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alternative lengthening of telomeres

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https://www.readbyqxmd.com/read/29113290/telomere-dna-damage-signaling-regulates-cancer-stem-cell-evolution-epithelial-mesenchymal-transition-and-metastasis
#1
Angelica M Lagunas, Jianchun Wu, David L Crowe
Chromosome ends are protected by telomeres that prevent DNA damage response and degradation. When telomeres become critically short, the DNA damage response is activated at chromosome ends which induces cellular senescence or apoptosis. Telomeres are protected by the double stranded DNA binding protein TRF2 and maintained by telomerase or a recombination based mechanism known as alternative lengthening of telomeres (ALT). Telomerase is expressed in the basal layer of the epidermis, and stem cells in epidermis have longer telomeres than proliferating populations...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29106411/extrachromosomal-telomere-repeat-dna-is-linked-to-alt-development-via-cgas-sting-dna-sensing-pathway
#2
Yi-An Chen, Yi-Ling Shen, Hsuan-Yu Hsia, Yee-Peng Tiang, Tzu-Ling Sung, Liuh-Yow Chen
Extrachromosomal telomere repeat (ECTR) DNA is unique to cancer cells that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, but the role of ECTRs in ALT development remains elusive. We found that induction of ECTRs in normal human fibroblasts activated the cGAS-STING-TBK1-IRF3 signaling axis to trigger IFNβ production and a type I interferon response, resulting in cell-proliferation defects. In contrast, ALT cancer cells are commonly defective in sensing cytosolic DNA. We found that STING expression was inhibited in ALT cancer cell lines and transformed ALT cells...
November 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29093807/biological-and-clinical-implications-of-telomere-dysfunction-in-myeloid-malignancies
#3
REVIEW
Ashwin Kishtagari, Justin Watts
Telomeres at the ends of linear chromosomes protect the genome. Telomeres shorten with each round of cell division, placing a finite limit on cell growth. Telomere attrition is associated with cell senescence and apoptosis. Telomerase, a specialized ribonucleoprotein complex, maintains telomeres homeostasis through repeat addition of telomere sequences to the 3' telomeric overhang. Telomere biology is closely related to cancer and normal aging. Upregulation of telomerase or activation of the alternative pathway of telomere lengthening is a hallmark of cancer cells, making telomerase an attractive target for cancer therapeutics...
November 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28969871/alternative-lengthening-of-telomeres-dna-repair-pathways-converge
#4
REVIEW
Alexander P Sobinoff, Hilda A Pickett
Telomeres shorten during each cellular division, with cumulative attrition resulting in telomeric damage and replicative senescence. Bypass of replicative senescence precipitates catastrophic telomere shortening or crisis, and is characterized by widespread genomic instability. Activation of a telomere maintenance mechanism (TMM) is necessary to stabilise the genome and establish cellular immortality through the reconstitution of telomere capping function. The alternative lengthening of telomeres (ALT) pathway is a TMM frequently activated in tumors of mesenchymal or neuroepithelial origin...
September 29, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28877996/blm-and-slx4-play-opposing-roles-in-recombination-dependent-replication-at-human-telomeres
#5
Alexander P Sobinoff, Joshua Am Allen, Axel A Neumann, Sile F Yang, Monica E Walsh, Jeremy D Henson, Roger R Reddel, Hilda A Pickett
Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM-TOP3A-RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3-dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA...
October 2, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28796347/clinicopathological-analysis-of-atrx-daxx-and-notch-receptor-expression-in-angiosarcomas
#6
Gauri Panse, John Sa Chrisinger, Cheuk H Leung, Davis R Ingram, Samia Khan, Khalida Wani, Heather Lin, Alexander J Lazar, Wei-Lien Wang
AIMS: Multiple genetic alterations, including alternative lengthening of telomeres (ALT) and NOTCH mutations, have been described in angiosarcoma. Loss of α-thalassaemia/mental retardation syndrome X-linked (ATRX) and death domain-associated protein 6 (DAXX) expression is frequently associated with the ALT phenotype. Additionally, inhibition of NOTCH signalling induces the development of malignant vascular tumours in mice, indicating a tumour suppressive role of the NOTCH pathway in the pathogenesis of angiosarcoma...
August 10, 2017: Histopathology
https://www.readbyqxmd.com/read/28760773/alternative-lengthening-of-telomeres-mediated-by-mitotic-dna-synthesis-engages-break-induced-replication-processes
#7
Jaewon Min, Woodring E Wright, Jerry W Shay
Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in Saccharomyces cerevisiae Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers...
October 15, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28755323/detection-of-the-alternative-lengthening-of-telomeres-pathway-in-malignant-gliomas-for-improved-molecular-diagnosis
#8
Anne Fogli, Marie-Véronique Demattei, Laetitia Corset, Catherine Vaurs-Barrière, Emmanuel Chautard, Julian Biau, Jean-Louis Kémény, Catherine Godfraind, Bruno Pereira, Toufik Khalil, Nathalie Grandin, Philippe Arnaud, Michel Charbonneau, Pierre Verrelle
Human malignant gliomas exhibit acquisition of either one of two telomere maintenance mechanisms, resulting from either reactivation of telomerase expression or activation of an alternative lengthening of telomeres (ALT) mechanism. In the present study, we analyzed 63 human malignant gliomas for the presence of ALT-specific extrachromosomal circles of telomeric DNA (C-circles) and measured telomerase expression, telomeric DNA content (Telo/Alu method), and telomeric repeat-containing RNAs (TERRA) levels. We also assessed histomolecular markers routinely used in clinical practice...
November 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28716051/mir-380-5p-mediated-repression-of-tep1-and-tspyl5-interferes-with-telomerase-activity-and-favours-the-emergence-of-an-alt-like-phenotype-in-diffuse-malignant-peritoneal-mesothelioma-cells
#9
Graziella Cimino-Reale, Paolo Gandellini, Francesca Santambrogio, Marta Recagni, Nadia Zaffaroni, Marco Folini
BACKGROUND: Understanding the molecular/cellular underpinnings of diffuse malignant peritoneal mesothelioma (DMPM), a fatal malignancy with limited therapeutic options, is of utmost importance for the fruitful management of the disease. In this context, we previously found that telomerase activity (TA), which accounts for the limitless proliferative potential of cancer cells, is prognostic for disease relapse and cancer-related death in DMPM patients. Consequently, the identification of factors involved in telomerase activation/regulation may pave the way towards the development of novel therapeutic interventions for the disease...
July 17, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28673972/fancm-brca1-and-blm-cooperatively-resolve-the-replication-stress-at-the-alt-telomeres
#10
Xiaolei Pan, William C Drosopoulos, Louisa Sethi, Advaitha Madireddy, Carl L Schildkraut, Dong Zhang
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...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28652867/scattered-genomic-amplification-in-dedifferentiated-liposarcoma
#11
Nils Mandahl, Linda Magnusson, Jenny Nilsson, Björn Viklund, Elsa Arbajian, Fredrik Vult von Steyern, Anders Isaksson, Fredrik Mertens
BACKGROUND: Atypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes...
2017: Molecular Cytogenetics
https://www.readbyqxmd.com/read/28636942/extensive-proliferation-of-human-cancer-cells-with-ever-shorter-telomeres
#12
Rebecca A Dagg, Hilda A Pickett, Axel A Neumann, Christine E Napier, Jeremy D Henson, Erdahl T Teber, Jonathan W Arthur, C Patrick Reynolds, Jayne Murray, Michelle Haber, Alexander P Sobinoff, Loretta M S Lau, Roger R Reddel
Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28597868/loss-of-progesterone-receptor-expression-is-an-early-tumorigenesis-event-associated-with-tumor-progression-and-shorter-survival-in-pancreatic-neuroendocrine-tumor-patients
#13
Sung Joo Kim, Soyeon An, Jae Hoon Lee, Joo Young Kim, Ki-Byung Song, Dae Wook Hwang, Song Cheol Kim, Eunsil Yu, Seung-Mo Hong
BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic neoplasms and there is no well-elucidated biomarker to stratify their detection and prognosis. Previous studies have reported that progesterone receptor (PR) expression status was associated with poorer survival in PanNET patients. METHODS: To validate previous studies, PR protein expression was assessed in 21 neuroendocrine microadenomas and 277 PanNETs and compared with clinicopathologic factors including patient survival...
July 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28521363/a-cisplatin-derivative-tetra-pt-bpy-as-an-oncotherapeutic-agent-for-targeting-alt-cancer
#14
Xiao-Hui Zheng, Xin Nie, Yiming Fang, Zepeng Zhang, Yingnan Xiao, Zongwan Mao, Haiying Liu, Jian Ren, Feng Wang, Lixin Xia, Junjiu Huang, Yong Zhao
Background: In approximately 15% of human cancers, telomere length is maintained independently of telomerase by the homologous recombination (HR)-mediated alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for therapeutic treatment remains unknown. The purpose of this study is to develop oncotherapeutic agent to target ALT cancers. Methods: Surface plasmon resonance assay, antibody to G-quadruplex, and fluorescence in situ hybridization (FISH) were used to discover Tetra-Pt(bpy), a cisplatin derivative that specifically targets telomeric G-quadruplex...
October 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28513547/epigenetic-regulation-of-telomere-maintenance-for-therapeutic-interventions-in-gliomas
#15
REVIEW
Elisabeth Naderlinger, Klaus Holzmann
High-grade astrocytoma of WHO grade 4 termed glioblastoma multiforme (GBM) is a common human brain tumor with poor patient outcome. Astrocytoma demonstrates two known telomere maintenance mechanisms (TMMs) based on telomerase activity (TA) and on alternative lengthening of telomeres (ALT). ALT is associated with lower tumor grades and better outcome. In contrast to ALT, regulation of TA in tumors by direct mutation and epigenetic activation of the hTERT promoter is well established. Here, we summarize the genetic background of TMMs in non-malignant cells and in cancer, in addition to clinical and pathological features of gliomas...
May 17, 2017: Genes
https://www.readbyqxmd.com/read/28500256/tzap-ing-telomeres-down-to-size
#16
Laura Garcia-Exposito, Roderick J O'Sullivan
The phenomenon of gradual telomere shortening has become a paradigm for how we understand the biology of aging and cancer. Cell proliferation is accompanied by cumulative telomere loss, and the aged cell either senesces, dies or transforms toward cancer. This transformation requires the activation of telomere elongation mechanisms in order to restore telomere length such that cell death or senescence programs are not induced. Most of the time, this occurs through telomerase reactivation. In other rare cases, the Alternative lengthening of telomeres (ALT) pathway hijacks DNA recombination-associated mechanisms to hyperextend telomeres, often to more than 50 kb...
June 2017: EMBO Reports
https://www.readbyqxmd.com/read/28487353/the-chromatin-remodelling-factor-atrx-suppresses-r-loops-in-transcribed-telomeric-repeats
#17
Diu Tt Nguyen, Hsiao Phin J Voon, Barbara Xella, Caroline Scott, David Clynes, Christian Babbs, Helena Ayyub, Jon Kerry, Jacqueline A Sharpe, Jackie A Sloane-Stanley, Sue Butler, Chris A Fisher, Nicki E Gray, Thomas Jenuwein, Douglas R Higgs, Richard J Gibbons
ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n ATRX mutations are found in nearly all tumours that maintain their telomeres via the alternative lengthening of telomere (ALT) pathway, and ATRX is known to suppress this pathway. Here, we show that recruitment of ATRX to telomeric repeats depends on repeat number, orientation and, critically, on repeat transcription. Importantly, the transcribed telomeric repeats form RNA-DNA hybrids (R-loops) whose abundance correlates with the recruitment of ATRX Here, we show loss of ATRX is also associated with increased R-loop formation...
June 2017: EMBO Reports
https://www.readbyqxmd.com/read/28468887/stabilization-of-telomere-g-quadruplexes-interferes-with-human-herpesvirus-6a-chromosomal-integration
#18
Shella Gilbert-Girard, Annie Gravel, Sara Artusi, Sara N Richter, Nina Wallaschek, Benedikt B Kaufer, Louis Flamand
Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance...
July 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28467829/whole-genome-landscapes-of-major-melanoma-subtypes
#19
Nicholas K Hayward, James S Wilmott, Nicola Waddell, Peter A Johansson, Matthew A Field, Katia Nones, Ann-Marie Patch, Hojabr Kakavand, Ludmil B Alexandrov, Hazel Burke, Valerie Jakrot, Stephen Kazakoff, Oliver Holmes, Conrad Leonard, Radhakrishnan Sabarinathan, Loris Mularoni, Scott Wood, Qinying Xu, Nick Waddell, Varsha Tembe, Gulietta M Pupo, Ricardo De Paoli-Iseppi, Ricardo E Vilain, Ping Shang, Loretta M S Lau, Rebecca A Dagg, Sarah-Jane Schramm, Antonia Pritchard, Ken Dutton-Regester, Felicity Newell, Anna Fitzgerald, Catherine A Shang, Sean M Grimmond, Hilda A Pickett, Jean Y Yang, Jonathan R Stretch, Andreas Behren, Richard F Kefford, Peter Hersey, Georgina V Long, Jonathan Cebon, Mark Shackleton, Andrew J Spillane, Robyn P M Saw, Núria López-Bigas, John V Pearson, John F Thompson, Richard A Scolyer, Graham J Mann
Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28452859/tert-mediated-and-atrx-mediated-telomere-maintenance-and-neuroblastoma
#20
Xiao-Feng Duan, Qiang Zhao
Neuroblastomas (NB) are one of the most common extracranial solid tumors in children, and they frequently display high heterogeneity in the disease course. With ongoing research, more information regarding the genetic etiology and molecular mechanisms underlying these contrasting phenotypes is being uncovered. The proto-oncogene MYCN is amplified in approximately 20% of NB cases and is considered a indicator of poor prognosis and an indicator of high-risk NB. The poor prognosis of high risk NB is incompletely explained by MYCN amplification...
April 27, 2017: Journal of Pediatric Hematology/oncology
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