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alternative lengthening of telomeres

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https://www.readbyqxmd.com/read/29776332/telnet-a-database-for-human-and-yeast-genes-involved-in-telomere-maintenance
#1
Delia M Braun, Inn Chung, Nick Kepper, Katharina I Deeg, Karsten Rippe
BACKGROUND: The ends of linear chromosomes, the telomeres, comprise repetitive DNA sequences in complex with proteins that protects them from being processed by the DNA repair machinery. Cancer cells need to counteract the shortening of telomere repeats during replication for their unlimited proliferation by reactivating the reverse transcriptase telomerase or by using the alternative lengthening of telomeres (ALT) pathway. The different telomere maintenance (TM) mechanisms appear to involve hundreds of proteins but their telomere repeat length related activities are only partly understood...
May 18, 2018: BMC Genetics
https://www.readbyqxmd.com/read/29751586/telomere-maintenance-mechanisms-in-cancer
#2
REVIEW
Tiago Bordeira Gaspar, Ana Sá, José Manuel Lopes, Manuel Sobrinho-Simões, Paula Soares, João Vinagre
Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance...
May 3, 2018: Genes
https://www.readbyqxmd.com/read/29749098/essential-roles-of-telomerase-reverse-transcriptase-htert-in-cancer-stemness-and-metastasis
#3
REVIEW
Ricarda Hannen, Jörg W Bartsch
Maintenance of chromosomal telomere length is a hallmark of cancer cells and a prerequisite for stemness. In 85-90% of all human cancers, telomere length maintenance is achieved by reactivation of telomerase, whereas in the remaining 10-15% cancers, alternative lengthening of telomeres (ALT) is observed. Reactivation of telomerase occurs by various mechanisms, one of which is accumulation of point mutations in the promoter region of the gene encoding the protein subunit hTERT. There are numerous studies linking either hTERT overexpression or the presence of hTERT mutations to an aggressive phenotype of several human cancers...
May 10, 2018: FEBS Letters
https://www.readbyqxmd.com/read/29725455/alternative-lengthening-of-telomeres-phenotype-and-loss-of-atrx-expression-in-sarcomas
#4
REVIEW
Xiaolei Ren, Chao Tu, Zhenchu Tang, Ruofei Ma, Zhihong Li
Sarcoma is a rare and heterogeneous type of cancer with an early mean onset age and a poor prognosis. However, its genetic basis remains unclear. A series of recent genomic studies in sarcomas have identified the occurrence of mutations in the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene. The ATRX protein belongs to the SWI/SNF family of chromatin remodeling proteins, which are frequently associated with α-thalassemia syndrome. Cancer cells depend on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative programmed mortality...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29722072/htert-promotes-tumor-progression-by-enhancing-tspan13-expression-in-osteosarcoma-cells
#5
Rishi Kumar Jaiswal, Pramod Kumar, Manoj Kumar, Pramod Kumar Yadava
Telomerase complex maintains the length of the telomere and protects erosion of the physical ends of the eukaryotic chromosome in all actively dividing cells including cancer cells. Telomerase activation extends the lifespan of cells in culture by maintaining the length of the telomere. Compared to terminally differentiated somatic cells, telomerase activity remains high in over 90% of cancer cells. It has now become clear that the role of telomerase is much more complex than just telomere lengthening. The remaining 10% of cancers deploy ALT (alternative lengthening of telomeres) pathway to maintain telomere length...
May 2, 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29718321/telomere-sequence-content-can-be-used-to-determine-alt-activity-in-tumours
#6
Michael Lee, Erdahl T Teber, Oliver Holmes, Katia Nones, Ann-Marie Patch, Rebecca A Dagg, Loretta M S Lau, Joyce H Lee, Christine E Napier, Jonathan W Arthur, Sean M Grimmond, Nicholas K Hayward, Peter A Johansson, Graham J Mann, Richard A Scolyer, James S Wilmott, Roger R Reddel, John V Pearson, Nicola Waddell, Hilda A Pickett
The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not...
April 30, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29669917/ribosomal-dna-copy-loss-and-repeat-instability-in-atrx-mutated-cancers
#7
Maheshi Udugama, Elaine Sanij, Hsiao P J Voon, Jinbae Son, Linda Hii, Jeremy D Henson, F Lyn Chan, Fiona T M Chang, Yumei Liu, Richard B Pearson, Paul Kalitsis, Jeffrey R Mann, Philippe Collas, Ross D Hannan, Lee H Wong
ATRX (alpha thalassemia/mental retardation X-linked) complexes with DAXX to deposit histone variant H3.3 into repetitive heterochromatin. Recent genome sequencing studies in cancers have revealed mutations in ATRX and their association with ALT (alternative lengthening of telomeres) activation. Here we report depletion of ATRX in mouse ES cells leads to selective loss in ribosomal RNA gene (rDNA) copy number. Supporting this, ATRX-mutated human ALT-positive tumors also show a substantially lower rDNA copy than ALT-negative tumors...
May 1, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29668072/a-unique-telomere-dna-expansion-phenotype-in-human-retinal-rod-photoreceptors-associated-with-aging-and-disease
#8
W Robert Bell, Alan K Meeker, Anthony Rizzo, Sumit Rajpara, Ian M Rosenthal, Miguel Flores Bellver, Silvia Aparicio Domingo, Xiufeng Zhong, John R Barber, Corinne E Joshu, M Valeria Canto-Soler, Charles G Eberhart, Christopher M Heaphy
We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non-neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non-telomerase-mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra-bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types...
April 18, 2018: Brain Pathology
https://www.readbyqxmd.com/read/29662610/human-cancer-cells-utilize-mitotic-dna-synthesis-to-resist-replication-stress-at-telomeres-regardless-of-their-telomere-maintenance-mechanism
#9
Özgün Özer, Rahul Bhowmick, Ying Liu, Ian D Hickson
Telomeres resemble common fragile sites (CFSs) in that they are difficult-to-replicate and exhibit fragility in mitosis in response to DNA replication stress. At CFSs, this fragility is associated with a delay in the completion of DNA replication until early mitosis, whereupon cells are proposed to switch to a RAD52-dependent form of break-induced replication. Here, we show that this mitotic DNA synthesis (MiDAS) is also a feature of human telomeres. Telomeric MiDAS is not restricted to those telomeres displaying overt fragility, and is a feature of a wide range of cell lines irrespective of whether their telomeres are maintained by telomerase or by the alternative lengthening of telomeres (ALT) mechanism...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29545335/mutant-idh1-cooperates-with-atrx-loss-to-drive-the-alternative-lengthening-of-telomere-alt-phenotype-in-glioma
#10
Joydeep Mukherjee, Tor-Christian Aase Johannessen, Shigeo Ohba, Tracy T Chow, Lindsey E Jones, Ajay Pandita, Russell O Pieper
A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower-grade astrocytomas (LGA) and secondary glioblastoma, we examined an hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis...
March 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29542055/use-of-u-stela-for-accurate-measurement-of-extremely-short-telomeres
#11
Nedime Serakinci, Huseyin Cagsin, Merdiye Mavis
Telomeres are repetitive genetic materials that protect the chromosomes by capping the ends of chromosomes. Each time a cell divides, telomeres get shorter. Telomere length is mainly maintained by telomerase. This enzyme is present in the embryonic stem cells in high concentrations and declines with age. It is still unclear to what extend there is telomerase in adult stem cells, but considering these are the founder cells to the cells of the all tissues in a body, understanding the telomere dynamics and expression of telomerase in adult stem cells is very important...
March 15, 2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29494831/increased-terra-levels-and-rnase-h-sensitivity-are-conserved-hallmarks-of-post-senescent-survivors-in-budding-yeast
#12
Stefano Misino, Diego Bonetti, Sarah Luke-Glaser, Brian Luke
Cancer cells activate telomere maintenance mechanisms (TMMs) to bypass replicative senescence and achieve immortality by either upregulating telomerase or promoting homology-directed repair (HDR) at chromosome ends to maintain telomere length, the latter being referred to as ALT (Alternative Lengthening of Telomeres). In yeast telomerase mutants, the HDR-based repair of telomeres leads to the generation of 'survivors' that escape senescence and divide indefinitely. So far, yeast has proven to provide an accurate model to study the generation and maintenance of telomeres via HDR...
March 2018: Differentiation; Research in Biological Diversity
https://www.readbyqxmd.com/read/29483835/loss-of-p21-promoted-tumorigenesis-in-the-background-of-telomere-dysfunctions-induced-by-trf2-and-wrn-deficiency
#13
Xiaoyu Si, Chihao Shao, Jing Li, Shuting Jia, Wenru Tang, Jihong Zhang, Julun Yang, Xiaoming Wu, Ying Luo
Werner syndrome (WS) is a rare autosomal recessive progeria disease with genetic instability/cancer predisposition, thus a good model in understanding aging related carcinogenesis. Telomere dysfunction induced cellular senescence is essential in the manifestation of the WS phenotype. Our previous data has shown that p21 (encoded by Cdkn1a gene) could induce cellular senescence and suppress cellular growth of ALT (alternative lengthening of telomere) tumors derived from WS, suggested that p21 might play a key role in maintaining senescence of WS cells...
2018: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29463031/telomere-length-maintenance-in-cancer-at-the-crossroad-between-telomerase-and-alternative-lengthening-of-telomeres-alt
#14
REVIEW
Marco De Vitis, Francesco Berardinelli, Antonella Sgura
Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated senescence and/or apoptosis. For this reason, telomere maintenance is an essential step in cancer progression. Most human tumors maintain their telomeres expressing telomerase, whereas a lower but significant proportion activates the alternative lengthening of telomeres (ALT) pathway...
February 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29458755/direct-quantitative-monitoring-of-homology-directed-dna-repair-of-damaged-telomeres
#15
Priyanka Verma, Robert L Dilley, Melina T Gyparaki, Roger A Greenberg
Homology-directed DNA repair (HDR) is an evolutionary conserved mechanism that is required for genome integrity and organismal fitness across species. While a myriad of different factors and mechanisms are able to execute HDR, all forms necessitate common steps of DNA damage recognition, homology search and capture, and assembly of a DNA polymerase complex to conduct templated DNA synthesis. The central question of what determines HDR mechanism utilization in mammalian cells has been limited by an inability to directly monitor the DNA damage response and products of repair as they arise from a defined genomic lesion...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29415479/telomere-length-dynamics-and-the-evolution-of-cancer-genome-architecture
#16
REVIEW
Kez Cleal, Kevin Norris, Duncan Baird
Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci...
February 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29361030/epigenetic-features-of-human-telomeres
#17
María D Cubiles, Sonia Barroso, María I Vaquero-Sedas, Alicia Enguix, Andrés Aguilera, Miguel A Vega-Palas
Although subtelomeric regions in humans are heterochromatic, the epigenetic nature of human telomeres remains controversial. This controversy might have been influenced by the confounding effect of subtelomeric regions and interstitial telomeric sequences (ITSs) on telomeric chromatin structure analyses. In addition, different human cell lines might carry diverse epigenetic marks at telomeres. We have developed a reliable procedure to study the chromatin structure of human telomeres independently of subtelomeres and ITSs...
March 16, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29360938/long-term-persistent-organic-pollutants-exposure-induced-telomere-dysfunction-and-senescence-associated-secretary-phenotype
#18
Jinghua Yuan, Yang Liu, Juan Wang, Yuxia Zhao, Keqiu Li, Yaqing Jing, Xiaoning Zhang, Qiang Liu, Xin Geng, Guang Li, Feng Wang
Environmentally persistent organic pollutant (POPs) is the general term for refractory organic compounds that show long-range atmospheric transport, environmental persistence, and bioaccumulation. It has been reported that the accumulation of POPs could lead to cellular DNA damage and adverse effects of on metabolic health. To better understand the mechanism of the health risks associated with POPs, we conducted an evidence based cohort investigation (n=5955) at the Jinghai e-waste disposal center in China from 2009-2016, where people endure serious POPs exposure...
January 19, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/29351238/telomeres-implications-for-cancer-development
#19
REVIEW
Aina Bernal, Laura Tusell
Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR). This is most likely achieved by a lariat structure that hides the linear telomeric DNA through protein-protein and protein-DNA interactions. The telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in unmasked telomeres. Then, the subsequent activation of the DDR will define the fate of cells according to the functionality of cell cycle checkpoints...
January 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29321523/integrative-genomic-and-transcriptomic-analysis-of-leiomyosarcoma
#20
Priya Chudasama, Sadaf S Mughal, Mathijs A Sanders, Daniel Hübschmann, Inn Chung, Katharina I Deeg, Siao-Han Wong, Sophie Rabe, Mario Hlevnjak, Marc Zapatka, Aurélie Ernst, Kortine Kleinheinz, Matthias Schlesner, Lina Sieverling, Barbara Klink, Evelin Schröck, Remco M Hoogenboezem, Bernd Kasper, Christoph E Heilig, Gerlinde Egerer, Stephan Wolf, Christof von Kalle, Roland Eils, Albrecht Stenzinger, Wilko Weichert, Hanno Glimm, Stefan Gröschel, Hans-Georg Kopp, Georg Omlor, Burkhard Lehner, Sebastian Bauer, Simon Schimmack, Alexis Ulrich, Gunhild Mechtersheimer, Karsten Rippe, Benedikt Brors, Barbara Hutter, Marcus Renner, Peter Hohenberger, Claudia Scholl, Stefan Fröhling
Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism...
January 10, 2018: Nature Communications
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