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alternative lengthening of telomeres

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https://www.readbyqxmd.com/read/28064387/the-role-of-histone-modifications-and-telomere-alterations-in-the-pathogenesis-of-diffuse-gliomas-in-adults-and-children
#1
REVIEW
Julieann Lee, D A Solomon, Tarik Tihan
Genetic profiling is an increasingly useful tool for sub-classification of gliomas in adults and children. Specific gene mutations, structural rearrangements, DNA methylation patterns, and gene expression profiles are now recognized to define molecular subgroups of gliomas that arise in distinct anatomic locations and patient age groups, and also provide a better prediction of clinical outcomes for glioma patients compared to histologic assessment alone. Understanding the role of these distinctive genetic alterations in gliomagenesis is also important for the development of potential targeted therapeutic interventions...
January 7, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28040793/tert-promoter-mutations-but-not-the-alternative-lengthening-of-telomeres-phenotype-are-present-in-a-subset-of-ependymomas-and-are-associated-with-adult-onset-and-progression-to-ependymosarcoma
#2
Fabienne Brügger, Matthias S Dettmer, Maja Neuenschwander, Aurel Perren, Ilaria Marinoni, Ekkehard Hewer
Genetic signatures related to telomere maintenance have emerged as powerful classifiers among CNS tumors. These include the alternative lengthening of telomeres (ALT) phenotype associated with mutations in the ATRX and DAXX genes and recurrent point mutations in the TERT gene promoter. We investigated a patient cohort covering the entire spectrum of childhood and adult ependymomas (n = 128), including subependymomas and myxopapillary ependymomas, for the presence of TERT promoter mutations, for loss of ATRX or DAXX expression by immunohistochemistry (as surrogates as underlying gene mutations), and for the ALT phenotype by fluorescence in situ hybridization (FISH)...
December 31, 2016: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/27943596/the-telomere-lengthening-conundrum-it-could-be-biology
#3
Melissa Bateson, Daniel Nettle
Longitudinal studies of human leucocyte telomere length often report a percentage of individuals whose telomeres appear to lengthen. However, based on theoretical considerations and empirical data, Steenstrup et al. (Nucleic Acids Research, 2013, vol 41(13): e131) concluded that this lengthening is unlikely to be a real biological phenomenon and is more likely to be an artefact of measurement error. We dispute the logic underlying this claim. We argue that Steenstrup et al.'s analysis is incomplete because it failed to compare predictions derived from assuming a scenario with no true telomere lengthening with alternative scenarios in which true lengthening occurs...
December 12, 2016: Aging Cell
https://www.readbyqxmd.com/read/27892716/life-and-cancer-without-telomerase-alt-and-other-strategies-for-making-sure-ends-don-t-meet
#4
Manasi S Apte, Julia Promisel Cooper
While most cancer cells rely on telomerase expression/re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10-15%) employs telomerase-independent strategies, collectively dubbed Alternative Lengthening of Telomeres (ALT). Most ALT cells relax the usual role of telomeres as inhibitors of local homologous recombination while maintaining the ability of telomeres to prohibit local non-homologous end joining reactions. Here we review current concepts surrounding how ALT telomeres achieve this new balance via alterations in chromatin landscape, DNA damage repair processes and handling of telomeric transcription...
November 28, 2016: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27889084/linking-telomere-regulation-to-stem-cell-pluripotency
#5
REVIEW
Lin Liu
Embryonic stem cells (ESCs), somatic cell nuclear transfer ESCs, and induced pluripotent stem cells (iPSCs) represent the most studied group of PSCs. Unlimited self-renewal without incurring chromosomal instability and pluripotency are essential for the potential use of PSCs in regenerative therapy. Telomere length maintenance is critical for the unlimited self-renewal, pluripotency, and chromosomal stability of PSCs. While telomerase has a primary role in telomere maintenance, alternative lengthening of telomere pathways involving recombination and epigenetic modifications are also required for telomere length regulation, notably in mouse PSCs...
January 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/27833022/hdac9-regulates-the-alternative-lengthening-of-telomere-alt-pathway-via-the-formation-of-alt-associated-pml-bodies
#6
Mohd Raeed Jamiruddin, Taku Kaitsuka, Farzana Hakim, Atsushi Fujimura, Fan-Yan Wei, Hisato Saitoh, Kazuhito Tomizawa
Cancer cells overcome cellular senescence by activating the telomere maintenance mechanism, which can be either through telomerase or the alternative lengthening of telomeres (ALT). Being exclusive to cancer cells, targeting ALT is a more promising route for the development of drugs against cancer. The histone deacetylase (HDAC) family plays significant roles in various cellular processes. In addition to the regulation of gene expression, HDACs are also known to directly interact with many proteins. We focused on this family, and found that HDAC9 was up-regulated in ALT-positive cells...
December 2, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27829156/proteomic-profiling-reveals-a-specific-role-for-translesion-dna-polymerase-%C3%AE-in-the-alternative-lengthening-of-telomeres
#7
Laura Garcia-Exposito, Elodie Bournique, Valérie Bergoglio, Arindam Bose, Jonathan Barroso-Gonzalez, Sufang Zhang, Justin L Roncaioli, Marietta Lee, Callen T Wallace, Simon C Watkins, Patricia L Opresko, Jean-Sébastien Hoffmann, Roderick J O'Sullivan
Cancer cells rely on the activation of telomerase or the alternative lengthening of telomeres (ALT) pathways for telomere maintenance and survival. ALT involves homologous recombination (HR)-dependent exchange and/or HR-associated synthesis of telomeric DNA. Utilizing proximity-dependent biotinylation (BioID), we sought to determine the proteome of telomeres in cancer cells that employ these distinct telomere elongation mechanisms. Our analysis reveals that multiple DNA repair networks converge at ALT telomeres...
November 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/27821557/telomeres-reproductive-aging-and-genomic-instability-during-early-development
#8
David L Keefe
Implantation rate decreases and miscarriage rate increases with advancing maternal age. The oocyte must be the locus of reproductive aging because donation of oocytes from younger to older women abrogates the effects of aging on fecundity. Nuclear transfer experiments in a mouse model of reproductive aging show that the reproductive aging phenotype segregates with the nucleus rather than the cytoplasm. A number of factors within the nucleus have been hypothesized to mediate reproductive aging, including disruption of cohesions, reduced chiasma, aneuploidy, disrupted meiotic spindles, and DNA damage caused by chronic exposure to reactive oxygen species...
December 2016: Reproductive Sciences
https://www.readbyqxmd.com/read/27806302/telomere-internal-double-strand-breaks-are-repaired-by-homologous-recombination-and-parp1-lig3-dependent-end-joining
#9
Ylli Doksani, Titia de Lange
Shelterin protects chromosome ends from the DNA damage response. Although the mechanism of telomere protection has been studied extensively, the fate of double-strand breaks (DSBs) inside telomeres is not known. Here, we report that telomere-internal FokI-induced DSBs activate ATM kinase-dependent signaling in S-phase but are well tolerated and repaired efficiently. Homologous recombination contributes to repair, leading to increased telomere length heterogeneity typical of the alternative lengthening of telomeres (ALT) pathway...
November 1, 2016: Cell Reports
https://www.readbyqxmd.com/read/27793809/alternative-lengthening-of-telomeres-requires-a-specialized-replisome
#10
(no author information available yet)
A specialized replisome mediates break-induced telomere synthesis to promote telomere maintenance.
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27793328/telomere-biology-including-tert-rearrangements-in-neuroblastoma-a-useful-indicator-for-surgical-treatments
#11
Masumi Kawashima, Masato Kojima, Yuka Ueda, Sho Kurihara, Eiso Hiyama
PURPOSE: Our telomere biology study of neuroblastomas (NBLs) has revealed that unfavorable NBLs acquired telomere stabilization by telomerase activation or ALT (alternative lengthening of telomeres). Recently, genomic rearrangements in a region proximal to the telomerase reverse transcriptase (TERT) gene have been discovered in NBLs. In this study, TERT rearrangements were examined in NBLs along with their relationship to other aspects of telomere biology. METHODS: In 121 NBLs, including 67 cases detected by mass-screening whose telomere length, telomerase activity, ALT with ATRX/DAXX alterations, and MYCN amplification were already known, TERT rearrangements were examined using GeneChip SNP arrays...
December 2016: Journal of Pediatric Surgery
https://www.readbyqxmd.com/read/27768860/means-to-the-ends-the-role-of-telomeres-and-telomere-processing-machinery-in-metastasis
#12
REVIEW
Nathaniel J Robinson, William P Schiemann
Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origin to distant secondary sites. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27760777/alternative-lengthening-of-human-telomeres-is-a-conservative-dna-replication-process-with-features-of-break-induced-replication
#13
Fani-Marlen Roumelioti, Sotirios K Sotiriou, Vasiliki Katsini, Maria Chiourea, Thanos D Halazonetis, Sarantis Gagos
Human malignancies overcome replicative senescence either by activating the reverse-transcriptase telomerase or by utilizing a homologous recombination-based mechanism, referred to as alternative lengthening of telomeres (ALT). In budding yeast, ALT exhibits features of break-induced replication (BIR), a repair pathway for one-ended DNA double-strand breaks (DSBs) that requires the non-essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase-negative cancer cells...
December 2016: EMBO Reports
https://www.readbyqxmd.com/read/27760120/break-induced-telomere-synthesis-underlies-alternative-telomere-maintenance
#14
Robert L Dilley, Priyanka Verma, Nam Woo Cho, Harrison D Winters, Anne R Wondisford, Roger A Greenberg
Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10-15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance...
November 3, 2016: Nature
https://www.readbyqxmd.com/read/27726944/effect-of-silencing-key-proteins-in-telomerase-mechanism-and-alternative-lengthening-of-telomeres-mechanism-in-laryngeal-cancer-cells
#15
Yong Xu, Xiao Wang, Shi-Ming Chen, Chen Chen, Yan Wang, Bo-Kui Xiao, Ze-Zhang Tao
PURPOSE: To explore the influences of telomerase and alternative lengthening of telomeres mechanism on telomere length and laryngeal squamous cell carcinoma in vitro and in vivo. MATERIALS AND METHODS: Short hairpin RNA expression vectors targeting the messenger TERT, TRF2, RAD51 and NBS1 were constructed. The mRNA and protein expression of targeted genes in human laryngeal squamous carcinoma cell line HEp-2 was evaluated by reverse transcription polymerase chain reaction and Western blotting separately...
November 2016: American Journal of Otolaryngology
https://www.readbyqxmd.com/read/27718012/in-japanese-patients-with-papillary-thyroid-carcinoma-tert-promoter-mutation-is-associated-with-poor-prognosis-in-contrast-to-braf-v600e-mutation
#16
Almira Nasirden, Tsuyoshi Saito, Yuki Fukumura, Kieko Hara, Keisuke Akaike, Aiko Kurisaki-Arakawa, Miki Asahina, Atsushi Yamashita, Ran Tomomasa, Takuo Hayashi, Atsushi Arakawa, Takashi Yao
The prognostic value of BRAF (V600E) and TERT promoter mutation in papillary thyroid carcinoma (PTC) is controversial. We examined alterations in BRAF (V600E) and TERT promoter by PCR-direct sequencing in PTC of 144 Japanese patients. Alternative lengthening of telomeres was examined as another mechanism of telomere maintenance by immunohistochemical staining for ATRX and DAXX. Of the clinicopathological characteristics, regional lymph node metastasis, extra-thyroid extension, multifocality/intrathyroidal spread, and advanced stage (III/V) were associated with shorter disease-free survival rate (DFSR)...
December 2016: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/27663587/alternative-lengthening-of-telomeres-in-primary-pancreatic-neuroendocrine-neoplasms-is-associated-with-aggressive-clinical-behavior-and-poor-survival
#17
Joo Young Kim, Jacqueline A Brosnan-Cashman, Soyeon An, Sung Joo Kim, Ki Byung Song, Min-Sun Kim, Mi-Ju Kim, Dae Wook Hwang, Alan K Meeker, Eunsil Yu, Song Cheol Kim, Ralph H Hruban, Christopher M Heaphy, Seung-Mo Hong
PURPOSE: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNETs). EXPERIMENTAL DESIGN: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. RESULTS: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20...
September 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27604461/dna-methylation-mediated-up-regulation-of-terra-non-coding-rna-is-coincident-with-elongated-telomeres-in-the-human-placenta
#18
Boris Novakovic, Christine E Napier, Regan Vryer, Eva Dimitriadis, Ursula Manuelpillai, Andrew Sharkey, Jeffrey M Craig, Roger R Reddel, Richard Saffery
STUDY QUESTION: What factors regulate elongated telomere length in the human placenta? SUMMARY ANSWER: Hypomethylation of TERRA promoters in the human placenta is associated with high expression TERRA genes, however, no clear mechanistic link between these phenomena and elongated telomere length in the human placenta was found. WHAT IS KNOWN ALREADY: Human placenta tissue and trophoblasts show longer telomere lengths compared to gestational age-matched somatic cells...
September 7, 2016: Molecular Human Reproduction
https://www.readbyqxmd.com/read/27602331/cancer-cells-with-alternative-lengthening-of-telomeres-do-not-display-a-general-hypersensitivity-to-atr-inhibition
#19
Katharina I Deeg, Inn Chung, Caroline Bauer, Karsten Rippe
Telomere maintenance is a hallmark of cancer as it provides cancer cells with cellular immortality. A significant fraction of tumors uses the alternative lengthening of telomeres (ALT) pathway to elongate their telomeres and to gain an unlimited proliferation potential. Since the ALT pathway is unique to cancer cells, it represents a potentially valuable, currently unexploited target for anti-cancer therapies. Recently, it was proposed that ALT renders cells hypersensitive to ataxia telangiectasia- and RAD3-related (ATR) protein inhibitors (Flynn et al...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27595911/the-c-circle-assay-for-alternative-lengthening-of-telomeres-activity
#20
Jeremy D Henson, Loretta M Lau, Sylvia Koch, Nancy Martin La Rotta, Rebecca A Dagg, Roger R Reddel
The C-Circle Assay has satisfied the need for a rapid, robust and quantitative ALT assay that responds quickly to changes in ALT activity. The C-Circle Assay involves (i) extraction or simple preparation (Quick C-Circle Preparation) of the cell's DNA, which includes C-Circles (ii) amplification of the self-primed C-Circles with a rolling circle amplification reaction and (iii) sequence specific detection of the amplification products by native telomeric DNA dot blot or telomeric qPCR. Here we detail the protocols and considerations required to perform the C-Circle Assay and its controls, which include exonuclease removal of linear telomeric DNA, production of the synthetic C-Circle C96 and modulation of ALT activity by γ-irradiation...
September 2, 2016: Methods: a Companion to Methods in Enzymology
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