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https://www.readbyqxmd.com/read/28096402/establishment-of-expression-state-boundaries-by-rif1-and-taz1-in-fission-yeast
#1
Tea Toteva, Bethany Mason, Yutaka Kanoh, Peter Brøgger, Daniel Green, Janne Verhein-Hansen, Hisao Masai, Geneviève Thon
The Shelterin component Rif1 has emerged as a global regulator of the replication-timing program in all eukaryotes examined to date, possibly by modulating the 3D-organization of the genome. In fission yeast a second Shelterin component, Taz1, might share similar functions. Here, we identified unexpected properties for Rif1 and Taz1 by conducting high-throughput genetic screens designed to identify cis- and trans-acting factors capable of creating heterochromatin-euchromatin boundaries in fission yeast. The preponderance of cis-acting elements identified in the screens originated from genomic loci bound by Taz1 and associated with origins of replication whose firing is repressed by Taz1 and Rif1...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28052260/telomere-recognition-and-assembly-mechanism-of-mammalian-shelterin
#2
Fabian Erdel, Katja Kratz, Smaranda Willcox, Jack D Griffith, Eric C Greene, Titia de Lange
Shelterin is a six-subunit protein complex that plays crucial roles in telomere length regulation, protection, and maintenance. Although several shelterin subunits have been studied in vitro, the biochemical properties of the fully assembled shelterin complex are not well defined. Here, we characterize shelterin using ensemble biochemical methods, electron microscopy, and single-molecule imaging to determine how shelterin recognizes and assembles onto telomeric repeats. We show that shelterin complexes can exist in solution and primarily locate telomeric DNA through a three-dimensional diffusive search...
January 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/27940556/the-drosophila-telomere-capping-protein-verrocchio-binds-single-stranded-dna-and-protects-telomeres-from-dna-damage-response
#3
Alessandro Cicconi, Emanuela Micheli, Fiammetta Vernì, Alison Jackson, Ana Citlali Gradilla, Francesca Cipressa, Domenico Raimondo, Giuseppe Bosso, James G Wakefield, Laura Ciapponi, Giovanni Cenci, Maurizio Gatti, Stefano Cacchione, Grazia Daniela Raffa
Drosophila telomeres are sequence-independent structures maintained by transposition to chromosome ends of three specialized retroelements rather than by telomerase activity. Fly telomeres are protected by the terminin complex that includes the HOAP, HipHop, Moi and Ver proteins. These are fast evolving, non-conserved proteins that localize and function exclusively at telomeres, protecting them from fusion events. We have previously suggested that terminin is the functional analogue of shelterin, the multi-protein complex that protects human telomeres...
December 9, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27873269/the-use-of-3d-telomere-fish-for-the-characterization-of-the-nuclear-architecture-in-ebv-positive-hodgkin-s-lymphoma
#4
Hans Knecht, Sabine Mai
The 3D nuclear architecture is closely related to cellular functions and chromosomes are organized in distinct territories. Quantitative 3D telomere FISH analysis (3D Q-FISH) and 3D super-resolution imaging (3D-SIM) at a resolution up to 80 nm as well as the recently developed combined quantitative 3D TRF2-telomere immune FISH technique (3D TRF2/Telo-Q-FISH) have substantially contributed to elucidate molecular pathogenic mechanisms of hematological diseases. Here we report the methods we applied to uncover major molecular steps involved in the pathogenesis of EBV-associated Hodgkin's lymphoma...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27869160/pot1-ob-fold-mutations-unleash-telomere-instability-to-initiate-tumorigenesis
#5
P Gu, Y Wang, K K Bisht, L Wu, L Kukova, E M Smith, Y Xiao, S M Bailey, M Lei, J Nandakumar, S Chang
Chromosomal aberrations are a hallmark of human cancers, with complex cytogenetic rearrangements leading to genetic changes permissive for cancer initiation and progression. Protection of Telomere 1 (POT1) is an essential component of the shelterin complex and functions to maintain chromosome stability by repressing the activation of aberrant DNA damage and repair responses at telomeres. Sporadic and familial mutations in the oligosaccharide-oligonucleotide (OB) folds of POT1 have been identified in many human cancers, but the mechanism underlying how hPOT1 mutations initiate tumorigenesis has remained unclear...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27835648/mtv-an-ssdna-protecting-complex-essential-for-transposon-based-telomere-maintenance-in-drosophila
#6
Yi Zhang, Liang Zhang, Xiaona Tang, Shilpa R Bhardwaj, Jingyun Ji, Yikang S Rong
Multiple complexes protect telomeres. In telomerase-maintained organisms, Shelterin related complexes occupy the duplex region while the CST and Tpp1-Pot1 complexes bind the single stranded overhang of telomeres. Drosophila uses a transposon-based mechanism for end protection. We showed that the HOAP-HipHop complex occupies the duplex region. Whether an ssDNA-binding complex exists is not known. Here we discover a novel protein, Tea, that is specifically enriched at telomeres to prevent telomere fusion. We also identify a complex consisting of Tea and two known capping proteins, Ver and Moi...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27814571/telomere-protein-complexes-and-their-role-in-lymphoid-malignancies
#7
Julieta Panero, Patricia Dos Santos, Irma Slavutsky
Telomeres are highly regulated and dynamic complexes that protect the genomic DNA and prevent the end of linear chromosomes from being misrecognized as a broken DNA. Due to the end replication problem, telomeres of somatic cells shorten with each cell division, inducing cell senescence. Telomerase is a reverse transcriptase capable of compensating telomere attrition by adding telomere repeats to the ends of chromosomes. Human telomeres are associated with the shelterin complex which consists of six telomere-associated proteins that specifically bind to telomeric DNA...
January 1, 2017: Frontiers in Bioscience (Scholar Edition)
https://www.readbyqxmd.com/read/27806302/telomere-internal-double-strand-breaks-are-repaired-by-homologous-recombination-and-parp1-lig3-dependent-end-joining
#8
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/27785368/ercc1-and-telomere-status-in-breast-tumours-treated-with-neoadjuvant-chemotherapy-and-their-association-with-patient-prognosis
#9
Mathilde Gay-Bellile, Pierre Romero, Anne Cayre, Lauren Véronèse, Maud Privat, Shalini Singh, Patricia Combes, Fabrice Kwiatkowski, Catherine Abrial, Yves-Jean Bignon, Philippe Vago, Frédérique Penault-Llorca, Andreï Tchirkov
Dysfunctional telomeres and DNA damage repair (DDR) play important roles in cancer progression. Studies have reported correlations between these factors and tumour aggressiveness and clinical outcome in breast cancer. We studied the characteristics of telomeres and expression of ERCC1, a protein involved in a number of DNA repair pathways and in telomere homeostasis, to assess their prognostic value, alone or in combination, in 90 residual breast tumours after treatment with neoadjuvant chemotherapy (NCT). ERCC1 status was investigated at different molecular levels (protein and gene expression and gene copy-number variations) by immunohistochemistry, qRT-PCR and quantitative multiplex fluorescent-PCR (QMF-PCR)...
October 2016: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/27761787/telomeres-and-telomerase-in-the-clinical-management-of-colorectal-cancer
#10
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
https://www.readbyqxmd.com/read/27699234/telomere-dysfunction-in-alveolar-epithelial-cells-causes-lung-remodeling-and-fibrosis
#11
Ram P Naikawadi, Supparerk Disayabutr, Benat Mallavia, Matthew L Donne, Gary Green, Janet L La, Jason R Rock, Mark R Looney, Paul J Wolters
Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1(fl/fl) mice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung...
September 8, 2016: JCI Insight
https://www.readbyqxmd.com/read/27644416/haematological-cancer-shelterin-complex-mutated-in-familial-cll
#12
Peter Sidaway
No abstract text is available yet for this article.
September 20, 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27612935/telomere-length-defines-the-cardiomyocyte-differentiation-potency-of-mouse-induced-pluripotent-stem-cells
#13
Tania Aguado, Francisco J Gutiérrez, Esther Aix, Ralph P Schneider, Giovanna Giovinnazo, María A Blasco, Ignacio Flores
Induced pluripotent stem cells (iPSCs) can be differentiated in vitro and in vivo to all cardiovascular lineages and are therefore a promising cell source for cardiac regenerative therapy. However, iPSC lines do not all differentiate into cardiomyocytes (CMs) with the same efficiency. Here, we show that telomerase-competent iPSCs with relatively long telomeres and high expression of the shelterin-complex protein TRF1 (iPSC(highT) ) differentiate sooner and more efficiently into CMs than those with relatively short telomeres and low TRF1 expression (iPSC(lowT) )...
September 10, 2016: Stem Cells
https://www.readbyqxmd.com/read/27608724/transcription-of-telomeric-dna-leads-to-high-levels-of-homologous-recombination-and-t-loops
#14
Anirban Kar, Smaranda Willcox, Jack D Griffith
The formation of DNA loops at chromosome ends (t-loops) and the transcription of telomeres producing G-rich RNA (TERRA) represent two central features of telomeres. To explore a possible link between them we employed artificial human telomeres containing long arrays of TTAGGG repeats flanked by the T7 or T3 promoters. Transcription of these DNAs generates a high frequency of t-loops within individual molecules and homologous recombination events between different DNAs at their telomeric sequences. T-loop formation does not require a single strand overhang, arguing that both terminal strands insert into the preceding duplex...
November 2, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27586969/a-genetic-interaction-between-rap1-and-telomerase-reveals-an-unanticipated-role-for-rap1-in-telomere-maintenance
#15
Paula Martínez, Gonzalo Gómez-López, David G Pisano, Juana M Flores, Maria A Blasco
RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere length maintenance and protection has remained elusive. RAP1 also binds subtelomeric repeats and along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres, and its deficiency causes a premature aging in humans and mice. We describe an unanticipated genetic interaction between RAP1 and telomerase...
September 1, 2016: Aging Cell
https://www.readbyqxmd.com/read/27566293/influence-of-exposure-to-pesticides-on-telomere-length-in-tobacco-farmers-a-biology-system-approach
#16
Vivian Francília Silva Kahl, Juliana da Silva, Fernanda Rabaioli da Silva
Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood...
September 2016: Mutation Research
https://www.readbyqxmd.com/read/27563064/molecular-architecture-of-full-length-trf1-favors-its-interaction-with-dna
#17
Jasminka Boskovic, Jaime Martinez-Gago, Marinela Mendez-Pertuz, Alberto Buscato, Jorge Luis Martinez-Torrecuadrada, Maria A Blasco
Telomeres are specific DNA-protein structures found at both ends of eukaryotic chromosomes that protect the genome from degradation and from being recognized as double-stranded breaks. In vertebrates, telomeres are composed of tandem repeats of the TTAGGG sequence that are bound by a six-subunit complex called shelterin. Molecular mechanisms of telomere functions remain unknown in large part due to lack of structural data on shelterins, shelterin complex, and its interaction with the telomeric DNA repeats. TRF1 is one of the best studied shelterin components; however, the molecular architecture of the full-length protein remains unknown...
October 7, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27559927/shelterin-telomere-protection-protein-1-reduction-causes-telomere-attrition-and-cellular-senescence-via-sirtuin-1-deacetylase-in-chronic-obstructive-pulmonary-disease
#18
Tanveer Ahmad, Isaac K Sundar, Ana M Tormos, Chad A Lerner, Janice Gerloff, Hongwei Yao, Irfan Rahman
Lung cellular senescence and inflammatory response are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) when cigarette smoke (CS) is the main etiological factor. Telomere dysfunction is induced by either critical shortening or disruption of the shelterin complex, leading to cellular senescence. However, it remains unknown whether disruption of the shelterin complex is responsible for CS-induced lung cellular senescence. Here we show that telomere protection protein 1 (TPP1) levels are reduced on telomeres in lungs from mice with emphysema, as well as in lungs from smokers and from patients with COPD...
January 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27552152/brief-report-differential-effects-of-tenofovir-abacavir-emtricitabine-and-darunavir-on-telomerase-activity-in-vitro
#19
Natalia Stella-Ascariz, Rocío Montejano, Laura Pintado-Berninches, Susana Monge, José I Bernardino, Ignacio Pérez-Valero, María L Montes, Jesús Mingorance, Rosario Perona, José R Arribas
In vitro, tenofovir and abacavir induced a significant dose-dependent inhibition of telomerase activity at therapeutic concentrations in peripheral blood mononuclear cells of healthy subjects. Median inhibition of telomerase activity by tenofovir at 0.5 and 1 μM was 29% [Interquartile range (IQR) 29%-34%, P = 0.042] and 28% (IQR 28%-41%, P = 0.042), respectively. Abacavir inhibition was 12% (IQR 9%-13%, P = 0.043) at 3 μM and 14% (IQR 10%-29%, P = 0.043) at 10 μM. Tenofovir and abacavir did not change human telomerase reverse transcriptase (hTERT) levels or mRNA levels of other telomerase complex genes...
January 1, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/27528712/germline-mutations-in-shelterin-complex-genes-are-associated-with-familial-chronic-lymphocytic-leukemia
#20
Helen E Speedy, Ben Kinnersley, Daniel Chubb, Peter Broderick, Philip J Law, Kevin Litchfield, Sandrine Jayne, Martin J S Dyer, Claire Dearden, George A Follows, Daniel Catovsky, Richard S Houlston
Chronic lymphocytic leukemia (CLL) can be familial, however thus far no rare germline disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying four families where loss-of-function mutations in POT1 co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and ACD, part of the telomere-capping shelterin complex...
August 15, 2016: Blood
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