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https://www.readbyqxmd.com/read/28324506/induction-of-site-specific-oxidative-damage-at-telomeres-by-killerred-fused-shelretin-proteins
#1
Rong Tan, Li Lan
Chronic oxidative stress is the major endogenous metabolic stress and contributes directly to telomere shortening and senescence. Understanding the dysfunction of telomeres under oxidative stress will greatly facilitate healthy aging and advance the treatment of aging-related diseases. Here, we describe the KR-TEL (KillerRed induced DNA damage at telomeres) system that induces site-specific oxidative damage at telomeres. We have developed the KR-TEL system by fusing killerred with the shelterin component TRF1 (KR-TRF1) or other shelterin proteins...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28324505/probing-the-telomere-damage-response
#2
Rekha Rai, Sandy Chang
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases, and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant-negative mutant TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28254828/telomere-driven-diseases-and-telomere-targeting-therapies
#3
REVIEW
Paula Martínez, Maria A Blasco
Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis...
March 2, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28238220/telomeres-exercise-and-cardiovascular-disease-finding-the-means-to-justify-the-ends
#4
EDITORIAL
Warrick L Chilton, Brendan J O'Brien, Fergal Grace, Fadi J Charchar
Telomeres are repetitive tandem DNA sequences (TTAGGG) located at chromosomal ends where they protect genomic DNA from enzymatic degradation. Telomeres are scaffolded upon six regulatory proteins, collectively known as the shelterin complex. A state of replicative senescence is triggered when telomeres reach a critically shortened threshold. This article is protected by copyright. All rights reserved.
February 26, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28216227/nek7-protects-telomeres-from-oxidative-dna-damage-by-phosphorylation-and-stabilization-of-trf1
#5
Rong Tan, Satoshi Nakajima, Qun Wang, Hongxiang Sun, Jing Xue, Jian Wu, Sabine Hellwig, Xuemei Zeng, Nathan A Yates, Thomas E Smithgall, Ming Lei, Yu Jiang, Arthur S Levine, Bing Su, Li Lan
Telomeric repeat binding factor 1 (TRF1) is essential to the maintenance of telomere chromatin structure and integrity. However, how telomere integrity is maintained, especially in response to damage, remains poorly understood. Here, we identify Nek7, a member of the Never in Mitosis Gene A (NIMA) kinase family, as a regulator of telomere integrity. Nek7 is recruited to telomeres and stabilizes TRF1 at telomeres after damage in an ATM activation-dependent manner. Nek7 deficiency leads to telomere aberrations, long-lasting γH2AX and 53BP1 foci, and augmented cell death upon oxidative telomeric DNA damage...
March 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28176777/phylointeractomics-reconstructs-functional-evolution-of-protein-binding
#6
Dennis Kappei, Marion Scheibe, Maciej Paszkowski-Rogacz, Alina Bluhm, Toni Ingolf Gossmann, Sabrina Dietz, Mario Dejung, Holger Herlyn, Frank Buchholz, Matthias Mann, Falk Butter
Molecular phylogenomics investigates evolutionary relationships based on genomic data. However, despite genomic sequence conservation, changes in protein interactions can occur relatively rapidly and may cause strong functional diversification. To investigate such functional evolution, we here combine phylogenomics with interaction proteomics. We develop this concept by investigating the molecular evolution of the shelterin complex, which protects telomeres, across 16 vertebrate species from zebrafish to humans covering 450 million years of evolution...
February 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28166612/acute-exercise-activates-p38-mapk-and-increases-the-expression-of-telomere-protective-genes-in-cardiac-muscle
#7
Andrew T Ludlow, Laila Gratidao, Lindsay W Ludlow, Espen E Spangenburg, Stephen M Roth
Age is the greatest risk factor for cardiovascular disease. Telomere length is shorter in the hearts of aged mice compared to young mice, and short telomere length has been associated with an increased risk of cardiovascular disease. One year of voluntary wheel running exercise attenuates the age-associated loss of telomere length and results in altered gene expression of telomere length maintaining and genome stabilizing proteins in heart tissue of mice. Understanding the early adaptive response of the heart to an endurance exercise bout is paramount to understanding the impact of endurance exercise on heart tissue and cells...
February 6, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28146113/solving-the-telomere-replication-problem
#8
REVIEW
Laetitia Maestroni, Samah Matmati, Stéphane Coulon
Telomeres are complex nucleoprotein structures that protect the extremities of linear chromosomes. Telomere replication is a major challenge because many obstacles to the progression of the replication fork are concentrated at the ends of the chromosomes. This is known as the telomere replication problem. In this article, different and new aspects of telomere replication, that can threaten the integrity of telomeres, will be reviewed. In particular, we will focus on the functions of shelterin and the replisome for the preservation of telomere integrity...
January 31, 2017: Genes
https://www.readbyqxmd.com/read/28111257/fragile-sites-dysfunctional-telomere-and-chromosome-fusions-what-is-5s-rdna-role
#9
Alain Victor Barros, Michele Andressa Vier Wolski, Viviane Nogaroto, Mara Cristina Almeida, Orlando Moreira-Filho, Marcelo Ricardo Vicari
Repetitive DNA regions are known as fragile chromosomal sites which present a high flexibility and low stability. Our focus was characterize fragile sites in 5S rDNA regions. The Ancistrus sp. species shows a diploid number of 50 and an indicative Robertsonian fusion at chromosomal pair 1. Two sequences of 5S rDNA were identified: 5S.1 rDNA and 5S.2 rDNA. The first sequence gathers the necessary structures to gene expression and shows a functional secondary structure prediction. Otherwise, the 5S.2 rDNA sequence does not contain the upstream sequences that are required to expression, furthermore its structure prediction reveals a nonfunctional ribosomal RNA...
April 15, 2017: Gene
https://www.readbyqxmd.com/read/28096402/establishment-of-expression-state-boundaries-by-rif1-and-taz1-in-fission-yeast
#10
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 31, 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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
REVIEW
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
#20
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
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