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https://www.readbyqxmd.com/read/28500257/zbtb48-is-both-a-vertebrate-telomere-binding-protein-and-a-transcriptional-activator
#1
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...
May 12, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28490498/shelterin-components-mediate-genome-reorganization-in-response-to-replication-stress
#2
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 10, 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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
https://www.readbyqxmd.com/read/28324506/induction-of-site-specific-oxidative-damage-at-telomeres-by-killerred-fused-shelretin-proteins
#17
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
#18
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
#19
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...
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28238220/telomeres-exercise-and-cardiovascular-disease-finding-the-means-to-justify-the-ends
#20
EDITORIAL
W L Chilton, B J O'Brien, F Grace, F J Charchar
No abstract text is available yet for this article.
February 26, 2017: Acta Physiologica
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