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Telomere and telomerase

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https://www.readbyqxmd.com/read/27932351/telomerase-reverse-transcriptase-deficiency-prevents-neointima-formation-through-chromatin-silencing-of-e2f1-target-genes
#1
Elizabeth B Endorf, Hua Qing, Jun Aono, Naoto Terami, Geneviève Doyon, Eric Hyzny, Karrie L Jones, Hannes M Findeisen, Dennis Bruemmer
OBJECTIVE: Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation...
December 8, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27930670/ku-binding-on-telomeres-occurs-at-sites-distal-from-the-physical-chromosome-ends
#2
Mélanie V Larcher, Emeline Pasquier, R Stephen MacDonald, Raymund J Wellinger
The Ku complex binds non-specifically to DNA breaks and ensures repair via NHEJ. However, Ku is also known to bind directly to telomeric DNA ends and its presence there is associated with telomere capping, but avoiding NHEJ. How the complex discriminates between a DNA break and a telomeric extremity remains unknown. Our results using a tagged Ku complex, or a chromosome end capturing method, in budding yeast show that yKu association with telomeres can occur at sites distant from the physical end, on sub-telomeric elements, as well as on interstitial telomeric repeats...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27927215/functional-characterisation-of-long-intergenic-non-coding-rnas-through-genetic-interaction-profiling-in-saccharomyces-cerevisiae
#3
Dimitris Kyriakou, Emmanouil Stavrou, Panayiota Demosthenous, Georgia Angelidou, Bryan-Joseph San Luis, Charles Boone, Vasilis J Promponas, Antonis Kirmizis
BACKGROUND: Transcriptome studies have revealed that many eukaryotic genomes are pervasively transcribed producing numerous long non-coding RNAs (lncRNAs). However, only a few lncRNAs have been ascribed a cellular role thus far, with most regulating the expression of adjacent genes. Even less lncRNAs have been annotated as essential hence implying that the majority may be functionally redundant. Therefore, the function of lncRNAs could be illuminated through systematic analysis of their synthetic genetic interactions (GIs)...
December 7, 2016: BMC Biology
https://www.readbyqxmd.com/read/27925632/sepsis-induces-telomere-shortening-a-potential-mechanism-responsible-for-delayed-pathophysiological-events-in-sepsis-survivors
#4
Naara Mendes Oliveira, Ester C S Rios, Thais Martins de Lima, Vanessa Jacob Victorino, Hermes Barbeiro, Fabiano Pinheiro da Silva, Csaba Szabo, Francisco Garcia Soriano
Sepsis survivors suffer from additional morbidities, including higher disk of readmissions, nervous system disturbances and cognitive dysfunction, and increased mortality, even several years after the initial episode of sepsis. In many ways, the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging. Since telomere shortening is a hallmark of aging, we investigated whether sepsis also leads to telomere shortening. Male balb/c mice were divided into two groups: the control group received 100 μl of normal saline intraperitoneally; the sepsis group received 15 mg/kg of bacterial lipopolysaccharide i...
December 5, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27922187/tomentosin-induces-telomere-shortening-and-caspase-dependant-apoptosis-in-cervical-cancer-cells
#5
Nawel Merghoub, Hassan El Btaouri, Laila Benbacer, Saïd Gmouh, Chantal Trentesaux, Bertrand Brassart, Mohammed Attaleb, Claudie Madoulet, Thomas Wenner, Saaid Amzazi, Hamid Morjani, Mohamed El Mzibri
Tomentosin, a natural sesquiterpene lactone purified from of Inula viscosa L., was investigated for its anti-proliferative, telomere shortening and apoptotic effects on human cervical cancer HeLa and SiHa cell lines. Tomentosin was found to inhibit the growth of SiHa and HeLa cell lines in dose and time-dependent manner (IC50 values of 7.10 ± 0.78µM and 5.87 ± 0.36µM, respectively after 96h of treatment). As evidenced by TTAGGG telomere length assay, tomentosin target specifically the telomeric overhang lengthening...
December 6, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27918544/a-balance-between-elongation-and-trimming-regulates-telomere-stability-in-stem-cells
#6
Teresa Rivera, Candy Haggblom, Sandro Cosconati, Jan Karlseder
Telomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbs1, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively...
December 5, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27904002/diffuse-mesangial-sclerosis-in-a-child-with-dyskeratosis-congenita-leading-to-end-stage-renal-disease
#7
Abidi Kamel, Taha Sayari, Manel Jellouli, Yousra Hammi, Rim Ghoucha Louzir, Tahar Gargah
Dyskeratosis congenita (DC) is a very rare inherited disorder. It is caused by dysfunction of telomere maintenance. It involves RNA telomerase components relevant to various mutations leading to a classic triad of physical findings consisting of nail dystrophy of the hands and feet, mucosal leukoplakia, and reticular pigmentation of the skin, most commonly on the head, neck, and trunk. Bone marrow failure along with pulmonary complications and malignancies are all common causes of premature death in patients with DC as well as other abnormalities...
November 2016: Iranian Journal of Kidney Diseases
https://www.readbyqxmd.com/read/27903905/human-mlh1-suppresses-the-insertion-of-telomeric-sequences-at-intra-chromosomal-sites-in-telomerase-expressing-cells
#8
Pingping Jia, Megan Chastain, Ying Zou, Chengtao Her, Weihang Chai
Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27900472/tissue-specific-expression-of-telomerase-reverse-transcriptase-gene-variants-in-nicotiana-tabacum
#9
Jana Fišerová Jurečková, Eva Sýkorová, Said Hafidh, David Honys, Jiří Fajkus, Miloslava Fojtová
In tobacco, three sequence variants of the TERT gene have been described. We revealed unbalanced levels of TERT variant transcripts in vegetative tobacco tissues and enhanced TERT transcription and telomerase activity in reproductive tissues. Telomerase is a ribonucleoprotein complex responsible for the maintenance of telomeres, structures delimiting ends of linear eukaryotic chromosomes. In the Nicotiana tabacum (tobacco) allotetraploid plant, three sequence variants (paralogs) of the gene coding for the telomerase reverse transcriptase subunit (TERT) have been described, two of them derived from the maternal N...
November 29, 2016: Planta
https://www.readbyqxmd.com/read/27899638/structure-and-folding-of-the-tetrahymena-telomerase-rna-pseudoknot
#10
Darian D Cash, Juli Feigon
Telomerase maintains telomere length at the ends of linear chromosomes using an integral telomerase RNA (TER) and telomerase reverse transcriptase (TERT). An essential part of TER is the template/pseudoknot domain (t/PK) which includes the template, for adding telomeric repeats, template boundary element (TBE), and pseudoknot, enclosed in a circle by stem 1. The Tetrahymena telomerase holoenzyme catalytic core (p65-TER-TERT) was recently modeled in our 9 Å resolution cryo-electron microscopy map by fitting protein and TER domains, including a solution NMR structure of the Tetrahymena pseudoknot...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27899264/cyclic-ferrocenylnaphthalene-diimide-derivative-as-a-new-class-of-g-quadruplex-dna-binding-ligand
#11
Md Monirul Islam, Shinobu Sato, Shingo Shinozaki, Shigeori Takenaka
To identify an effective ligand that binds to a G-quadruplex structure but not a double-stranded DNA (dsDNA), a set of biophysical and biochemical experiments were carried out using newly synthesized cyclic ferrocenylnaphthalene diimide (cFNDI, 1) or the non-cyclic derivative (2) with various structures of G-quadruplex DNAs and dsDNA. Compound 1 bound strongly to G-quadruplexes DNAs (10(6)M(-1) order) with diminished binding to dsDNA (10(4)M(-1) order) in 100mM AcOH-AcOK buffer (pH 5.5) containing 100mM KCl...
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27898051/preparation-of-6-8-11-amino-chloro-oxoisoaporphine-and-group-10-metal-complexes-and-evaluation-of-their-in-vitro-and-in-vivo-antitumor-activity
#12
Qi-Pin Qin, Jiao-Lan Qin, Ting Meng, Gui-Ai Yang, Zu-Zhuang Wei, Yan-Cheng Liu, Hong Liang, Zhen-Feng Chen
A series of group-10 metal complexes 1-14 of oxoisoaporphine derivatives were designed and synthesized. 1-14 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 1-6, 7, 8, 10 and 11, especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 1-6 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand L(a) exhibited less side effects than 6 with 8-amino substituted ligand L(b) and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27895115/shared-subunits-of-tetrahymena-telomerase-holoenzyme-and-replication-protein-a-have-different-functions-in-different-cellular-complexes
#13
Heather E Upton, Henry Chan, Juli Feigon, Kathleen Collins
In most eukaryotes, telomere maintenance relies on telomeric repeat synthesis by a reverse transcriptase named telomerase. To synthesize telomeric repeats, the catalytic subunit telomerase reverse transcriptase (TERT) uses the RNA subunit (TER) as a template. In the ciliate Tetrahymena thermophila,the telomerase holoenzyme consists of TER, TERT, and eight additional proteins including the telomeric-repeat single-stranded DNA binding protein Teb1 and its heterotrimer partners Teb2 and Teb3. Teb1 is paralogous to the large subunit of the general single-stranded DNA binding heterotrimer Replication Protein A (RPA)...
November 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27893208/kanahia-laniflora-methanolic-extract-suppressed-proliferation-of-human-non-small-cell-lung-cancer-a549-cells
#14
Mohammad Yahya Alfaifi
Introduction: Lung cancer is one of the most common cancers worldwide. In certain countries such as United States of America, it is the leading cause of related cancer mortality among both men and women. Natural products play an important role in overcoming the limitations of chemotherapy and radiotherapy. Objectives: In this study, we investigated the antiproliferative and apoptotic activities of Kanahia laniflora methanolic extract against human non-small cell lung cancer cells (A549). Methods: Sulforhodamine B colorimetric assays were used to determine the inhibitory effects of a leaf methanolic extract against A549 cells...
January 10, 2016: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/27892716/life-and-cancer-without-telomerase-alt-and-other-strategies-for-making-sure-ends-don-t-meet
#15
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
#16
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...
November 23, 2016: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/27872149/endogenous-tert-n-terminal-tagging-affects-human-telomerase-function-at-telomeres-in-vivo
#17
Kunitoshi Chiba, Jacob M Vogan, Robert A Wu, Manraj S Gill, Xiaozhu Zhang, Kathleen Collins, Dirk Hockemeyer
Telomerase action at telomeres is essential for the immortal phenotype of stem cells and the aberrant proliferative potential of cancer cells. Insufficient telomere maintenance can cause stem cell and tissue failure syndromes, while increased telomerase levels are associated with tumorigenesis. Both pathologies can arise from only small perturbation of telomerase function. To analyze telomerase at its low endogenous expression level, we genetically engineered human pluripotent stem cells (hPSCs) to express various N-terminal fusion proteins of the telomerase reverse transcriptase from its endogenous locus...
November 21, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27861975/convergence-of-the-nobel-fields-of-telomere-biology-and-dna-repair
#18
Elise Fouquerel, Patricia Opresko
The fields of telomere biology and DNA repair have enjoyed a great deal of cross-fertilization and convergence in recent years. Telomeres function at chromosome ends to prevent them from being falsely recognized as chromosome breaks by the DNA damage response and repair machineries. Conversely, both canonical and non-conical functions of numerous DNA repair proteins have been found to be critical for preserving telomere structure and function. In 2009 Elizabeth Blackburn, Carol Greider, and Jack Szostak were awarded the Nobel prize in Physiology or Medicine for the discovery of telomeres and telomerase...
November 18, 2016: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/27859428/low-p16-ink4a-expression-in-early-passage-human-prostate-basal-epithelial-cells-enables-immortalization-by-telomerase-expression-alone
#19
Mindy Kim Graham, Lorenzo Principessa, Lizamma Antony, Alan K Meeker, John T Isaacs
BACKGROUND: There are two principal senescence barriers that must be overcome to successfully immortalize primary human epithelial cells in culture, stress-induced senescence, and replicative senescence. The p16(INK4a) /retinoblastoma protein (p16/Rb) pathway mediates stress-induced senescence, and is generally upregulated by primary epithelial cells in response to the artificial conditions from tissue culture. Replicative senescence is associated with telomere loss. Following each round of cell division, telomeres progressively shorten...
November 8, 2016: Prostate
https://www.readbyqxmd.com/read/27855118/tethering-telomerase-to-telomeres-increases-genome-instability-and-promotes-chronological-aging-in-yeast
#20
Jun Liu, Ming-Hong He, Jing Peng, Yi-Min Duan, Yi-Si Lu, Zhenfang Wu, Ting Gong, Hong-Tao Li, Jin-Qiu Zhou
Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS)...
November 13, 2016: Aging
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