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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
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
Peter Sidaway
No abstract text is available yet for this article.
September 20, 2016: Nature Reviews. Clinical Oncology
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 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 cardiomyocytes than those with relatively short telomeres and low TRF1 expression (iPSC(lowT) )...
September 10, 2016: Stem Cells
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...
September 7, 2016: Nucleic Acids Research
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
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
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...
August 25, 2016: Journal of Biological Chemistry
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) where 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 shelterin complex is responsible for CS-induced lung cellular senescence. Here we show that TPP1 levels are reduced on telomeres in mouse lungs with emphysema, as well as in lungs from smokers and COPD patients...
August 25, 2016: American Journal of Respiratory Cell and Molecular Biology
Natalia Stella-Ascariz, Rocío Montejano, Laura Pintado-Berninches, Susana Monge, José I Bernardino, Ignacio Pérez-Valero, Ma Luisa 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 PBMCs of healthy subjects. Median inhibition of telomerase activity by tenofovir at 0.5µM and 1µM 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 3µM and 14% (IQR 10%-29%, p=0.043) at 10µM. Tenofovir and abacavir did not change human telomerase reverse transcriptase (hTERT) levels or mRNA levels of other telomerase complex genes...
August 20, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
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
Akimitsu Konishi, Takashi Izumi, Shigeomi Shimizu
Mammalian chromosome ends are protected by a specialized nucleoprotein complex called telomeres. Both shelterin, a telomere-specific multi-protein complex, and higher order telomeric chromatin structures combine to stabilize the chromosome ends. Here, we showed that TRF2, a component of shelterin, binds to core histones to protect chromosome ends from inappropriate DNA damage response and loss of telomeric DNA. The N-terminal Gly/Arg-rich domain (GAR domain) of TRF2 directly binds to the globular domain of core histones...
September 23, 2016: Journal of Biological Chemistry
Romina Burla, Mariateresa Carcuro, Mattia La Torre, Federica Fratini, Marco Crescenzi, Maria Rosaria D'Apice, Paola Spitalieri, Grazia Daniela Raffa, Letizia Astrologo, Giovanna Lattanzi, Enrico Cundari, Domenico Raimondo, Annamaria Biroccio, Maurizio Gatti, Isabella Saggio
AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1...
August 2016: Open Biology
Ilgen Mender, Jerry W Shay
Telomerase maintains telomeric DNA in eukaryotes during early developments, ~90% of cancer cells and some proliferative stem like cells. Telomeric repeats at the end of chromosomes are associated with the shelterin complex. This complex consists of TRF1, TRF2, Rap1, TIN2, TPP1, POT1 which protect DNA from being recognized as DNA double-stranded breaks. Critically short telomeres or impaired shelterin proteins can cause telomere dysfunction, which eventually induces DNA damage responses at the telomeres. DNA damage responses can be identified by antibodies to 53BP1, gammaH2AX, Rad17, ATM, and Mre11...
November 20, 2015: Bio-protocol
Romain Guièze, Mélanie Pages, Lauren Véronèse, Patricia Combes, Richard Lemal, Mathilde Gay-Bellile, Martine Chauvet, Mary Callanan, Fabrice Kwiatkowski, Bruno Pereira, Philippe Vago, Jacques-Olivier Bay, Olivier Tournilhac, Andreï Tchirkov
In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients...
July 29, 2016: Oncotarget
Lihua Yao, Xiaolan Guo
As an important telomere binding protein, TPP1 protects the ends of telomeres and maintains the stability and integrity of its structure and function by interacting with other five essential core proteins (POT1, TRF1, TRF2, TIN2, and RAP1) to form a complex called Shelterin. Recently, researchers have discovered that TPP1 participates in protection of telomeres and regulation of telomerase activity. The relationship between TPP1 and tumorigenesis, tumor progression and treatment has also been investigated. This paper reviews the latest findings of TPP1 regarding to its structure, function and interaction with other proteins involved in tumorigenesis...
August 2016: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Umesh Kalathiya, Monikaben Padariya, Maciej Baginski
Shelterin is a six-protein complex (TRF1, TRF2, POT1, RAP1, TIN2, and TPP1) that also functions in smaller subsets in regulation and protection of human telomeres. Two closely related proteins, TRF1 and TRF2, make high-affinity contact directly with double-stranded telomeric DNA and serve as a molecular platform. Protein TIN2 binds to TRF1 and TRF2 dimer-forming domains, whereas Apollo makes interaction only with TRF2. To elucidate the molecular basis of these interactions, we employed molecular dynamics (MD) simulations of TRF1TRFH-TIN2TBM and TRF2TRFH-TIN2TBM/ApolloTBM complexes and of the isolated proteins...
July 22, 2016: European Biophysics Journal: EBJ
Daniel E Cook, Stefan Zdraljevic, Robyn E Tanny, Beomseok Seo, David D Riccardi, Luke M Noble, Matthew V Rockman, Mark J Alkema, Christian Braendle, Jan E Kammenga, John Wang, Leonid Kruglyak, Marie-Anne Félix, Junho Lee, Erik C Andersen
Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length...
September 2016: Genetics
Mark J Swanson, Michelle E Baribault, Joanna N Israel, Nancy S Bae
Telomeres are important for maintaining the integrity of the genome through the action of the shelterin complex. Previous studies indicted that the length of the telomere did not have an effect on the amount of the shelterin subunits; however, those experiments were performed using immortalized cells with stable telomere lengths. The interest of the present study was to observe how decreasing telomere lengths over successive generations would affect the shelterin subunits. As neonatal human dermal fibroblasts aged and their telomeres became shorter, the levels of the telomere-binding protein telomeric repeat factor 2 (TRF2) decreased significantly...
August 2016: Biomedical Reports
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
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