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Telomere and telomerase

Taxiarchis Konstantinos Nikolouzakis, Loukia Vassilopoulou, Persefoni Fragkiadaki, Theodoros Mariolis Sapsakos, George Papadakis, Demetrios A Spandidos, Aristides M Tsatsakis, John Tsiaoussis
Colorectal cancer (CRC) is among the most common cancers. In fact, it is placed in the third place among the most diagnosed cancer in men, after lung and prostate cancer, and in the second one for the most diagnosed cancer in women, following breast cancer. Moreover, its high mortality rates classifies it among the leading causes of cancer‑related death worldwide. Thus, in order to help clinicians to optimize their practice, it is crucial to introduce more effective tools that will improve not only early diagnosis, but also prediction of the most likely progression of the disease and response to chemotherapy...
March 21, 2018: Oncology Reports
Giovanni E Lombardo, Valentina Maggisano, Marilena Celano, Donato Cosco, Chiara Mignogna, Federica Baldan, Saverio M Lepore, Lorenzo Allegri, Sonia Moretti, Cosimo Durante, Giuseppe Damante, Massimo Fresta, Diego Russo, Stefania Bulotta, Efisio Puxeddu
The high frequency of hTERT-promoting mutations and the increased expression of hTERT mRNA in anaplastic thyroid cancer (ATC) make TERT a suitable molecular target for the treatment of this lethal neoplasm. In this study, we encapsulated an anti-hTERT oligonucleotide in biocompatible nanoparticles and analyzed the effects of this novel pharmaceutical preparation in preclinical models of ATC. Biocompatible nanoparticles were obtained in an acidified aqueous solution containing chitosan, anti-hTERT oligoRNAs and poloxamer 188 as a stabilizer...
March 21, 2018: Molecular Cancer Therapeutics
Gao Zhang, Lawrence W Wu, Ilgen Mender, Michal Barzily-Rokni, Marc R Hammond, Omotayo Ope, Chaoran Cheng, Sergio Randell, Norah Sadek, Aurelie Beroard, Min Xiao, Tian Tian, Jiufeng Tan, Umar Saeed, Eric Sugarman, Clemens Krepler, Patricia A Brafford, Katrin Sproesser, Sengottuvelan Murugan, Rajasekharan Somasundaram, Bradley Garman, Bradley Wubbenhorst, Jonathan Woo, Xiangfan Yin, Qin Liu, Dennie T Frederick, Benchun Miao, Wei Xu, Giorgos C Karakousis, Xiaowei Xu, Lynn M Schuchter, Tara C Mitchell, Lawrence N Kwong, Ravi K Amaravadi, Yiling Lu, Genevieve Boland, Zhi Wei, Katherine L Nathanson, Gordon B Mills, Keith T Flaherty, Jerry W Shay, Meenhard Herlyn, Themistoklis Vasilopoulos, Utz Herbig
PURPOSE: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies and there is an unmet and urgent need to prolong disease control for those patients. EXPERIMENTAL DESIGN: Numerous pre-clinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcriptomics and proteomics approaches were used to identify genes and proteins that were significantly down-regulated by 6-thio-dG...
March 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Neal F Lue
Recent studies have resulted in deeper understanding of a variety of telomere maintenance mechanisms as well as plausible models of telomere evolution. Often overlooked in the discussion of telomere regulation and evolution is the synthesis of the DNA strand that bears the 5'-end (i.e., the C-strand). Herein, I describe a scenario for telomere evolution that more explicitly accounts for the evolution of the C-strand synthesis machinery. In this model, CTC1-STN1-TEN1 (CST), the G-strand-binding complex that regulates primase-Pol α-mediated C-strand synthesis, emerges as a pivotal player and evolutionary link...
March 14, 2018: Trends in Biochemical Sciences
Balal Brazvan, Abbas Ebrahimi-Kalan, Kobra Velaei, Ahmad Mehdipour, Zeynab Aliyari Serej, Ayyub Ebrahimi, Mohammad Ghorbani, Omid Cheraghi, Hojjatollah Nozad Charoudeh
The end of linear chromosomes is formed of a special nucleoprotein heterochromatin structure with repetitive TTAGGG sequences called telomere. Telomere length is regulated by a special enzyme called telomerase, a specific DNA polymerase that adds new telomeric sequences to the chromosome ends. Telomerase consists of two parts; the central protein part and the accessory part which is a RNA component transported by the central part. Regulation of telomere length by this enzyme is a multi-stage process. Telomere length elongation is strongly influenced by the level of telomerase and has a strong correlation with the activity of telomerase enzyme...
March 13, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Hua Zhou, Abdul Mondal, Aleksandra Dakic, Lama Alhawas, Xuefeng Liu, Zhixu He
The roles of protection of telomeres 1 (POT1) in human ovarian cancer have not been fully elucidated. Here, we investigated the impact of POT1 knockdown (POT1-KD) on in vitro cell proliferation, tumorigenesis, and histone deacetylase inhibitor (HDACi) response in human ovarian cancer-derived SK-OV3 cells. The POT1 gene was knocked down by infection with POT1 lenti-shRNA. POT1, c-Myc, and hTERT mRNA levels and relative telomere length were determined by qRT-PCR; POT1 protein levels were determined by western blot...
2018: BioMed Research International
Marco A Moro-García, Juan C Mayo, Rosa M Sainz, Rebeca Alonso-Arias
T lymphocytes, from their first encounter with their specific antigen as naïve cell until the last stages of their differentiation, in a replicative state of senescence, go through a series of phases. In several of these stages, T lymphocytes are subjected to exponential growth in successive encounters with the same antigen. This entire process occurs throughout the life of a human individual and, earlier, in patients with chronic infections/pathologies through inflammatory mediators, first acutely and later in a chronic form...
2018: Frontiers in Immunology
Jinyu Wang, Haitao Zhang, Mohammed Al Shibar, Belinda Willard, Alo Ray, Kurt W Runge
Telomeres, the ends of eukaryotic chromosomes, consist of repetitive DNA sequences and their bound proteins that protect the end from the DNA damage response. Short telomeres with fewer repeats are preferentially elongated by telomerase. Tel1, the yeast homolog of human ATM kinase, is preferentially recruited to short telomeres and Tel1 kinase activity is required for telomere elongation. Rif1, a telomere-binding protein, negatively regulates telomere length by forming a complex with two other telomere binding proteins, Rap1 and Rif2, to block telomerase recruitment...
March 7, 2018: DNA Repair
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
Reinier Snetselaar, Matthijs F M van Oosterhout, Jan C Grutters, Coline H M van Moorsel
The enzyme telomerase reverse transcriptase (TERT) is essential for telomere maintenance. In replicating cells, maintenance of telomere length is important for the preservation of vital genetic information and prevention of genomic instability. A common genetic variant in TERT , rs2736100 C/A, is associated with both telomere length and multiple diseases. Carriage of the C allele is associated with longer telomere length, while carriage of the A allele is associated with shorter telomere length. Furthermore, some diseases have a positive association with the C and some with the A allele...
2018: Frontiers in Medicine
Nabeel Quryshi, Laura E Norwood Toro, Karima Ait-Aissa, Amanda Kong, Andreas M Beyer
Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage (mt DNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects...
March 10, 2018: International Journal of Molecular Sciences
Sylwia Kedziora, Vamsi K Gali, Rosemary H C Wilson, Kate R M Clark, Conrad A Nieduszynski, Shin-Ichiro Hiraga, Anne D Donaldson
The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast Saccharomyces cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore, we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant defective for PP1 interaction causes a long-telomere phenotype, similar to that of rif1Δ cells. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control...
February 26, 2018: Nucleic Acids Research
Ricardo Leão, Joana Dias Apolónio, Donghyun Lee, Arnaldo Figueiredo, Uri Tabori, Pedro Castelo-Branco
BACKGROUND: Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. MAIN BODY: The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability...
March 12, 2018: Journal of Biomedical Science
Saumya R Bollam, Michael E Berens, Harshil D Dhruv
PURPOSE OF REVIEW: High-throughput genomic sequencing has identified alterations in the gene encoding human telomerase reverse transcriptase (TERT) as points of interest for elucidating the oncogenic mechanism of multiple different cancer types, including gliomas. In gliomas, the TERT promoter mutation (TPM) and resultant overexpression of TERT are observed mainly in the most aggressive (primary glioblastoma/grade IV astrocytoma) and the least aggressive (grade II oligodendroglioma) cases...
March 10, 2018: Current Neurology and Neuroscience Reports
Rosa M Porreca, Galina Glousker, Aya Awad, Maria I Matilla Fernandez, Anne Gibaud, Christian Naucke, Scott B Cohen, Tracy M Bryan, Yehuda Tzfati, Irena Draskovic, Arturo Londoño-Vallejo
Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase...
March 7, 2018: Nucleic Acids Research
Quinn A Conklin, Brandon G King, Anthony P Zanesco, Jue Lin, Anahita B Hamidi, Jennifer J Pokorny, María Jesús Álvarez-López, Marta Cosín-Tomás, Colin Huang, Perla Kaliman, Elissa S Epel, Clifford D Saron
A growing body of evidence suggests that meditation training may have a range of salubrious effects, including improved telomere regulation. Telomeres and the enzyme telomerase interact with a variety of molecular components to regulate cell-cycle signaling cascades, and are implicated in pathways linking psychological stress to disease. We investigated the effects of intensive meditation practice on these biomarkers by measuring changes in telomere length (TL), telomerase activity (TA), and telomere-related gene (TRG) expression during a 1-month residential Insight meditation retreat...
March 5, 2018: Brain, Behavior, and Immunity
D D Zhdanov, Yu A Gladilina, M V Pokrovskaya, S S Aleksandrova, D V Grishin, O V Podobed, N N Sokolov
The effect of apoptotic endonuclease EndoG on alternative splicing of mRNA of human telomerase catalytic subunit hTERT (human telomerase reverse transcriptase) and telomerase activity in normal human lymphocytes were studied. Human CD4+ , CD8+ , B, and NK cells were transfected with a plasmid pEndoG-GFP containing EndoG gene or control plasmid pGFP. The levels of mRNA of EndoG or hTERT splicing variants were analyzed by real-time PCR. Protein content was assessed by Western blotting. Telomerase activity was measured by the telomere repeats amplification protocol...
March 5, 2018: Bulletin of Experimental Biology and Medicine
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...
February 16, 2018: Differentiation; Research in Biological Diversity
Elissa S Epel, Aric A Prather
Telomeres play an important part in aging and show relationships to lifetime adversity, particularly childhood adversity. Meta-analyses demonstrate reliable associations between psychopathology (primarily depression) and shorter telomere length, but the nature of this relationship has not been fully understood. Here, we review and evaluate the evidence for impaired telomere biology as a consequence of psychopathology or as a contributing factor, and the important mediating roles of chronic psychological stress and impaired allostasis...
March 1, 2018: Annual Review of Clinical Psychology
Toshio Maekawa, Binbin Liu, Daisuke Nakai, Keisuke Yoshida, Ken-Ichi Nakamura, Mami Yasukawa, Manabu Koike, Kaiyo Takubo, Bruno Chatton, Fuyuki Ishikawa, Kenkichi Masutomi, Shunsuke Ishii
Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-α-induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex...
February 27, 2018: Nucleic Acids Research
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