HP1α to constitutive heterochromatin, recognizes parallel G-quadruplex (G4) assemblies formed by the TElomeric Repeat-containing RNA (TERRA) transcribed from the telomere. This provides a mechanism by which TERRA can lead to the enrichment of HP1α at telomeres to maintain heterochromatin. Furthermore, we show that HP1α binds with a faster association rate to DNA G4s of parallel topology compared to antiparallel G4s that bind slowly or not at all. Such G4–DNAs are found in the regulatory regions of several oncogenes. This implicates specific non-canonical nucleic acid structures as determinants of HP1α function and thus RNA and DNA G4s need to be considered as contributors to chromatin domain organization and the epigenome.
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Tamar, Samira, and Barbara Papadopoulou. "A Telomere-mediated Chromosome Fragmentation Approach to Assess Mitotic Stability and Ploidy Alterations ofLeishmaniaChromosomes." Journal of Biological Chemistry 276, no. 15 (January 10, 2001): 11662–73. http://dx.doi.org/10.1074/jbc.m009006200.
Full textAbstract:
We have used a telomere-associated chromosome fragmentation strategy to induce internal chromosome-specific breakage ofLeishmaniachromosomes. The integration of telomeric repeats from the kinetoplastidTrypanosoma bruceiinto defined positions of theLeishmaniagenome by homologous recombination can induce chromosome breakage accompanied by the deletion of the chromosomal part that is distal to the site of the break. The cloned telomeric DNA at the end of the truncated chromosomes is functional and it can seed the formation of new telomeric repeats. We found that genome ploidy is often altered upon telomere-mediated chromosome fragmentation events resulting in large chromosomal deletions. In most cases diploidy is either preserved, or partial trisomic cells are observed, but interestingly we report here the generation of partial haploid mutants in this diploid organism. Partial haploidLeishmaniamutants should facilitate studies on the function of chromosome-assigned genes. We also present several lines of evidence for the presence of sequences involved in chromosome mitotic stability and segregation during cell cycle in this parasitic protozoan. Telomere-directed chromosome fragmentation studies inLeishmaniamay constitute a useful tool to assay for centromere function.
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Weiden, M., Y. N. Osheim, A. L. Beyer, and L. H. Van der Ploeg. "Chromosome structure: DNA nucleotide sequence elements of a subset of the minichromosomes of the protozoan Trypanosoma brucei." Molecular and Cellular Biology 11, no. 8 (August 1991): 3823–34. http://dx.doi.org/10.1128/mcb.11.8.3823.
Full textAbstract:
The genome of the protozoan Trypanosoma brucei contains a set of about 100 minichromosomes of about 50 to 150 kb in size. The small size of these chromosomes, their involvement in antigenic variation, and their mitotic stability make them ideal candidates for a structural analysis of protozoan chromosomes and their telomeres. We show that a subset of the minichromosomes is composed predominantly of simple-sequence DNA, with over 90% of the length of the minichromosome consisting of a tandem array of 177-bp repeats, indicating that these molecules have limited protein-coding capacity. Proceeding from the tip of the telomere to a chromosome internal position, a subset of the minichromosomes contained the GGGTTA telomere repeat, a 29-bp telomere-derived repeat, a region containing 74-bp G + C-rich direct repeats separated by approximately 155 bp of A + T-rich DNA that has a bent character, and 50 to 150 kb of the 177-bp repeat. Several of the minichromosome-derived telomeres did not encode protein-coding genes, indicating that the repertoire of telomeric variant cell surface glycoprotein genes is restricted to some telomeres only. The telomere organization in trypanosomes shares striking similarities to the organization of telomeres and subtelomeres in humans, yeasts, and plasmodia. An electron microscopic analysis of the minichromosomes showed that they are linear molecules without abnormal structures in the main body of the chromosome. The structure of replicating molecules indicated that minichromosomes probably have a single bidirectional origin of replication located in the body of the chromosome. We propose a model for the structure of the trypanosome minichromosomes.
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Weiden, M., Y. N. Osheim, A. L. Beyer, and L. H. Van der Ploeg. "Chromosome structure: DNA nucleotide sequence elements of a subset of the minichromosomes of the protozoan Trypanosoma brucei." Molecular and Cellular Biology 11, no. 8 (August 1991): 3823–34. http://dx.doi.org/10.1128/mcb.11.8.3823-3834.1991.
Full textAbstract:
The genome of the protozoan Trypanosoma brucei contains a set of about 100 minichromosomes of about 50 to 150 kb in size. The small size of these chromosomes, their involvement in antigenic variation, and their mitotic stability make them ideal candidates for a structural analysis of protozoan chromosomes and their telomeres. We show that a subset of the minichromosomes is composed predominantly of simple-sequence DNA, with over 90% of the length of the minichromosome consisting of a tandem array of 177-bp repeats, indicating that these molecules have limited protein-coding capacity. Proceeding from the tip of the telomere to a chromosome internal position, a subset of the minichromosomes contained the GGGTTA telomere repeat, a 29-bp telomere-derived repeat, a region containing 74-bp G + C-rich direct repeats separated by approximately 155 bp of A + T-rich DNA that has a bent character, and 50 to 150 kb of the 177-bp repeat. Several of the minichromosome-derived telomeres did not encode protein-coding genes, indicating that the repertoire of telomeric variant cell surface glycoprotein genes is restricted to some telomeres only. The telomere organization in trypanosomes shares striking similarities to the organization of telomeres and subtelomeres in humans, yeasts, and plasmodia. An electron microscopic analysis of the minichromosomes showed that they are linear molecules without abnormal structures in the main body of the chromosome. The structure of replicating molecules indicated that minichromosomes probably have a single bidirectional origin of replication located in the body of the chromosome. We propose a model for the structure of the trypanosome minichromosomes.
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Liu, Jia-Cheng, Qian-Jin Li, Ming-Hong He, Can Hu, Pengfei Dai, Fei-Long Meng, Bo O. Zhou, and Jin-Qiu Zhou. "Swc4 positively regulates telomere length independently of its roles in NuA4 and SWR1 complexes." Nucleic Acids Research 48, no. 22 (December 3, 2020): 12792–803. http://dx.doi.org/10.1093/nar/gkaa1150.
Full textAbstract:
Abstract Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C.
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Pan, Xiaolei, William C. Drosopoulos, Louisa Sethi, Advaitha Madireddy, Carl L. Schildkraut, and Dong Zhang. "FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres." Proceedings of the National Academy of Sciences 114, no. 29 (July 3, 2017): E5940—E5949. http://dx.doi.org/10.1073/pnas.1708065114.
Full textAbstract:
In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism. Using the telomere-specific single-molecule analysis of replicated DNA technique, we found that depletion of FANCM dramatically reduces the replication efficiency at ALT telomeres. We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. Mechanistically, we demonstrated that, in FANCM-depleted ALT cells, BRCA1 and BLM help to resolve the telomeric replication stress by stimulating DNA end resection and homologous recombination (HR). Consistent with their roles in resolving the replication stress induced by FANCM deficiency, simultaneous depletion of BLM and FANCM, or of BRCA1 and FANCM, leads to increased micronuclei formation and synthetic lethality in ALT cells. We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers.
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Jennings, Carol, and Don Powell. "Genome organisation in the murine sperm nucleus." Zygote 3, no. 2 (May 1995): 123–31. http://dx.doi.org/10.1017/s0967199400002495.
Full textAbstract:
SummaryThe organisation of DNA sequences in the murine sperm nucleus was studied using in situ hybridisation of biotinylated DNA probes. The efficiency of this reaction was assessed using a dispersed repetitive DNA probe. Telomeric DNA was distributed around the nucleus. Centromeric and ribosomal DNA sequences occupied restricted domains in the sperm nucleus. DNA sequences for a transgene and a cluster of homeogenes occupied different, and rather less defined, domains. Together these results imply that both repetitive and protein-coding sequences are arranged in the nucleus in an ordered fashion.
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Holstein, Eva-Maria, Greg Ngo, Conor Lawless, Peter Banks, Matthew Greetham, Darren Wilkinson, and David Lydall. "Systematic Analysis of the DNA Damage Response Network in Telomere Defective Budding Yeast." G3 Genes|Genomes|Genetics 7, no. 7 (July 1, 2017): 2375–89. http://dx.doi.org/10.1534/g3.117.042283.
Full textAbstract:
Abstract Functional telomeres are critically important to eukaryotic genetic stability. Scores of proteins and pathways are known to affect telomere function. Here, we report a series of related genome-wide genetic interaction screens performed on budding yeast cells with acute or chronic telomere defects. Genetic interactions were examined in cells defective in Cdc13 and Stn1, affecting two components of CST, a single stranded DNA (ssDNA) binding complex that binds telomeric DNA. For comparison, genetic interactions were also examined in cells with defects in Rfa3, affecting the major ssDNA binding protein, RPA, which has overlapping functions with CST at telomeres. In more complex experiments, genetic interactions were measured in cells lacking EXO1 or RAD9, affecting different aspects of the DNA damage response, and containing a cdc13-1 induced telomere defect. Comparing fitness profiles across these data sets helps build a picture of the specific responses to different types of dysfunctional telomeres. The experiments show that each context reveals different genetic interactions, consistent with the idea that each genetic defect causes distinct molecular defects. To help others engage with the large volumes of data, the data are made available via two interactive web-based tools: Profilyzer and DIXY. One particularly striking genetic interaction observed was that the chk1∆ mutation improved fitness of cdc13-1 exo1∆ cells more than other checkpoint mutations (ddc1∆, rad9∆, rad17∆, and rad24∆), whereas, in cdc13-1 cells, the effects of all checkpoint mutations were similar. We show that this can be explained by Chk1 stimulating resection—a new function for Chk1 in the eukaryotic DNA damage response network.
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Stroik, Susanna, Kevin Kurtz, Kevin Lin, Sergey Karachenets, Chad L. Myers, Anja-Katrin Bielinsky, and Eric A. Hendrickson. "EXO1 resection at G-quadruplex structures facilitates resolution and replication." Nucleic Acids Research 48, no. 9 (March 31, 2020): 4960–75. http://dx.doi.org/10.1093/nar/gkaa199.
Full textAbstract:
Abstract G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.
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Jamilena, M., C. Ruiz Rejon, and M. Ruiz Rejon. "A molecular analysis of the origin of the Crepis capillaris B chromosome." Journal of Cell Science 107, no. 3 (March 1, 1994): 703–8. http://dx.doi.org/10.1242/jcs.107.3.703.
Full textAbstract:
The origin of the B chromosome of Crepis capillaris has been studied by using in situ hybridization with different DNA probes. Genomic in situ hybridization (GISH) with DNA from plants with and without Bs as probes indicates that the B chromosome has many DNA sequences in common with A chromosomes, showing no region rich in B-specific sequences. Six additional DNA probes were used to test the possible origin of this B from the standard NOR chromosome (chromosome 3). In the short arm of the NOR chromosome, we detected not only 18 S + 25 S rDNA, but also 5 S rDNA and a specific repetitive sequence from the NOR chromosome (pCcH32); in the heterochromatic bands of the long arm, we found two different repetitive sequences (pCcE9 and pCcD29). In the B chromosome, however, only the 18 S + 25 S rDNA and the telomeric sequences from Arabidopsis thaliana were observed. Our in situ hybridization data with telomeric repeats indicate that the two telomeres of the B are larger than those of the A chromosomes, confirming the isochromosomal nature of this B. Hybridizations of 18 S + 25 S rDNA and telomeric repeats to blots of DNA from plants with and without Bs reveal a high homology between A and B 18 S + 25 S rDNA genes, but some sequence dissimilarities between A and B telomeres. Taken as a whole, these data indicate that the entire B of C. capillaris, although possibly having originated from the standard genome, did not derive directly from the NOR chromosome.
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Kapila, Ritu, Sandip Das, Malathi Lakshmikumaran, and P. S. Srivastava. "A novel species-specific tandem repeat DNA family from Sinapis arvensis: detection of telomere-like sequences." Genome 39, no. 4 (August 1, 1996): 758–66. http://dx.doi.org/10.1139/g96-095.
Full textAbstract:
DNA sequences representing a tandemly repeated DNA family of the Sinapis arvensis genome were cloned and characterized. The 700-bp tandem repeat family is represented by two clones, pSA35 and pSA52, which are 697 and 709 bp in length, respectively. Dot matrix analysis of the sequences indicates the presence of repeated elements within each monomeric unit. Sequence analysis of the repetitive region of clones pSA35 and pSA52 shows that there are several copies of a 7-bp repeat element organized in tandem. The consensus sequence of this repeat element is 5′-TTTAGGG-3′. These elements are highly mutated and the difference in length between the two clones is due to different copy numbers of these elements. The repetitive region of clone pSA35 has 26 copies of the element TTTAGGG, whereas clone pSA52 has 28 copies. The repetitive region in both clones is flanked on either side by inverted repeats that may be footprints of a transposition event. Sequence comparison indicates that the element TTTAGGG is identical to telomeric repeats present in Arabidopsis, maize, tomato, and other plants. However, Bal31digestion kinetics indicates non-telomeric localization of the 700-bp tandem repeats. The clones represent a novel repeat family as (i) they contain telomere-like motifs as subrepeats within each unit; and (ii) they do not hybridize to related crucifers and are species-specific in nature. Key words : Brassica species, Sinapis arvensis, tandem repeats, telomeres.
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Atallah, David M., Stephanie Antoun, Malak Moubarak, Nadine EL Kassis, Georges Y. Chahine, and George Hilal. "Telomere length and its implication as prognostic marker in ovarian cancer patients." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e17055-e17055. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17055.
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e17055 Background: Telomeres are DNA structures protecting the linear ends of eukaryotic chromosomes against degradation and fusion, thereby maintaining genome stability. Telomerase is an enzyme that stabilizes the length of linear chromosomes by de novo synthesizing telomeric repeats during incomplete DNA replication, thus ensuring immortalization. This enzyme is expressed in 80% of cancers, including ovarian carcinoma. The human telomerase reverse transcriptase has been investigated as a detection marker for cancers in early stages, and a prognosis marker in late stages disease. The aim of this study is to investigate telomere length as a marker for survival and recurrence in ovarian carcinoma. Methods: 37 ovarian cancer biopsies have been isolated from Lebanese patients. The biopsies were subjected to DNA extraction, and then telomere length was assayed in cancer cells following the method elaborated by R. Cawthon (2002). The results obtained were expressed as ratios (36B4 is a single copy gene) Ct Telomere/Ct 36B4. Clinical data of each patient have been retrieved, including survival, recurrence, lymph node ratio, age, weight. Results: The results obtained revealed a direct relation between telomere length and survival. In fact, patients with shorter survival rates (less than 1 year) exhibited 30% longer telomeres compared with patients with longer survival rates (3 to 5 years). Moreover, recurrence rates increased with longer telomeres. Higher ratios (35%) were detected in patients with early recurrence (less than 1 year) compared to patients with late or absent recurrence. However, no direct effect between telomere length and the other parameters was spotted. Conclusions: telomere length could be used as a prognostic marker in patients with ovarian cancer by predicting better survival and lower recurrence in case of shorter telomeres. This will be of a great value when making therapeutic decisions in a heterogeneous and aggressive disease as ovarian cancer.
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Santagostino, Marco, Francesca M. Piras, Eleonora Cappelletti, Simone Del Giudice, Ornella Semino, Solomon G. Nergadze, and Elena Giulotto. "Insertion of Telomeric Repeats in the Human and Horse Genomes: An Evolutionary Perspective." International Journal of Molecular Sciences 21, no. 8 (April 18, 2020): 2838. http://dx.doi.org/10.3390/ijms21082838.
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Interstitial telomeric sequences (ITSs) are short stretches of telomeric-like repeats (TTAGGG)n at nonterminal chromosomal sites. We previously demonstrated that, in the genomes of primates and rodents, ITSs were inserted during the repair of DNA double-strand breaks. These conclusions were derived from sequence comparisons of ITS-containing loci and ITS-less orthologous loci in different species. To our knowledge, insertion polymorphism of ITSs, i.e., the presence of an ITS-containing allele and an ITS-less allele in the same species, has not been described. In this work, we carried out a genome-wide analysis of 2504 human genomic sequences retrieved from the 1000 Genomes Project and a PCR-based analysis of 209 human DNA samples. In spite of the large number of individual genomes analyzed we did not find any evidence of insertion polymorphism in the human population. On the contrary, the analysis of ITS loci in the genome of a single horse individual, the reference genome, allowed us to identify five heterozygous ITS loci, suggesting that insertion polymorphism of ITSs is an important source of genetic variability in this species. Finally, following a comparative sequence analysis of horse ITSs and of their orthologous empty loci in other Perissodactyla, we propose models for the mechanism of ITS insertion during the evolution of this order.