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https://www.readbyqxmd.com/read/28643740/telomere-length-variation-and-expression-analysis-of-shelterin-complex-genes-during-gallbladder-carcinogenesis
#1
Satish S Poojary, Gunja Mishra, Tekcham Dinesh Singh, Sanjiv Gupta, Braj Raj Shrivastav, Pramod Kumar Tiwari
BACKGROUND: Telomeres, which are bound with shelterin protein complex, play an important role in maintaining genomic stability and its dysfunction may lead to carcinogenesis. Here, we aimed to analyze whether shelterin complex gene expression and telomere length variation, play any role in gallbladder carcinogenesis. METHODS: Telomere length analysis was carried out by monochrome multiplex qPCR, whereas expression analysis of shelterin genes was carried out using RT-qPCR...
April 2017: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/28587932/preliminary-evidence-that-age-and-sex-affect-exercise-induced-htert-expression
#2
Travis G Cluckey, Nathan C Nieto, Bridger M Rodoni, Tinna Traustadóttir
The ability to repair cellular damage is reduced with aging, resulting in cellular senescence. Telomeres shorten as cells divide but the rate of telomere attrition is modulated by telomerase, an enzyme that adds nucleotides to the chromosome. Shelterin is a protein complex that acts as a negative regulator of telomerase. The aim of the present study was to investigate age-related differences in telomerase and shelterin responses to acute exercise. We hypothesized that acute exercise would stimulate an increased activity of telomerase (measured by telomerase reverse transcriptase, hTERT) without an increase in activity of shelterin (measured by telomeric repeat binding factor 2, TRF2) in both young and older individuals and that hTERT response would be attenuated in older individuals...
June 3, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28586040/low-expression-of-pinx1-is-associated-with-malignant-behavior-in-basal-like-breast-cancer
#3
Yu-Zhen Feng, Qing-Yan Zhang, Mei-Ting Fu, Zhen-Fei Zhang, Min Wei, Jue-Yu Zhou, Rong Shi
Human Pinx1 protein, associated with shelterin proteins, is widely revealed as a haploinsufficient tumor suppressor. Growing evidence has manifested the deregulation of PinX1 in distinct cancers. Nonetheless, the loss status of PinX1 and its diagnostic, prognostic and clinicopathological significance in Basal-like breast cancer are still unclear. In the present study, the PinX1 expression levels of breast cancer tissues were investigated by qRT-PCR and immunoblotting assays. Then immunohistochemistry (IHC) was performed to detect PinX1 expression on a tissue microarray...
June 2, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28575699/a-novel-spliced-variant-of-the-tin2-shelterin-is-present-in-chronic-lymphocytic-leukemia
#4
Ganchimeg Ishdorj, Sara E F Kost, Sara Beiggi, Yunli Zang, Spencer B Gibson, James B Johnston
The shelterin proteins play important roles in telomere maintenance and genome stability. These proteins have been found to be mutated in many cancers including CLL. Herein, we demonstrate here the presence of a novel spliced isoform of TIN2S in chronic lymphocytic leukemia (CLL), related to deletion of exon 2 in the TIN2 gene. The expressions of spliced TIN2S mRNA varied widely in CLL and there was an inverse relationship between the mRNA levels of full-length TIN2S and the spliced moiety. Small amounts of spliced TIN2S were also observed in normal B cells but not in T cells...
May 29, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28500257/zbtb48-is-both-a-vertebrate-telomere-binding-protein-and-a-transcriptional-activator
#5
Arne Jahn, Grishma Rane, Maciej Paszkowski-Rogacz, Sergi Sayols, Alina Bluhm, Chung-Ting Han, Irena Draškovič, José Arturo Londoño-Vallejo, Alan Prem Kumar, Frank Buchholz, Falk Butter, Dennis Kappei
Telomeres constitute the ends of linear chromosomes and together with the shelterin complex form a structure essential for genome maintenance and stability. In addition to the constitutive binding of the shelterin complex, other direct, yet more transient interactions are mediated by the CST complex and HOT1/HMBOX1, while subtelomeric variant repeats are recognized by NR2C/F transcription factors. Recently, the Kruppel-like zinc finger protein ZBTB48/HKR3/TZAP has been described as a novel telomere-associated factor in the vertebrate lineage...
June 2017: EMBO Reports
https://www.readbyqxmd.com/read/28490498/shelterin-components-mediate-genome-reorganization-in-response-to-replication-stress
#6
Takeshi Mizuguchi, Nitika Taneja, Emiko Matsuda, Jon-Matthew Belton, Peter FitzGerald, Job Dekker, Shiv I S Grewal
The dynamic nature of genome organization impacts critical nuclear functions including the regulation of gene expression, replication, and DNA damage repair. Despite significant progress, the mechanisms responsible for reorganization of the genome in response to cellular stress, such as aberrant DNA replication, are poorly understood. Here, we show that fission yeast cells carrying a mutation in the DNA-binding protein Sap1 show defects in DNA replication progression and genome stability and display extensive changes in genome organization...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28482095/prl-3-promotes-telomere-deprotection-and-chromosomal-instability
#7
Shenyi Lian, Lin Meng, Yongyong Yang, Ting Ma, Xiaofang Xing, Qin Feng, Qian Song, Caiyun Liu, Zhihua Tian, Like Qu, Chengchao Shou
Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence...
May 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28437249/the-differential-spatiotemporal-expression-pattern-of-shelterin-genes-throughout-lifespan
#8
Kay-Dietrich Wagner, Yilin Ying, Waiian Leong, Jie Jiang, Xuefei Hu, Yi Chen, Jean-François Michiels, Yiming Lu, Eric Gilson, Nicole Wagner, Jing Ye
Shelterin forms the core complex of telomere proteins and plays critical roles in protecting telomeres against unwanted activation of the DNA damage response and in Emaintaining telomere length homeostasis. Although shelterin expression is believed to be ubiquitous for stabilization of chromosomal ends. Evidences suggest that some shelterin subunits have tissue-specific functions. However, very little is known regarding how shelterin subunit gene expression is regulated during development and aging. Using two different animal models, the mouse and zebrafish, we reveal herein that shelterin subunits exhibit distinct spatial and temporal expression patterns that do not correlate with the proliferative status of the organ systems examined...
April 2017: Aging
https://www.readbyqxmd.com/read/28436953/disruption-of-direct-3d-telomere-trf2-interaction-through-two-molecularly-disparate-mechanisms-is-a-hallmark-of-primary-hodgkin-and-reed-sternberg-cells
#9
Hans Knecht, Nathalie A Johnson, Tina Haliotis, Daniel Lichtensztejn, Sabine Mai
In classical Hodgkin's lymphoma (cHL), specific changes in the 3D telomere organization cause progression from mononuclear Hodgkin cells (H) to multinucleated Reed-Sternberg cells (RS). In a post-germinal center B-cell in vitro model, permanent latent membrane protein 1 (LMP1) expression, as observed in Epstein-Barr virus (EBV)-associated cHL, results in multinuclearity and complex chromosomal aberrations through downregulation of key element of the shelterin complex, the telomere repeat binding factor 2 (TRF2)...
April 24, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28430596/snm1b-apollo-in-the-dna-damage-response-and-telomere-maintenance
#10
REVIEW
Maren Schmiester, Ilja Demuth
hSNM1B/Apollo is a member of the highly conserved β-CASP subgroup within the MBL superfamily of proteins. It interacts with several DNA repair proteins and functions within the Fanconi anemia pathway in response to DNA interstrand crosslinks. As a shelterin accessory protein, hSNM1B/Apollo is also vital for the generation and maintenance of telomeric overhangs. In this review, we will summarize studies on hSNM1B/Apollo's function, including its contribution to DNA damage signaling, replication fork maintenance, control of topological stress and telomere protection...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28428263/different-requirements-of-functional-telomeres-in-neural-stem-cells-and-terminally-differentiated-neurons
#11
Anastasia Lobanova, Robert She, Simon Pieraut, Charlie Clapp, Anton Maximov, Eros Lazzerini Denchi
Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons...
April 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28425274/profile-of-pot1-as-telomerase-shelterin-component-discriminatesbetween-cervical-cancer-and-normal-cervical-cells
#12
Andreas Budi Wijaya, Furqan Hidayatullah, Verina Veronica Setyabudhi, Faizal Reza Pahlevi, Rasyad Indra, Tatit Nurseta
BACKGROUND/AIM: Telomerase activity is influenced by hTERT transcriptional regulation, shelterin, and posttranscriptional alternative splicing. Telomerase shelterin such as POT1 is highly correlated with various cancers. However, the profile of POT1 in cervical cancer has not been clearly identified. Therefore, it is important to identify its profile in cervical cancer biopsy tissue and normal cervical smears. MATERIALS AND METHODS: Biopsy tissue of cervical cancer patients and normal cervical smears were characterized using SDS-PAGE and western blot...
April 18, 2017: Turkish Journal of Medical Sciences
https://www.readbyqxmd.com/read/28393832/structural-insights-into-pot1-tpp1-interaction-and-pot1-c-terminal-mutations-in-human-cancer
#13
Cong Chen, Peili Gu, Jian Wu, Xianyun Chen, Shuangshuang Niu, Hong Sun, Lijie Wu, Na Li, Junhui Peng, Shaohua Shi, Cuiying Fan, Min Huang, Catherine C L Wong, Qingguo Gong, Chandan Kumar-Sinha, Rongguang Zhang, Lajos Pusztai, Rekha Rai, Sandy Chang, Ming Lei
Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPα-β complex, POT1-TPP1 adopts an elongated V-shaped conformation...
April 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28393830/structural-and-functional-analysis-of-the-human-pot1-tpp1-telomeric-complex
#14
Cory Rice, Prashanth Krishna Shastrula, Andrew V Kossenkov, Robert Hills, Duncan M Baird, Louise C Showe, Tzanko Doukov, Susan Janicki, Emmanuel Skordalakes
POT1 and TPP1 are part of the shelterin complex and are essential for telomere length regulation and maintenance. Naturally occurring mutations of the telomeric POT1-TPP1 complex are implicated in familial glioma, melanoma and chronic lymphocytic leukaemia. Here we report the atomic structure of the interacting portion of the human telomeric POT1-TPP1 complex and suggest how several of these mutations contribute to malignant cancer. The POT1 C-terminus (POT1C) forms a bilobal structure consisting of an OB-fold and a holiday junction resolvase domain...
April 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28389767/a-new-pot1-germline-mutation-expanding-the-spectrum-of-pot1-associated-cancers
#15
Tremika Le-Shan Wilson, Namita Hattangady, Antonio Marcondes Lerario, Carmen Williams, Erika Koeppe, Shane Quinonez, Jenae Osborne, Kelly B Cha, Tobias Else
Melanomas are associated with several hereditary conditions. We present a large family with several family members affected with primary melanomas and dysplastic nevi as well as thyroid cancer and other malignant tumors. Clinical work-up did not reveal a mutation in any of the genes usually considered with evaluation for predisposition to melanoma (BRCA1/2, CDKN2A, CDK4, PTEN, TP53). Whole exome sequencing of five affected family members showed a new variant in POT1. POT1 is associated with the telomere shelterin complex that regulates telomere protection and telomerase access...
April 7, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28381412/the-ddr-at-telomeres-lacking-intact-shelterin-does-not-require-substantial-chromatin-decompaction
#16
Leonid A Timashev, Hazen Babcock, Xiaowei Zhuang, Titia de Lange
Telomeres are protected by shelterin, a six-subunit protein complex that represses the DNA damage response (DDR) at chromosome ends. Extensive data suggest that TRF2 in shelterin remodels telomeres into the t-loop structure, thereby hiding telomere ends from double-stranded break repair and ATM signaling, whereas POT1 represses ATR signaling by excluding RPA. An alternative protection mechanism was suggested recently by which shelterin subunits TRF1, TRF2, and TIN2 mediate telomeric chromatin compaction, which was proposed to minimize access of DDR factors...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28381410/the-telomeric-dna-damage-response-occurs-in-the-absence-of-chromatin-decompaction
#17
Aleksandra Vancevska, Kyle M Douglass, Verena Pfeiffer, Suliana Manley, Joachim Lingner
Telomeres are specialized nucleoprotein structures that protect chromosome ends from DNA damage response (DDR) and DNA rearrangements. The telomeric shelterin protein TRF2 suppresses the DDR, and this function has been attributed to its abilities to trigger t-loop formation or prevent massive decompaction and loss of density of telomeric chromatin. Here, we applied stochastic optical reconstruction microscopy (STORM) to measure the sizes and shapes of functional human telomeres of different lengths and dysfunctional telomeres that elicit a DDR...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28369633/mutations-in-xlf-nhej1-cernunnos-gene-results-in-downregulation-of-telomerase-genes-expression-and-telomere-shortening
#18
Jaime Carrillo, Oriol Calvete, Laura Pintado-Berninches, Cristina Manguan-García, Julian Sevilla Navarro, Elena G Arias-Salgado, Leandro Sastre, Guillermo Guenechea, Eduardo López Granados, Jean-Pierre de Villartay, Patrick Revy, Javier Benitez, Rosario Perona
NHEJ1-patients develop severe progressive lymphocytopenia and premature aging of hematopoietic stem cells (HSCs) at a young age. Here we show a patient with a homozygous-NHEJ1 mutation identified by whole exome-sequencing that developed severe pancytopenia and bone marrow aplasia correlating with the presence of short telomeres. The mutation resulted in a truncated protein. In an attempt to identify the mechanism behind the short telomere phenotype found in the NHEJ1-patient we downregulated NHEJ1 expression in 293T and CD34+cells...
May 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28350373/dna-replication-origins-and-fork-progression-at-mammalian-telomeres
#19
REVIEW
Mitsunori Higa, Masatoshi Fujita, Kazumasa Yoshida
Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed that replication of telomeric repeats is a potential cause of chromosomal instability, because DNA replication through telomeres is challenged by the repetitive telomeric sequences and specific structures that hamper the replication fork...
March 28, 2017: Genes
https://www.readbyqxmd.com/read/28342451/tert-promoter-mutations-in-telomere-biology
#20
REVIEW
Barbara Heidenreich, Rajiv Kumar
Telomere repeats at chromosomal ends, critical to genome integrity, are maintained through an elaborate network of proteins and pathways. Shelterin complex proteins shield telomeres from induction of DNA damage response to overcome end protection problem. A specialized ribonucleic protein, telomerase, maintains telomere homeostasis through repeat addition to counter intrinsic shortcomings of DNA replication that leads to gradual sequence shortening in successive mitoses. The biogenesis and recruitment of telomerase composed of telomerase reverse transcriptase (TERT) subunit and an RNA component, takes place through the intricate machinery that involves an elaborate number of molecules...
January 2017: Mutation Research
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