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alternative lengthening of telomeres

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...
September 6, 2016: American Journal of Otolaryngology
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)...
October 7, 2016: Virchows Archiv: An International Journal of Pathology
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
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
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
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
Theresa Kreilmeier, Sandra Sampl, Abigail J Deloria, Ingrid Walter, Martin Reifinger, Marlene Hauck, Luke B Borst, Klaus Holzmann, Miriam Kleiter
Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism (TMM) found in some human tumors such as sarcomas. Canine tumors are not characterized for ALT and the study aim was to identify if the ALT phenotype exists in canine sarcomas. Sixty-four canine sarcoma samples (20 snap-frozen, 44 FFPE) as well as six canine sarcoma cell lines were screened for ALT by C-circle assay. ALT was further evaluated by measuring telomere length via qPCR and telomere restriction-fragments including pulsed-field electrophoresis...
September 1, 2016: Molecular Carcinogenesis
Brooke R Druliner, Xiaoyang Ruan, Ruth Johnson, Diane Grill, Daniel O'Brien, Tsung-Po Lai, Shahrooz Rashtak, Donna Felmlee-Devine, Jill Washechek-Aletto, Andrei Malykh, Thomas Smyrk, Ann Oberg, Hongfang Liu, Jerry W Shay, David A Ahlquist, Lisa A Boardman
OBJECTIVE: Whereas few adenomas become cancer, most colorectal cancers arise from adenomas. Telomere length is a recognized biomarker in multiple cancers, and telomere maintenance mechanisms (TMM) are exploited by malignant cells. We sought to determine whether telomere length and TMM distinguish cancer-associated adenomas from those that are cancer-free. METHODS: Tissues were identified as cancer-adjacent polyp (CAP)-residual adenoma contiguous with cancer-and cancer-free polyp (CFP)-adenomas without malignancy...
2016: Clinical and Translational Gastroenterology
Beomseok Seo, Junho Lee
Telomere is a ribonucleoprotein structure that protects chromosomal ends from aberrant fusion and degradation. Telomere length is maintained by telomerase or an alternative pathway, known as alternative lengthening of telomeres (ALT)(1). Recently, C. elegans has emerged as a multicellular model organism for the study of telomere and ALT(2). Visualization of repetitive sequences in the genome is critical in understanding the biology of telomeres. While telomere length can be measured by telomere restriction fragment assay or quantitative PCR, these methods only provide the averaged telomere length...
2016: Journal of Visualized Experiments: JoVE
Yang Hu, Guang Shi, Laichen Zhang, Feng Li, Yuanling Jiang, Shuai Jiang, Wenbin Ma, Yong Zhao, Zhou Songyang, Junjiu Huang
Activation of telomerase or alternative lengthening of telomeres (ALT) is necessary for tumours to escape from dysfunctional telomere-mediated senescence. Anti-telomerase drugs might be effective in suppressing tumour growth in approximately 85-90% of telomerase-positive cancer cells. However, there are still chances for these cells to bypass drug treatment after switching to the ALT mechanism to maintain their telomere integrity. But the mechanism underlying this switch is unknown. In this study, we used telomerase-positive cancer cells (HTC75) to discover the mechanism of the telomerase-ALT switch by inducing telomere-specific DNA damage, alpha-thalassemia X-linked syndrome protein (ATRX) knockdown and deletion of death associated protein (DAXX)...
2016: Scientific Reports
M Cives, M Ghayouri, B Morse, M Brelsford, M Black, A Rizzo, A Meeker, J Strosberg
The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor...
September 2016: Endocrine-related Cancer
Theresa Kreilmeier, Doris Mejri, Marlene Hauck, Miriam Kleiter, Klaus Holzmann
Long non-coding transcripts from telomeres, called telomeric repeat-containing RNA (TERRA), were identified as blocking telomerase activity (TA), a telomere maintenance mechanism (TMM), in tumors. We expressed recombinant TERRA transcripts in tumor cell lines with TA and with alternative lengthening of telomeres (ALT) to study effects on TMM and cell growth. Adeno- and lentivirus constructs (AV and LV) were established for transient and stable expression of approximately 130 units of telomere hexanucleotide repeats under control of cytomegalovirus (CMV) and human RNase P RNA H1 (hH1) promoters with and without polyadenylation, respectively...
2016: Genes
Nam Woo Cho, Michael A Lampson, Roger A Greenberg
Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) requires mobilization of chromatin for homology searches that allow interaction of the sequence to be repaired and its template DNA. Here we describe a system to rapidly induce DSBs at telomeres and track their movement, as well as a semi-automated workflow for quantitative analysis. We have successfully used this approach to show that DSBs targeted to telomeres in cells utilizing the alternative lengthening of telomeres (ALT) mechanism increase their diffusion and subsequent long-range directional movement to merge with telomeres on other chromosomes...
August 1, 2016: Methods: a Companion to Methods in Enzymology
Heather Root, Andrew Larsen, Martin Komosa, Fakhriya Al'Azri, Ren Li, David P Bazett-Jones, M Stephen Meyn
Fanconi Anemia and Bloom syndrome are genomic instability syndromes caused by mutations in proteins that participate in overlapping DNA repair and replication pathways. Here, we show that the monoubiquitinated form of the Fanconi Anemia protein FANCD2 acts in opposition to the BLM DNA helicase to restrain telomere replication and recombination in human cells that utilize the Alternative Lengthening of Telomeres (ALT) pathway. ALT relies on exchanges of telomeric DNA to maintain telomeres, a process that we show FANCD2 suppresses...
July 17, 2016: Human Molecular Genetics
João Vinagre, Joana Nabais, Jorge Pinheiro, Rui Batista, Rui Caetano Oliveira, António Pedro Gonçalves, Ana Pestana, Marta Reis, Bárbara Mesquita, Vasco Pinto, Joana Lyra, Maria Augusta Cipriano, Miguel Godinho Ferreira, José Manuel Lopes, Manuel Sobrinho-Simões, Paula Soares
One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT...
2016: Scientific Reports
Aatur D Singhi, Ta-Chiang Liu, Justin L Roncaioli, Dengfeng Cao, Herbert J Zeh, Amer H Zureikat, Allan Tsung, J Wallis Marsh, Kenneth K Lee, Melissa E Hogg, Nathan Bahary, Randall Brand, Kevin M McGrath, Adam Slivka, Kristi L Cressman, Kimberly Fuhrer, Roderick J O'Sullivan
PURPOSE: Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs...
July 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Carol W Greider
Telomere length is regulated around an equilibrium set point. Telomeres shorten during replication and are lengthened by telomerase. Disruption of the length equilibrium leads to disease; thus, it is important to understand the mechanisms that regulate length at the molecular level. The prevailing protein-counting model for regulating telomerase access to elongate the telomere does not explain accumulating evidence of a role of DNA replication in telomere length regulation. Here I present an alternative model: the replication fork model that can explain how passage of a replication fork and regulation of origin firing affect telomere length...
July 1, 2016: Genes & Development
Wenzel M Hackeng, Lodewijk A A Brosens, Katherine E Poruk, Michaël Noë, Waki Hosoda, Justin S Poling, Anthony Rizzo, Martha Campbell-Thompson, Mark A Atkinson, Björn Konukiewitz, Günter Klöppel, Christopher M Heaphy, Alan K Meeker, Laura D Wood
Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins...
October 2016: Human Pathology
Mohammad A Jafri, Shakeel A Ansari, Mohammed H Alqahtani, Jerry W Shay
Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control...
2016: Genome Medicine
Carl Koschmann, Pedro R Lowenstein, Maria G Castro
Alpha thalassemia/mental retardation syndrome X-linked (ATRX) is mutated in nearly a third of pediatric glioblastoma (GBM) patients. We developed an animal model of ATRX-deficient GBM. Using this model combined with analysis of multiple human glioma genome-wide datasets, we determined that ATRX mutation leads to genetic instability, impaired non-homologous end joining, and alternate lengthening of telomeres (ALT).
May 2016: Molecular & Cellular Oncology
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