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https://www.readbyqxmd.com/read/29663033/how-long-does-telomerase-extend-telomeres-regulation-of-telomerase-release-and-telomere-length-homeostasis
#1
REVIEW
Kazunori Tomita
Telomerase, the enzyme that replenishes telomeres, is essential for most eukaryotes to maintain their generations. Telomere length homeostasis is achieved via a balance between telomere lengthening by telomerase, and erosion over successive cell divisions. Impaired telomerase regulation leads to shortened telomeres and can cause defects in tissue maintenance. Telomeric DNA is composed of a repetitive sequence, which recruits the protective protein complex, shelterin. Shelterin, together with chromatin remodelling proteins, shapes the heterochromatic structure at the telomere and protects chromosome ends...
April 16, 2018: Current Genetics
https://www.readbyqxmd.com/read/29581185/the-c-terminal-extension-unique-to-the-long-isoform-of-the-shelterin-component-tin2-enhances-its-interaction-with-trf2-in-a-phosphorylation-and-dyskeratosis-congenita-cluster-dependent-fashion
#2
Nya D Nelson, Lois M Dodson, Laura Escudero, Ann T Sukumar, Christopher L Williams, Ivana Mihalek, Alessandro Baldan, Duncan M Baird, Alison A Bertuch
TIN2 is central to the shelterin complex, linking the telomeric proteins TRF1 and TRF2 with TPP1/POT1. Mutations in TINF2 , which encodes TIN2, that are found in dyskeratosis congenita (DC) result in very short telomeres and cluster in a region shared by the two TIN2 isoforms, TIN2S (short) and TIN2L (long). Here we show that TIN2L, but not TIN2S, is phosphorylated. TRF2 interacts more with TIN2L than TIN2S, and both the DC-cluster and phosphorylation promote this enhanced interaction. The binding of TIN2L, but not TIN2S, is affected by TRF2-F120, which is also required for TRF2's interaction with end processing factors such as Apollo...
March 26, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29550946/the-role-of-telomere-binding-molecules-for-normal-and-abnormal-hematopoiesis
#3
REVIEW
Kentaro Hosokawa, Fumio Arai
In order to maintain the homeostasis of the hematopoietic system, hematopoietic stem cells (HSCs) need to be maintained while slowly dividing over their lifetime. However, repeated cell divisions lead to the gradual accumulation of DNA damage and ultimately impair HSC function. Since telomeres are particularly fragile when subjected to replication stress, cells have several defense machinery to protect telomeres. Moreover, HSCs must protect their genome against possible DNA damage, while maintaining telomere length...
March 17, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29550242/evolving-linear-chromosomes-and-telomeres-a-c-strand-centric-view
#4
REVIEW
Neal F Lue
Recent studies have resulted in deeper understanding of a variety of telomere maintenance mechanisms as well as plausible models of telomere evolution. Often overlooked in the discussion of telomere regulation and evolution is the synthesis of the DNA strand that bears the 5'-end (i.e., the C-strand). Herein, I describe a scenario for telomere evolution that more explicitly accounts for the evolution of the C-strand synthesis machinery. In this model, CTC1-STN1-TEN1 (CST), the G-strand-binding complex that regulates primase-Pol α-mediated C-strand synthesis, emerges as a pivotal player and evolutionary link...
March 14, 2018: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/29428209/the-structurally-similar-trfh-domain-of-trf1-and-trf2-dimers-shows-distinct-behaviour-towards-tin2
#5
Umesh Kalathiya, Monikaben Padariya, Maciej Baginski
The telomere repeat binding-factor 1 and 2 (TRF1 and TRF2) proteins of the shelterin complex bind to duplex telomeric DNA as homodimers, and the homodimerization is mediated by their TRFH (TRF-homology) domains. We performed molecular dynamic (MD) simulations of the dimer forms of TRF1TRFH and TRF2TRFH in the presence/absence of the TIN2TBM (TIN2, TRF-interacting nuclear protein 2, TBM, TRF-binding motif) peptide. The MD results suggest that TIN2TBM is necessary to ensure the stability of TRF1TRFH homodimer but not the TRF2TRFH homodimer...
February 8, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29358759/trf1-participates-in-chromosome-end-protection-by-averting-trf2-dependent-telomeric-r-loops
#6
Yong Woo Lee, Rajika Arora, Harry Wischnewski, Claus M Azzalin
The shelterin protein TRF2 assembles protective T loops at chromosome ends by stimulating intramolecular invasion of the telomeric G-rich single-stranded DNA (ssDNA) overhang into the duplex telomeric array. The other shelterin factor, TRF1, is thought to mainly facilitate telomeric dsDNA replication without directly participating in end protection. Here we show that in vitro human TRF2 stimulates invasion of G-rich TERRA-like RNA into telomeric dsDNA, leading to formation of telomeric RNA-DNA hybrids (telR loops)...
February 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29335368/-in-medio-stat-virtus-unanticipated-consequences-of-telomere-dysequilibrium
#7
REVIEW
Lea Harrington, Fabio Pucci
The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones...
March 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29331736/dysfunctional-telomeres-and-hematological-disorders
#8
REVIEW
Elena Fiorini, Andrea Santoni, Simona Colla
Telomere biology disorders, which are characterized by telomerase activity haploinsufficiency and accelerated telomere shortening, most commonly manifest as degenerative diseases. Tissues with high rates of cell turnover, such as those in the hematopoietic system, are particularly vulnerable to defects in telomere maintenance genes that eventually culminate in bone marrow (BM) failure syndromes, in which the BM cannot produce sufficient new blood cells. Here, we review how telomere defects induce degenerative phenotypes across multiple organs, with particular focus on how they impact the hematopoietic stem and progenitor compartment and affect hematopoietic stem cell (HSC) self-renewal and differentiation...
March 2018: Differentiation; Research in Biological Diversity
https://www.readbyqxmd.com/read/29311622/dual-roles-of-trf1-in-tethering-telomeres-to-the-nuclear-envelope-and-protecting-them-from-fusion-during-meiosis
#9
Lina Wang, Zhaowei Tu, Chao Liu, Hongbin Liu, Philipp Kaldis, Zijiang Chen, Wei Li
Telomeres integrity is indispensable for chromosomal stability by preventing chromosome erosion and end-to-end fusions. During meiosis, telomeres attach to the inner nuclear envelope and cluster into a highly crowded microenvironment at the bouquet stage, which requires specific mechanisms to protect the telomeres from fusion. Here, we demonstrate that germ cell-specific knockout of a shelterin complex subunit, Trf1, results in arrest of spermatocytes at two different stages. The obliterated telomere-nuclear envelope attachment in Trf1-deficient spermatocytes impairs homologue synapsis and recombination, resulting in a pachytene-like arrest, while the meiotic division arrest might stem from chromosome end-to-end fusion due to the failure of recruiting meiosis specific telomere associated proteins...
January 8, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29305433/pinx1-and-tert-are-required-for-tnf-%C3%AE-induced-airway-smooth-muscle-chemokine-gene-expression
#10
Karl Deacon, Alan J Knox
Airway smooth muscle (ASM) cells contribute to asthmatic lung pathology with chemokine hypersecretion and increased ASM cell mass. With little recent progress in the development of asthma therapies, a greater understanding of lung inflammation mechanisms has become a priority. Chemokine gene expression in ASM cells is dependent upon NF-κB transcription factor activity. The telomerase/shelterin complex maintains chromosomal telomere ends during cell division. Telomerase is a possible cofactor for NF-κB activity, but its role in NF-κB activity in airway tissue inflammation is not known...
February 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29240257/altered-expression-of-telomere-associated-genes-in-leukocytes-among-brca1-and-brca2-carriers
#11
Hiromi Tanaka, Elizabeth A Phipps, Ting Wei, Xi Wu, Chirayu Goswami, Yunlong Liu, George W Sledge, Lida Mina, Brittney-Shea Herbert
Telomere dysfunction resulting from telomere shortening and deregulation of shelterin components has been linked to the pathogenesis of age-related disorders, including cancer. Recent evidence suggests that BRCA1/2 (BRCA1 and BRCA2) tumor suppressor gene products play an important role in telomere maintenance. Although telomere shortening has been reported in BRCA1/2 carriers, the direct effects of BRCA1/2 haploinsufficiency on telomere maintenance and predisposition to cancer development are not completely understood...
April 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29227966/pot1-inhibits-the-efficiency-but-promotes-the-fidelity-of-nonhomologous-end-joining-at-non-telomeric-dna-regions
#12
Yang Yu, Rong Tan, Qian Ren, Boya Gao, Zhejin Sheng, Juanlian Zhang, Xiaoqing Zheng, Ying Jiang, Li Lan, Zhiyong Mao
Robust DNA double strand break (DSB) repair and stabilized telomeres help maintain genome integrity, preventing the onset of aging or tumorigenesis. POT1 is one of the six factors in the shelterin complex, which protects telomeres from being recognized as DNA damages. TRF1 and TRF2, two other shelterin proteins, have been shown to participate in DNA DSB repair at non-telomeric regions, but whether POT1, which binds to single strand telomeric DNA at chromosomal ends, is involved in DNA DSB repair has not been assessed...
December 8, 2017: Aging
https://www.readbyqxmd.com/read/29216371/fission-yeast-ccq1-is-a-modulator-of-telomerase-activity
#13
Christine A Armstrong, Vera Moiseeva, Laura C Collopy, Siân R Pearson, Tomalika R Ullah, Shidong T Xi, Jennifer Martin, Shaan Subramaniam, Sara Marelli, Hanna Amelina, Kazunori Tomita
Shelterin, the telomeric protein complex, plays a crucial role in telomere homeostasis. In fission yeast, telomerase is recruited to chromosome ends by the shelterin component Tpz1 and its binding partner Ccq1, where telomerase binds to the 3' overhang to add telomeric repeats. Recruitment is initiated by the interaction of Ccq1 with the telomerase subunit Est1. However, how telomerase is released following elongation remains to be established. Here, we show that Ccq1 also has a role in the suppression of telomere elongation, when coupled with the Clr4 histone H3 methyl-transferase complex and the Clr3 histone deacetylase and nucleosome remodelling complex, SHREC...
January 25, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29203363/mechanism-of-action-of-g-quadruplex-forming-oligonucleotide-homologous-to-the-telomere-overhang-in-melanoma
#14
Gagan Chhabra, Luke Wojdyla, Mark Frakes, Zachary Schrank, Brandon Leviskas, Marko Ivancich, Pooja Vinay, Ramesh Ganapathy, Benjamin E Ramirez, Neelu Puri
T-oligo, a guanine-rich oligonucleotide homologous to the 3'-telomeric overhang of telomeres, elicits potent DNA-damage responses in melanoma cells; however, its mechanism of action is largely unknown. Guanine-rich oligonucleotides can form G-quadruplexes (G4), which are stabilized by the hydrogen bonding of guanine residues. In this study, we confirmed the G4-forming capabilities of T-oligo using nondenaturing PAGE, nuclear magnetic resonance, and immunofluorescence. Using an anti-G-quadruplex antibody, we showed that T-oligo can form G4 in the nuclei of melanoma cells...
December 2, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29192673/trfh-domain-at-the-root-of-telomere-protein-evolution
#15
Marie-Joseph Giraud-Panis, Jing Ye, Eric Gilson
Two articles in Cell Research focus on the structure-function relationships in the shelterin complex that binds to telomeres and is essential for their stability and functions. These studies concerning both mammalian and Schizosaccharomyces pombe proteins reveal unexpected structural conservation of a motif called TRFH (Telomeric Repeat Factors Homology) domain between several subunits in these complexes, providing a rationale for further dissection of the role of telomeres in chromosome stability, aging and cancer, and encouraging us to revisit the evolution of telomere proteins...
January 2018: Cell Research
https://www.readbyqxmd.com/read/29160297/structural-and-functional-analyses-of-the-mammalian-tin2-tpp1-trf2-telomeric-complex
#16
Chunyi Hu, Rekha Rai, Chenhui Huang, Cayla Broton, Juanjuan Long, Ying Xu, Jing Xue, Ming Lei, Sandy Chang, Yong Chen
Telomeres are nucleoprotein complexes that play essential roles in protecting chromosome ends. Mammalian telomeres consist of repetitive DNA sequences bound by the shelterin complex. In this complex, the POT1-TPP1 heterodimer binds to single-stranded telomeric DNAs, while TRF1 and TRF2-RAP1 interact with double-stranded telomeric DNAs. TIN2, the linchpin of this complex, simultaneously interacts with TRF1, TRF2, and TPP1 to mediate the stable assembly of the shelterin complex. However, the molecular mechanism by which TIN2 interacts with these proteins to orchestrate telomere protection remains poorly understood...
December 2017: Cell Research
https://www.readbyqxmd.com/read/29160296/structure-of-the-fission-yeast-s-pombe-telomeric-tpz1-poz1-rap1-complex
#17
Jing Xue, Hongwen Chen, Jian Wu, Miho Takeuchi, Haruna Inoue, Yanmei Liu, Hong Sun, Yong Chen, Junko Kanoh, Ming Lei
Telomeric shelterin complex caps chromosome ends and plays a crucial role in telomere maintenance and protection. In the fission yeast Schizosaccharomyces pombe, shelterin is composed of telomeric single- and double-stranded DNA-binding protein subcomplexes Pot1-Tpz1 and Taz1-Rap1, which are bridged by their interacting protein Poz1. However, the structure of Poz1 and how Poz1 functions as an interaction hub in the shelterin complex remain unclear. Here we report the crystal structure of Poz1 in complex with Poz1-binding motifs of Tpz1 and Rap1...
December 2017: Cell Research
https://www.readbyqxmd.com/read/29150048/dna-dependent-protein-kinase-modulates-the-anti-cancer-properties-of-silver-nanoparticles-in-human-cancer-cells
#18
Hui Kheng Lim, Resham Lal Gurung, M Prakash Hande
Silver nanoparticles (Ag-np) were reported to be toxic to eukaryotic cells. These potentially detrimental effects of Ag-np can be advantageous in experimental therapeutics. They are currently being employed to enhance the therapeutic efficacy of cancer drugs. In this study, we demonstrate that Ag-np treatment trigger the activation of DNA-PKcs and JNK pathway at selected doses, presumably as a physiologic response to DNA damage and repair in normal and malignant cells. Ag-np altered the telomere dynamics by disrupting the shelterin complex located at the telomeres and telomere lengths...
December 2017: Mutation Research
https://www.readbyqxmd.com/read/29149597/structural-basis-for-shelterin-bridge-assembly
#19
Jin-Kwang Kim, Jinqiang Liu, Xichan Hu, Clinton Yu, Kyle Roskamp, Banumathi Sankaran, Lan Huang, Elizabeth A Komives, Feng Qiao
Telomere elongation through telomerase enables chromosome survival during cellular proliferation. The conserved multifunctional shelterin complex associates with telomeres to coordinate multiple telomere activities, including telomere elongation by telomerase. Similar to the human shelterin, fission yeast shelterin is composed of telomeric sequence-specific double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1, and Tpz1. Here, we report the crystal structure of the fission yeast Tpz1475-508 -Poz1-Rap1467-496 complex that provides the structural basis for shelterin bridge assembly...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29149592/dynamics-under-the-telomeric-bridge
#20
REVIEW
Sabrina Pisano, Eric Gilson, Marie-Josèphe Giraud-Panis
In this issue of Molecular Cell, Kim et al. (2017) have studied the structure and organization of the shelterin protein complex protecting telomeres in Schizosaccharomyces pombe and humans and discovered an allosteric structural transition that drives the formation of the shelterin complex and participates in telomere length regulation.
November 16, 2017: Molecular Cell
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