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Journal articles on the topic 'Alternative lengthening of telomeres (ALT)'

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Published: 4 June 2021

Last updated: 20 February 2023

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1

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 (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 maintai

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2

Udroiu, Ion, and Antonella Sgura. "Alternative Lengthening of Telomeres and Chromatin Status." Genes 11, no. 1 (2019): 45. http://dx.doi.org/10.3390/genes11010045.

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Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some auth

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3

Hou, Kailong, Yuyang Yu, Duda Li, et al. "Alternative Lengthening of Telomeres and Mediated Telomere Synthesis." Cancers 14, no. 9 (2022): 2194. http://dx.doi.org/10.3390/cancers14092194.

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Telomeres are DNA–protein complexes that protect eukaryotic chromosome ends from being erroneously repaired by the DNA damage repair system, and the length of telomeres indicates the replicative potential of the cell. Telomeres shorten during each division of the cell, resulting in telomeric damage and replicative senescence. Tumor cells tend to ensure cell proliferation potential and genomic stability by activating telomere maintenance mechanisms (TMMs) for telomere lengthening. The alternative lengthening of telomeres (ALT) pathway is the most frequently activated TMM in tumors of mesenchyma

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Gauchier, Mathilde, Sophie Kan, Amandine Barral, et al. "SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres." Science Advances 5, no. 5 (2019): eaav3673. http://dx.doi.org/10.1126/sciadv.aav3673.

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Alternative lengthening of telomeres, or ALT, is a recombination-based process that maintains telomeres to render some cancer cells immortal. The prevailing view is that ALT is inhibited by heterochromatin because heterochromatin prevents recombination. To test this model, we used telomere-specific quantitative proteomics on cells with heterochromatin deficiencies. In contrast to expectations, we found that ALT does not result from a lack of heterochromatin; rather, ALT is a consequence of heterochromatin formation at telomeres, which is seeded by the histone methyltransferase SETDB1. Heteroch

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Zhao, Shuang, Feng Wang, and Lin Liu. "Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells." Genes 10, no. 12 (2019): 1030. http://dx.doi.org/10.3390/genes10121030.

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A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telom

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6

Xu, Mafei, Jun Qin, Leiming Wang, et al. "Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway." Science Advances 5, no. 10 (2019): eaax6366. http://dx.doi.org/10.1126/sciadv.aax6366.

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Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA)

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7

Perrem, Kilian, Lorel M. Colgin, Axel A. Neumann, Thomas R. Yeager, and Roger R. Reddel. "Coexistence of Alternative Lengthening of Telomeres and Telomerase in hTERT-Transfected GM847 Cells." Molecular and Cellular Biology 21, no. 12 (2001): 3862–75. http://dx.doi.org/10.1128/mcb.21.12.3862-3875.2001.

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ABSTRACT It has been shown previously that some immortalized human cells maintain their telomeres in the absence of significant levels of telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Cells utilizing ALT have telomeres of very heterogeneous length, ranging from very short to very long. Here we report the effect of telomerase expression in the ALT cell line GM847. Expression of exogenous hTERT in GM847 (GM847/hTERT) cells resulted in lengthening of the shortest telomeres; this is the first evidence that expression of hTERT in ALT cells can induce

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8

Mentegari, Elisa, Federica Bertoletti, Miroslava Kissova та ін. "A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres". International Journal of Molecular Sciences 22, № 5 (2021): 2365. http://dx.doi.org/10.3390/ijms22052365.

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Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol λ) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol λ, strongly affects the survival of ALT cells. In vitro, Pol λ can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activ

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9

Sung, Ji-Yong, Hee-Woong Lim, Je-Gun Joung, and Woong-Yang Park. "Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity." Cancers 12, no. 8 (2020): 2207. http://dx.doi.org/10.3390/cancers12082207.

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Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low tel

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10

Bechard, Laura H., Bilge D. Butuner, George J. Peterson, Will McRae, Zeki Topcu, and Michael J. McEachern. "Mutant Telomeric Repeats in Yeast Can Disrupt the Negative Regulation of Recombination-Mediated Telomere Maintenance and Create an Alternative Lengthening of Telomeres-Like Phenotype." Molecular and Cellular Biology 29, no. 3 (2008): 626–39. http://dx.doi.org/10.1128/mcb.00423-08.

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ABSTRACT Some human cancers maintain telomeres using alternative lengthening of telomeres (ALT), a process thought to be due to recombination. In Kluyveromyces lactis mutants lacking telomerase, recombinational telomere elongation (RTE) is induced at short telomeres but is suppressed once telomeres are moderately elongated by RTE. Recent work has shown that certain telomere capping defects can trigger a different type of RTE that results in much more extensive telomere elongation that is reminiscent of human ALT cells. In this study, we generated telomeres composed of either of two types of mu

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Amato, Roberta, Martina Valenzuela, Francesco Berardinelli, et al. "G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells." Genes 11, no. 3 (2020): 304. http://dx.doi.org/10.3390/genes11030304.

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Most human tumors maintain telomere lengths by telomerase, whereas a portion of them (10–15%) uses a mechanism named alternative lengthening of telomeres (ALT). The telomeric G-quadruplex (G4) ligand RHPS4 is known for its potent antiproliferative effect, as shown in telomerase-positive cancer models. Moreover, RHPS4 is also able to reduce cell proliferation in ALT cells, although the influence of G4 stabilization on the ALT mechanism has so far been poorly investigated. Here we show that sensitivity to RHPS4 is comparable in ALT-positive (U2OS; SAOS-2) and telomerase-positive (HOS) osteosarco

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Jiang, Wei-Qin, Ze-Huai Zhong, Jeremy D. Henson, Axel A. Neumann, Andy C. M. Chang, and Roger R. Reddel. "Suppression of Alternative Lengthening of Telomeres by Sp100-Mediated Sequestration of the MRE11/RAD50/NBS1 Complex." Molecular and Cellular Biology 25, no. 7 (2005): 2708–21. http://dx.doi.org/10.1128/mcb.25.7.2708-2721.2005.

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ABSTRACT Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in telomere binding, DNA replication, and recombination. The ALT mechanism appears to involve re

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13

Iyer, Shilpa, Ashley D. Chadha, and Michael J. McEachern. "A Mutation in the STN1 Gene Triggers an Alternative Lengthening of Telomere-Like Runaway Recombinational Telomere Elongation and Rapid Deletion in Yeast." Molecular and Cellular Biology 25, no. 18 (2005): 8064–73. http://dx.doi.org/10.1128/mcb.25.18.8064-8073.2005.

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ABSTRACT Some human cancer cells achieve immortalization by using a recombinational mechanism termed ALT (alternative lengthening of telomeres). A characteristic feature of ALT cells is the presence of extremely long and heterogeneous telomeres. The molecular mechanism triggering and maintaining this pathway is currently unknown. In Kluyveromyces lactis, we have identified a novel allele of the STN1 gene that produces a runaway ALT-like telomeric phenotype by recombination despite the presence of an active telomerase pathway. Additionally, stn1-M1 cells are synthetically lethal in combination

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14

Siddiqa, Aisha, David Cavazos, Jeffery Chavez, Linda Long, and Robert A. Marciniak. "Modulation of Telomeres in Alternative Lengthening of Telomeres Type I Like Human Cells by the Expression of Werner Protein and Telomerase." Journal of Oncology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/806382.

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The alternative lengthening of telomeres (ALT) is a recombination-based mechanism of telomere maintenance activated in 5–20% of human cancers. InSaccharomyces cerevisiae, survivors that arise after inactivation of telomerase can be classified as type I or type II ALT. In type I, telomeres have a tandem array structure, with each subunit consisting of a subtelomeric Y′ element and short telomere sequence. Telomeres in type II have only long telomere repeats and require Sgs1, theS. cerevisiaeRecQ family helicase. We previously described the first human ALT cell line, AG11395, that has a telomere

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15

Lee, Yoo-Kyung, Noh-Hyun Park, and Hyunsook Lee. "Prognostic Value of Alternative Lengthening of Telomeres–Associated Biomarkers in Uterine Sarcoma and Uterine Carcinosarcoma." International Journal of Gynecologic Cancer 22, no. 3 (2012): 434–41. http://dx.doi.org/10.1097/igc.0b013e31823ca017.

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ObjectiveA subset of cancer cells maintains telomere lengths in a telomerase-independent manner known as the alternative lengthening of telomeres (ALT). The goal of this study was to evaluate the frequency of ALT in uterine sarcoma and carcinosarcoma and to assess its association with clinical parameters.MethodsRetrospectively collected paraffin blocks from 41 patients with uterine sarcomas and carcinosarcomas were analyzed for ALT-associated promyelocytic leukemia bodies (APBs), which are a significant feature of ALT cells, using combined immunofluorescence and telomere fluorescence in situ h

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Toubiana, Shir, Aya Tzur-Gilat, and Sara Selig. "Epigenetic Characteristics of Human Subtelomeres Vary in Cells Utilizing the Alternative Lengthening of Telomeres (ALT) Pathway." Life 11, no. 4 (2021): 278. http://dx.doi.org/10.3390/life11040278.

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Most human cancers circumvent senescence by activating a telomere length maintenance mechanism, most commonly involving telomerase activation. A minority of cancers utilize the recombination-based alternative lengthening of telomeres (ALT) pathway. The exact requirements for unleashing normally repressed recombination at telomeres are yet unclear. Epigenetic modifications at telomeric regions were suggested to be pivotal for activating ALT; however, conflicting data exist regarding their exact nature and necessity. To uncover common ALT-positive epigenetic characteristics, we performed a compr

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Damle, Rajendra N., Taraneh Banapour, Cristina Sison, Steven L. Allen, Kanti R. Rai, and Nicholas Chiorazzi. "Evidence for Alternative Lengthening of Telomeres in Chronic Lymphocytic Leukemia Patients." Blood 106, no. 11 (2005): 1179. http://dx.doi.org/10.1182/blood.v106.11.1179.1179.

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Abstract Telomere shortening is a consequence of repetitive clonal replication and leads to clonal deletion unless DNA extension and repair occur. All tumors must circumvent this problem by up-regulating mechanisms that lead to chromosomal lengthening. Two mechanisms have been identified that maintain chromosome ends- telomerase that does so by reverse transcription and alternative lengthening of telomeres (ALT) that occurs by homologous recombination. The latter function is characterized by the presence of promyelocytic leukemia protein-associated nuclear bodies (PML-NBs) and the presence of

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18

Conomos, Dimitri, Michael D. Stutz, Mark Hills, et al. "Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells." Journal of Cell Biology 199, no. 6 (2012): 893–906. http://dx.doi.org/10.1083/jcb.201207189.

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Telomeres in cells that use the recombination-mediated alternative lengthening of telomeres (ALT) pathway elicit a DNA damage response that is partly independent of telomere length. We therefore investigated whether ALT telomeres contain structural abnormalities that contribute to ALT activity. Here we used next generation sequencing to analyze the DNA content of ALT telomeres. We discovered that variant repeats were interspersed throughout the telomeres of ALT cells. We found that the C-type (TCAGGG) variant repeat predominated and created a high-affinity binding site for the nuclear receptor

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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 (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 indefin

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Jiang, Wei-Qin, Ze-Huai Zhong, Akira Nguyen, et al. "Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins." Journal of Cell Biology 185, no. 5 (2009): 797–810. http://dx.doi.org/10.1083/jcb.200810084.

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Alternative lengthening of telomeres (ALT) is a recombination-mediated process that maintains telomeres in telomerase-negative cancer cells. In asynchronously dividing ALT-positive cell populations, a small fraction of the cells have ALT-associated promyelocytic leukemia nuclear bodies (APBs), which contain (TTAGGG)n DNA and telomere-binding proteins. We found that restoring p53 function in ALT cells caused p21 up-regulation, growth arrest/senescence, and a large increase in cells containing APBs. Knockdown of p21 significantly reduced p53-mediated induction of APBs. Moreover, we found that he

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Royle, Nicola J., Aarón Méndez-Bermúdez, Athanasia Gravani, et al. "The role of recombination in telomere length maintenance." Biochemical Society Transactions 37, no. 3 (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 t

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De Vitis, Marco, Francesco Berardinelli, Elisa Coluzzi, Jessica Marinaccio, Roderick J. O’Sullivan, and Antonella Sgura. "X-rays Activate Telomeric Homologous Recombination Mediated Repair in Primary Cells." Cells 8, no. 7 (2019): 708. http://dx.doi.org/10.3390/cells8070708.

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Cancer cells need to acquire telomere maintenance mechanisms in order to counteract progressive telomere shortening due to multiple rounds of replication. Most human tumors maintain their telomeres expressing telomerase whereas the remaining 15%–20% utilize the alternative lengthening of telomeres (ALT) pathway. Previous studies have demonstrated that ionizing radiations (IR) are able to modulate telomere lengths and to transiently induce some of the ALT-pathway hallmarks in normal primary fibroblasts. In the present study, we investigated the telomere length modulation kinetics, telomeric DNA

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Rosso, Ilaria, and Fabrizio d’Adda di Fagagna. "Detection of Telomeric DNA:RNA Hybrids Using TeloDRIP-qPCR." International Journal of Molecular Sciences 21, no. 24 (2020): 9774. http://dx.doi.org/10.3390/ijms21249774.

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Because of their intrinsic characteristics, telomeres are genomic loci that pose significant problems during the replication of the genome. In particular, it has been observed that telomeres that are maintained in cancer cells by the alternative mechanism of the lengthening of telomeres (ALT) harbor higher levels of replicative stress compared with telomerase-positive cancer cells. R-loops are three-stranded structures formed by a DNA:RNA hybrid and a displaced ssDNA. Emerging evidence suggests that controlling the levels of R-loops at ALT telomeres is critical for telomere maintenance. In fac

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Hsu, Joseph K., Tao Lin, and Robert Y. L. Tsai. "Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1." Journal of Cell Biology 197, no. 5 (2012): 613–24. http://dx.doi.org/10.1083/jcb.201109038.

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Continuously dividing cells must be protected from telomeric and nontelomeric DNA damage in order to maintain their proliferative potential. Here, we report a novel telomere-protecting mechanism regulated by nucleostemin (NS). NS depletion increased the number of telomere damage foci in both telomerase-active (TA+) and alternative lengthening of telomere (ALT) cells and decreased the percentage of damaged telomeres associated with ALT-associated PML bodies (APB) and the number of APB in ALT cells. Mechanistically, NS could promote the recruitment of PML-IV to SUMOylated TRF1 in TA+ and ALT cel

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Cesare, Anthony J., and Jack D. Griffith. "Telomeric DNA in ALT Cells Is Characterized by Free Telomeric Circles and Heterogeneous t-Loops." Molecular and Cellular Biology 24, no. 22 (2004): 9948–57. http://dx.doi.org/10.1128/mcb.24.22.9948-9957.2004.

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ABSTRACT A prerequisite for cellular immortalization in human cells is the elongation of telomeres through the upregulation of telomerase or by the alternative lengthening of telomeres (ALT) pathway. In this study, telomere structure in multiple ALT cell lines was examined by electron microscopy. Nuclei were isolated from GM847, GM847-Tert, and WI-38 VA13 ALT cells, psoralen photo-cross-linked in situ, and the telomere restriction fragments were purified by gel filtration chromatography. Examination of telomere-enriched fractions revealed frequent extrachromosomal circles, ranging from 0.7 to

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Caslini, Corrado, and Jay L. Hess. "MLL Modulates Telomere Length in Mammalian Cells." Blood 108, no. 11 (2006): 2209. http://dx.doi.org/10.1182/blood.v108.11.2209.2209.

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Abstract In mammalian cells, the telomeric complex at the end of chromosomes consists of several thousand copies of the exanucleotide TTAGGG and associated proteins attached to the nuclear matrix. Chromatin modifying enzymes involved in histone H3/lysine 9 and histone H4/lysine 20 trimethylation, and DNA methylation are known to preserve the telomere heterochromatic structure, length and capping function. Loss of these heterochromatic marks leads to telomere lengthening, most likely through the negative regulation of telomerase or alternative lengthening of telomeres (ALT) mechanisms. The MLL

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Shi, Guang, Yang Hu, Xing Zhu, et al. "A critical role of telomere chromatin compaction in ALT tumor cell growth." Nucleic Acids Research 48, no. 11 (2020): 6019–31. http://dx.doi.org/10.1093/nar/gkaa224.

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Abstract ALT tumor cells often contain abundant DNA damage foci at telomeres and rely on the alternative lengthening of telomeres (ALT) mechanism to maintain their telomeres. How the telomere chromatin is regulated and maintained in these cells remains largely unknown. In this study, we present evidence that heterochromatin protein 1 binding protein 3 (HP1BP3) can localize to telomeres and is particularly enriched on telomeres in ALT cells. HP1BP3 inhibition led to preferential growth inhibition of ALT cells, which was accompanied by telomere chromatin decompaction, increased presence of C-cir

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Armendáriz-Castillo, Isaac, Andrés López-Cortés, Jennyfer García-Cárdenas, et al. "TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes." Genes 11, no. 7 (2020): 834. http://dx.doi.org/10.3390/genes11070834.

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Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85–90% reactivate telomerase, while 10–15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approa

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Idilli, Aurora Irene, Francesca Pagani, Emanuela Kerschbamer, et al. "Changes in the Expression of Pre-Replicative Complex Genes in hTERT and ALT Pediatric Brain Tumors." Cancers 12, no. 4 (2020): 1028. http://dx.doi.org/10.3390/cancers12041028.

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Background: The up-regulation of a telomere maintenance mechanism (TMM) is a common feature of cancer cells and a hallmark of cancer. Routine methods for detecting TMMs in tumor samples are still missing, whereas telomerase targeting treatments are becoming available. In paediatric cancers, alternative lengthening of telomeres (ALT) is found in a subset of sarcomas and malignant brain tumors. ALT is a non-canonical mechanism of telomere maintenance developed by cancer cells with no-functional telomerase. Methods: To identify drivers and/or markers of ALT, we performed a differential gene expre

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Sommer, Aurore, and Nicola J. Royle. "ALT: A Multi-Faceted Phenomenon." Genes 11, no. 2 (2020): 133. http://dx.doi.org/10.3390/genes11020133.

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One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanis

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Eid, Rita, Marie-Véronique Demattei, Harikleia Episkopou, et al. "Genetic Inactivation ofATRXLeads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells." Molecular and Cellular Biology 35, no. 16 (2015): 2818–30. http://dx.doi.org/10.1128/mcb.01317-14.

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Mutations in ATRX (alphathalassemia/mentalretardation syndromeX-linked), a chromatin-remodeling protein, are associated with the telomerase-independent ALT (alternative lengthening of telomeres) pathway of telomere maintenance in several types of cancer, including human gliomas. In telomerase-positive glioma cells, we found by immunofluorescence that ATRX localized not far from the chromosome ends but not exactly at the telomere termini. Chromatin immunoprecipitation (ChIP) experiments confirmed a subtelomeric localization for ATRX, yet short hairpin RNA (shRNA)-mediated genetic inactivation o

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Stagno D'Alcontres, Martina, Aaron Mendez-Bermudez, Jennifer L. Foxon, Nicola J. Royle, and Paolo Salomoni. "Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA." Journal of Cell Biology 179, no. 5 (2007): 855–67. http://dx.doi.org/10.1083/jcb.200703020.

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Alternative lengthening of telomere (ALT) tumors maintain telomeres by a telomerase-independent mechanism and are characterized by a nuclear structure called the ALT-associated PML body (APB). TRF2 is a component of a telomeric DNA/protein complex called shelterin. However, TRF2 function in ALT cells remains elusive. In telomerase-positive tumor cells, TRF2 inactivation results in telomere de-protection, activation of ATM, and consequent induction of p53-dependent apoptosis. We show that in ALT cells this sequence of events is different. First, TRF2 inactivation/silencing does not induce cell

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Geiller, Helene E. B., Adam Harvey, Rhiannon E. Jones, et al. "ATRX modulates the escape from a telomere crisis." PLOS Genetics 18, no. 11 (2022): e1010485. http://dx.doi.org/10.1371/journal.pgen.1010485.

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Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT) that leads to long and heterogenous telomere length distributions. Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene are frequently found in ALT cancers. Here, we demonstrate that the loss of ATRX, coupled with telomere dysfunction during crisis, is sufficient to initiate activation of the ALT pathway and that it confers replicative immorta

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Buttarelli, Francesca Romana, Simone Minasi, Maria Luisa Garrè, et al. "MEDB-68. Analysis of telomeres length and Alternative Lengthening of Telomeres (ALT) in molecular subgroups of infant medulloblastoma." Neuro-Oncology 24, Supplement_1 (2022): i122. http://dx.doi.org/10.1093/neuonc/noac079.442.

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Abstract We investigated the association between the molecular profile and telomere length in a infant medulloblastoma (iMB) cohort, retrospectively studied. Activation of telomeres maintenance mechanisms was analyzed to determine whether the senescence escape triggered by telomere-elongation mechanisms could explain the aggressivity of some iMB belonging to the same molecular subgroup. Interestingly, several telomerase- and ALT-targeted therapies have recently been tested on pediatric cancers and might represent a promising strategy for the future treatment of aggressive telomerase- or ALT-po

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Li, Duda, Kailong Hou, Ke Zhang, and Shuting Jia. "Regulation of Replication Stress in Alternative Lengthening of Telomeres by Fanconi Anaemia Protein." Genes 13, no. 2 (2022): 180. http://dx.doi.org/10.3390/genes13020180.

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Fanconi anaemia (FA)-related proteins function in interstrand crosslink (ICL) repair pathways and multiple damage repair pathways. Recent studies have found that FA proteins are involved in the regulation of replication stress (RS) in alternative lengthening of telomeres (ALT). Since ALT cells often exhibit high-frequency ATRX mutations and high levels of telomeric secondary structure, high levels of DNA damage and replicative stress exist in ALT cells. Persistent replication stress is required to maintain the activity of ALT mechanistically, while excessive replication stress causes ALT cell

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Jegou, Thibaud, Inn Chung, Gerrit Heuvelman, et al. "Dynamics of Telomeres and Promyelocytic Leukemia Nuclear Bodies in a Telomerase-negative Human Cell Line." Molecular Biology of the Cell 20, no. 7 (2009): 2070–82. http://dx.doi.org/10.1091/mbc.e08-02-0108.

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Telomerase-negative tumor cells maintain their telomeres via an alternative lengthening of telomeres (ALT) mechanism. This process involves the association of telomeres with promyelocytic leukemia nuclear bodies (PML-NBs). Here, the mobility of both telomeres and PML-NBs as well as their interactions were studied in human U2OS osteosarcoma cells, in which the ALT pathway is active. A U2OS cell line was constructed that had lac operator repeats stably integrated adjacent to the telomeres of chromosomes 6q, 11p, and 12q. By fluorescence microscopy of autofluorescent LacI repressor bound to the l

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Zhang, Huaiying, Rongwei Zhao, Jason Tones, et al. "Nuclear body phase separation drives telomere clustering in ALT cancer cells." Molecular Biology of the Cell 31, no. 18 (2020): 2048–56. http://dx.doi.org/10.1091/mbc.e19-10-0589.

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A chemical dimerization approach is developed to induce phase separation of APB nuclear bodies involved in telomere elongation in alternative lengthening of telomeres (ALT) cancer cells. It reveals that ALT telomere-associated promyelocytic leukemia nuclear body (APB) fusion leads to telomere clustering to provide templates for homology-directed telomere synthesis, an ability that is decoupled from APB function in enriching DNA repair factors.

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Robinson, Nathaniel J., Masaru Miyagi, Jessica A. Scarborough, Jacob G. Scott, Derek J. Taylor та William P. Schiemann. "SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling". Science Signaling 14, № 689 (2021): eabe9613. http://dx.doi.org/10.1126/scisignal.abe9613.

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The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling

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Grandin, Nathalie, and Michel Charbonneau. "Telomerase- and Rad52-Independent Immortalization of Budding Yeast by an Inherited-Long-Telomere Pathway of Telomeric Repeat Amplification." Molecular and Cellular Biology 29, no. 4 (2008): 965–85. http://dx.doi.org/10.1128/mcb.00817-08.

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ABSTRACT In the absence of telomerase, telomeres erode, provoking accumulation of DNA damage and death by senescence. Rare survivors arise, however, due to Rad52-based amplification of telomeric sequences by homologous recombination. The present study reveals that in budding yeast cells, postsenescence survival relying on amplification of the TG1-3 telomeric repeats can take place in the absence of Rad52 when overelongated telomeres are present during senescence (hence its designation ILT, for inherited-long-telomere, pathway). By growth competition, the Rad52-independent pathway was almost as

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Mukherjee, Joydeep, Ajay Pandita, Chatla Kamalakar, et al. "A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells." Science Translational Medicine 13, no. 592 (2021): eabc7211. http://dx.doi.org/10.1126/scitranslmed.abc7211.

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About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-

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Armendáriz-Castillo, Isaac, Katherine Hidalgo-Fernández, Andy Pérez-Villa, Jennyfer M. García-Cárdenas, Andrés López-Cortés, and Santiago Guerrero. "Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway." Biology 11, no. 2 (2022): 185. http://dx.doi.org/10.3390/biology11020185.

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Alternative lengthening of telomeres-associated promyelocytic leukemia nuclear bodies (APBs) are a hallmark of telomere maintenance. In the last few years, APBs have been described as the main place where telomeric extension occurs in ALT-positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multiomics analyses to evaluate genomic, transcriptomic and p

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Recagni, Marta, Joanna Bidzinska, Nadia Zaffaroni, and Marco Folini. "The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications." Cancers 12, no. 4 (2020): 949. http://dx.doi.org/10.3390/cancers12040949.

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Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibit

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Tornesello, Maria Lina, Andrea Cerasuolo, Noemy Starita, et al. "The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development." Cancers 14, no. 21 (2022): 5257. http://dx.doi.org/10.3390/cancers14215257.

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Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is universally enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein–Barr virus (EBV) LMP1, Kaposi’s sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) Tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TER

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Auchter, Morgan, Sandrine Medves, Laetitia Chambeau, et al. "Mechanisms of Telomere Maintenance Dysfunction in B-Chronic Lymphocytic Leukemia Through CpG Island Methylation." Blood 120, no. 21 (2012): 3489. http://dx.doi.org/10.1182/blood.v120.21.3489.3489.

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Abstract Abstract 3489 Telomeres are a repetitive DNA sequences associated with a protein complex named shelterin that protect chromosome ends. Two types of mechanisms maintain telomere in cancer cells. The first involves telomerase an enzyme able to copy the telomeric motif that consists of three principal subunits, including the telomerase reverse transcriptase hTERT. The second, named ALT (Alternative Lengthening of Telomere), corresponds to the recombination between telomeres that involves notably a complex formed by the topoisomerase III alpha (hTopoIIIa), BLM, RMI1 and RMI2. Little is kn

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Thompson, Connor A. H., and Judy M. Y. Wong. "Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance." Current Topics in Medicinal Chemistry 20, no. 6 (2020): 498–507. http://dx.doi.org/10.2174/1568026620666200131125110.

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Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expr

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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 (2017): E5940—E5949. http://dx.doi.org/10.1073/pnas.1708065114.

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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

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Stoklosa, Tomasz, Anna Deregowska, Katarzyna Pruszczyk, et al. "Role of Shelterin Complex and Alternative Telomere Lengthening in Genomic Instability and Disease Progression in Chronic Myeloid Leukemia." Blood 128, no. 22 (2016): 1880. http://dx.doi.org/10.1182/blood.v128.22.1880.1880.

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Abstract Genomic instability has many sources, among others, shortening of telomeres, nucleoprotein complexes located at the ends of chromosomes. Tumor cells have aberrant mechanisms of telomere maintenance: their telomeres are shortened, no longer preventing chromosome end-to-end fusion and recombination, but frequently not short enough to lead to cell senescence. Both telomerase and shelterin complexes are involved in telomere homeostasis. Reduction in the telomere length is considered as one of the features of chronic myeloid leukemia (CML) similar to other human malignancies and telomere s

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Lima, Matheus Fabiao de, Monique Oliveira Freitas, Mohammad K. Hamedani, Aline Rangel-Pozzo, Xu-Dong Zhu, and Sabine Mai. "Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin’s Lymphoma Cell Death." Biomedicines 10, no. 9 (2022): 2299. http://dx.doi.org/10.3390/biomedicines10092299.

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Telomere maintenance is key during cancer development. Malignant cells can either use telomerase or an alternative lengthening of telomere (ALT) pathway to maintain their telomere length. In Hodgkin’s Lymphoma (HL), the presence of telomerase activation is established. The activation of ALT has been reported recently. Our data confirm this notion describing co-localization of the phosphorylated form of telomeric repeat-binding factor 1 (pT371-TRF1) with ALT-associated promyelocytic leukemia bodies. Surprisingly, to our knowledge, there are no published studies targeting both telomere maintenan

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da Silva, Guilherme G., Karollyne S. Morais, Daniel S. Arcanjo, and Diêgo M. de Oliveira. "Clinical Relevance of Alternative Lengthening of Telomeres in Cancer." Current Topics in Medicinal Chemistry 20, no. 6 (2020): 485–97. http://dx.doi.org/10.2174/1568026620666200110112854.

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The alternative lengthening of telomere (ALT) is a pathway responsible for cell immortalization in some kinds of tumors. Since the first description of ALT is relatively recent in the oncology field, its mechanism remains elusive, but recent works address ALT-related proteins or cellular structures as potential druggable targets for more specific and efficient antitumor therapies. Moreover, some new generation compounds for antitelomerase therapy in cancer were able to provoke acquisition of ALT phenotype in treated tumors, enhancing the importance of studies on this alternative lengthening of

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Akter, Jesmin, and Takehiko Kamijo. "How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?" Biomolecules 11, no. 8 (2021): 1112. http://dx.doi.org/10.3390/biom11081112.

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Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts

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