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https://www.readbyqxmd.com/read/29909006/shelterin-differentially-respond-to-oxidative-stress-induced-by-tio-2-nps-and-regulate-telomere-length-in-human-hepatocytes-and-hepatocarcinoma-cells-in-vitro
#1
Han Wang, Juan Ni, Xihan Guo, Tao Zhou, Xiaoling Ma, Jinglun Xue, Xu Wang
Titanium dioxide nanoparticles (TiO2 -NPs) have raised serious attention for their widely use and potential adverse effects on human mainly due to producing ROS. However, the influence of TiO2 -NPs on telomere maintaining has not been studied clearly. Shelterin plays core roles in telomere length (TL) regulation. Abnormal TL are associated with chromosome instability (CIN) and high risk of diseases. This study investigated whether TiO2 -NPs affect TL to induce CIN through ROS generation and the possible mechanisms...
June 13, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29794139/what-i-got-wrong-about-shelterin
#2
Titia de Lange
The ASBMB 2018 Bert and Natalie Vallee award in Biomedical Sciences honors our work on shelterin, a protein complex that helps cells distinguish the chromosome ends from sites of DNA damage. Shelterin protects telomeres from all aspects of the DNA damage response, including ATM and ATR serine/threonine kinase signaling and several forms of double-strand break repair. Today, this six-subunit protein complex could easily be identified in one single proteomics step. But it took us more than 15 years to piece the entire shelterin complex together, one protein at a time...
May 24, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29727617/genome-wide-control-of-heterochromatin-replication-by-the-telomere-capping-protein-trf2
#3
Aaron Mendez-Bermudez, Liudmyla Lototska, Serge Bauwens, Marie-Josèphe Giraud-Panis, Olivier Croce, Karine Jamet, Agurtzane Irizar, Macarena Mowinckel, Stephane Koundrioukoff, Nicolas Nottet, Genevieve Almouzni, Mare-Paule Teulade-Fichou, Michael Schertzer, Mylène Perderiset, Arturo Londoño-Vallejo, Michelle Debatisse, Eric Gilson, Jing Ye
Hard-to-replicate regions of chromosomes (e.g., pericentromeres, centromeres, and telomeres) impede replication fork progression, eventually leading, in the event of replication stress, to chromosome fragility, aging, and cancer. Our knowledge of the mechanisms controlling the stability of these regions is essentially limited to telomeres, where fragility is counteracted by the shelterin proteins. Here we show that the shelterin subunit TRF2 ensures progression of the replication fork through pericentromeric heterochromatin, but not centromeric chromatin...
May 3, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29725012/nucleolar-trf2-attenuated-nucleolus-stress-induced-hcc-cell-cycle-arrest-by-altering-rrna-synthesis
#4
Fuwen Yuan, Chenzhong Xu, Guodong Li, Tanjun Tong
The nucleolus is an important organelle that is responsible for the biogenesis of ribosome RNA (rRNA) and ribosomal subunits assembly. It is also deemed to be the center of metabolic control, considering the critical role of ribosomes in protein translation. Perturbations of rRNA synthesis are closely related to cell proliferation and tumor progression. Telomeric repeat-binding factor 2 (TRF2) is a member of shelterin complex that is responsible for telomere DNA protection. Interestingly, it was recently reported to localize in the nucleolus of human cells in a cell-cycle-dependent manner, while the underlying mechanism and its role on the nucleolus remained unclear...
May 3, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29722029/a-regulatory-loop-connecting-wnt-signaling-and-telomere-capping-possible-therapeutic-implications-for-dyskeratosis-congenita
#5
REVIEW
Rafael Jesus Fernandez, F Brad Johnson
The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres...
April 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29681468/discrimination-against-rna-backbones-by-a-ssdna-binding-protein
#6
Neil R Lloyd, Deborah S Wuttke
Pot1 is the shelterin component responsible for the protection of the single-stranded DNA (ssDNA) overhang at telomeres in nearly all eukaryotic organisms. The C-terminal domain of the DNA-binding domain, Pot1pC, exhibits non-specific ssDNA recognition, achieved through thermodynamically equivalent alternative binding conformations. Given this flexibility, it is unclear how specificity for ssDNA over RNA, an activity required for biological function, is achieved. Examination of the ribose-position specificity of Pot1pC shows that ssDNA specificity is additive but not uniformly distributed across the ligand...
May 1, 2018: Structure
https://www.readbyqxmd.com/read/29663033/how-long-does-telomerase-extend-telomeres-regulation-of-telomerase-release-and-telomere-length-homeostasis
#7
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
#8
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
#9
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...
June 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29550242/evolving-linear-chromosomes-and-telomeres-a-c-strand-centric-view
#10
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...
May 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
#11
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...
March 15, 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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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...
April 2018: Journal of Investigative Dermatology
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