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Telomere and telomerase

Andreas Zietzer, Eva Elina Buschmann, Doreen Janke, Lulu Li, Michèle Brix, Heike Meyborg, Philipp Stawowy, Constantin Jungk, Ivo Buschmann, Philipp Hillmeister
AIM: Physical activity is a potent way to impede vascular aging. However, patients who suffer from peripheral artery disease (PAD) are often unable to exercise adequately. For those patients, we have developed individual shear rate therapy (ISRT), which is an adaptation of external counterpulsation and enhances endovascular fluid shear stress to increase collateral growth (arteriogenesis). To evaluate the effects of physical exercise and ISRT on the telomere biology of peripheral blood mononuclear cells (PBMCs), we conducted two clinical trials...
October 22, 2016: Acta Physiologica
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...
October 18, 2016: Biochimica et Biophysica Acta
Brody Holohan, Wanil Kim, Tsung-Po Lai, Hirotoshi Hoshiyama, Ning Zhang, Anas M Alazami, Woodring E Wright, M Stephen Meyn, Fowzan S Alkuraya, Jerry W Shay
BACKGROUND: Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. METHODS: Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7)...
October 17, 2016: BMC Genomics
C Piñol-Felis, T Fernández-Marcelo, J Viñas-Salas, C Valls-Bautista
Colorectal cancer (CRC) is the third most common cancer worldwide. Our aim is to describe the state of the art about the role of telomeres and telomerase in the clinical management of CRC and its potential utility as prognostic and diagnostic biomarkers and targets of new treatments. Telomere length could be a new diagnostic marker as an anomalous behavior is observed in peripheral blood cells when CRC patients and healthy people are compared. Moreover, telomeres and telomerase may be used as diagnostic markers considering that universal changes appear along the CRC process...
October 19, 2016: Clinical & Translational Oncology
Mi-Sun Kwon, Jaewon Min, Hee-Yeon Jeon, Kwangwoo Hwang, Chuna Kim, Junho Lee, Je-Gun Joung, Woong-Yang Park, Hyunsook Lee
BRCA2 is a multifunctional tumor suppressor involved in homologous recombination (HR), mitotic checkpoint regulation, and telomere homeostasis. Absence of Brca2 in mice results in progressive shortening of telomeres and senescence, yet cells are prone to neoplastic transformation with elongated telomeres, suggesting that BRCA2 has positive and negative effects on telomere length regulation along the path to tumorigenesis. Using Caenorhabditis elegans as a model, we show here that depletion of BRC-2, an ortholog of BRCA2, paradoxically delays senescence in telomerase-deficient mutant worms...
October 2016: FEBS Open Bio
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...
October 19, 2016: EMBO Reports
Elsa Vera, Nazario Bosco, Lorenz Studer
Modeling late-onset disorders such as Parkinson's disease (PD) using iPSC technology remains a challenge, as current differentiation protocols yield cells with the properties of fetal-stage cells. Here, we tested whether it is possible to accelerate aging in vitro to trigger late-onset disease phenotypes in an iPSC model of PD. In order to manipulate a factor that is involved in natural aging as well as in premature aging syndromes, we used telomere shortening as an age-inducing tool. We show that shortened telomeres result in age-associated as well as potentially disease-associated phenotypes in human pluripotent stem cell (hPSC)-derived midbrain dopamine (mDA) neurons...
October 18, 2016: Cell Reports
Shigeo Ohba, Joydeep Mukherjee, Tor-Christian Johannessen, Andrew Mancini, Tracy T Chow, Matthew Wood, Lindsey Jones, Tali Mazor, Roxanne E Marshall, Pavithra Viswanath, Kyle M Walsh, Arie Perry, Robert J A Bell, Joanna J Phillips, Joseph F Costello, Sabrina M Ronen, Russell O Pieper
Mutations in the isocitrate dehydrogenase gene IDH1 are common in lower-grade glioma where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation and gliomagenesis. IDH1 mutations also co-segregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine if and how this may occur, we investigated the phenotype of pRb/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H mutant (IDH1mut) genes as they progressed through their lifespan...
October 6, 2016: Cancer Research
Yu Zou, Huei Jinn Tong, Mingming Li, Kai Soo Tan, Tong Cao
The ability of human embryonic stem cells (hESCs) to proliferate indefinitely is attributed to its high telomerase activity and associated long telomere. However, factors regulating telomere length in hESCs remain largely uncharacterized. The aims of this study were, to identify factors which modulate telomere length of hESCs, and to determine if the telomere length of hESCs influences cellular senescence of its differentiated progeny cells. Telomerase reverse transcriptase (TERT) gene expression, telomerase activity and telomere length of hESCs cultured in different culture systems were compared...
October 18, 2016: Biogerontology
Karima Ait-Aissa, Joseph Hockenberry, David Gutterman, Aron Geurts, Andreas Beyer
OBJECTIVE: Flow mediated dilation (FMD) is the most physiological relevant form of endothelial-mediated vasodilation. Our laboratory has previously shown that telomerase, a ribo-nucleoprotein that counteracts telomere shortening, has a protective effect on endothelial function under conditions of oxidative stress in the human microcirculation. In the presence of coronary artery disease, decreased telomerase activity contributes to a shift in the mediator of FMD from atheroprotective nitric oxide (NO) to pro-inflammatory and atherogenic hydrogen peroxide (H2O2)...
September 2016: Journal of Hypertension
Karla Schmitt, Fabian Beier, Jens Panse, Tim H Brümmendorf
Telomere syndromes (syn. Telomeropathies) are inherited disorders hallmarked by accelerated telomere shortening based on a molecular defect within the telomerase/telomere complex. The rare, but well-defined model disorder Dyskeratosis congenita (DKC) characterized by typical skin manifestations and bone marrow failure represents the classical manifestation of telomere syndromes in childhood and adolescence. However, cryptic variants of DKC, clinically manifest through appearance of atypical bone marrow failure, lung fibrosis or liver cirrhosis - especially in adults up to the fifth decade of age - are frequently underdiagnosed...
October 2016: Deutsche Medizinische Wochenschrift
Irina D Strazhesko, Olga N Tkacheva, Dariga U Akasheva, Ekaterina N Dudinskaya, Ekaterina V Plokhova, Valentina S Pykhtina, Anna S Kruglikova, Natalia V Kokshagina, Natalia V Sharashkina, Mikhail V Agaltsov, Daria A Kashtanova, Vladimir A Vygodin, Irina N Ozerova, Dmitry A Skvortsov, Daria Vasilkova, Sergey A Boytsov
Background: Telomerase activity (TA) is considered as the biomarker for cardiovascular aging and cardiovascular diseases (CVDs). Recent studies suggest a link between statins and telomere biology that may be explained by anti-inflammatory actions of statins and their positive effect on TA. Until now, this effect has not been investigated in prospective randomized studies. We hypothesized that 12 months of atorvastatin therapy increased TA in peripheral blood mononuclear cells. Methods: In a randomized, placebo-controlled study 100 hypercholesterolemic patients, aged 35-75 years, free of known CVDs and diabetes mellitus type 2 received 20 mg of atorvastatin daily or placebo for 12 months...
2016: Frontiers in Pharmacology
Diqi Yang, Lei Wang, Pengfei Lin, Tingting Jiang, Nan Wang, Fan Zhao, Huatao Chen, Keqiong Tang, Dong Zhou, Aihua Wang, Yaping Jin
With granulosa and theca cells, the ovaries are responsible for producing oocytes and secreting sex steroids such as estrogen and progesterone. Endoplasmic reticulum stress (ERS) plays an important role in follicle atresia and embryo implantation. In this study, goat granulosa cells were isolated from medium-sized (4-6 mm) healthy follicles. Primary granulosa cells were immortalized by transfection with human telomerase reverse transcriptase (hTERT) to establish a goat granulosa cell line (hTERT-GGCs). These hTERT-GGCs expressed hTERT and had relatively long telomeres at passage 50...
October 15, 2016: Journal of Reproduction and Development
Jing Xu, Yanjun Wang, Luzhu Yang, Yanfang Gao, Baoxin Li, Yan Jin
Human telomerase RNA (hTR), works as a template for synthesis of telomeric DNA repeats at the ends of linear eukaryotic chromosomes, is overexpressed in tumor cells and its concentration has a positive correlation with telomerase activity. The lack of facile and reliable method for detection of hTR in complex matric limited its application for clinical diagnosis. To address the limitation, herein, we proposed a facile and reliable flow cytometric assay for sensitive and specific detection of hTR by combing magnetic enrichment with signal amplification of DNA toehold strand displacement reaction (TSDR)...
August 13, 2016: Biosensors & Bioelectronics
Christopher Gilfillan, Pratyusha Naidu, Florence Gunawan, Fadwa Hassan, Pei Tian, Ngaire Elwood
AIMS: Telomeres undergo shortening with cell division, accelerated by increased oxidative stress. We aimed to demonstrate shortened telomeres in the offspring of mothers who have diabetes as a consequence of exposure to increased oxidative stress during intrauterine development. METHODS: We examined the level of glycaemia (glucose, HbA1c, fructosamine), oxidative stress (lipid peroxidation) and the levels of antioxidant enzymes (Superoxide dismutase (SOD) and Selenium dependent glutathione peroxidase) and correlate these findings with mean telomere length (TL) in maternal and foetal blood in groups of pregnant women with pre-gestational diabetes (PGD), gestational diabetes (GD) and a euglycaemic control group...
2016: PloS One
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
Amandine Ketele, Tamás Kiss, Beáta E Jády
Mammalian cells express hundreds of intron-encoded box H/ACA RNAs which fold into a common hairpin-hinge-hairpin-tail structure, interact with four evolutionarily conserved proteins, dyskerin, Nop10, Nhp2 and Gar1, and function mainly in RNA pseudouridylation. The human telomerase H/ACA RNA (hTR) directs telomeric DNA synthesis and it carries a 5'-terminal domain encompassing the telomeric template sequence. The primary hTR transcript is synthesized from an independent gene by RNA polymerase II and undergoes 3' end processing controlled by the 3'-terminal H/ACA domain...
October 11, 2016: RNA Biology
Rajendra Kumar Agrawal, Hong-Wei Wang, Marlene Belfort
Group II introns are large catalytic RNAs that form a ribonucleoprotein (RNP) complex by binding to an intron-encoded protein (IEP). The IEP, which facilitates both RNA splicing and intron mobility, has multiple activities including reverse transcriptase. Recent structures of a group II intron RNP complex and of IEPs from diverse bacteria fuel arguments that group II introns are ancestrally related to eukaryotic spliceosomes as well as to telomerase and viruses. Furthermore, recent structural studies of various functional states of the spliceosome allow us to draw parallels between the group II intron RNP and the spliceosome...
October 11, 2016: RNA Biology
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
Tracey Beyer, Ted Weinert
DNA replication errors at certain sites in the genome initiate chromosome instability that ultimately leads to stable genomic rearrangements. Where instability begins is often unclear. And, early instability may form unstable chromosome intermediates whose transient nature also hinders mechanistic understanding. We report here a budding yeast model that reveals the genetic ontogeny of genome rearrangements, from initial replication error to unstable chromosome formation to their resolution. Remarkably, the initial error often arises in or near the telomere, and frequently forms unstable chromosomes...
October 2016: PLoS Genetics
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