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https://www.readbyqxmd.com/read/29141207/distinct-terb1-domains-regulate-different-protein-interactions-in-meiotic-telomere-movement
#1
Jingjing Zhang, Zhaowei Tu, Yoshinori Watanabe, Hiroki Shibuya
Meiotic telomeres attach to the nuclear envelope (NE) and drive the chromosome movement required for the pairing of homologous chromosomes. The meiosis-specific telomere proteins TERB1, TERB2, and MAJIN are required to regulate these events, but their assembly processes are largely unknown. Here, we developed a germ-cell-specific knockout mouse of the canonical telomere-binding protein TRF1 and revealed an essential role for TRF1 in directing the assembly of TERB1-TERB2-MAJIN. Further, we identified a TERB2 binding (T2B) domain in TERB1 that is dispensable for the TRF1-TERB1 interaction but is essential for the subsequent TERB1-TERB2 interaction and therefore for telomere attachment to the NE...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29137380/inhibitors-of-telomerase-and-poly-adp-ribose-polymerases-synergize-to-limit-the-lifespan-of-pancreatic-cancer-cells
#2
Katrina M Burchett, Asserewou Etekpo, Surinder K Batra, Ying Yan, Michel M Ouellette
Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 and L3.6pl. In both lines, chronic exposure to GRN163L led to an initial shortening of telomeres followed by a stabilization of extremely short telomeres. In AsPC1 cells, telomere attrition eventually led to the induction of crisis and the loss of the treated population...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136505/inhibition-of-trf1-telomere-protein-impairs-tumor-initiation-and-progression-in-glioblastoma-mouse-models-and-patient-derived-xenografts
#3
Leire Bejarano, Alberto J Schuhmacher, Marinela Méndez, Diego Megías, Carmen Blanco-Aparicio, Sonia Martínez, Joaquín Pastor, Massimo Squatrito, Maria A Blasco
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness...
November 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29134494/expression-of-telomere-associated-proteins-is-interdependent-to-stabilize-native-telomere-structure-and-telomere-dysfunction-by-g-quadruplex-ligand-causes-terra-upregulation
#4
Ratan Sadhukhan, Priyanka Chowdhury, Sourav Ghosh, Utpal Ghosh
Telomere DNA can form specialized nucleoprotein structure with telomere-associated proteins to hide free DNA ends or G-quadruplex structures under certain conditions especially in presence of G-quadruplex ligand. Telomere DNA is transcribed to form non-coding telomere repeat-containing RNA (TERRA) whose biogenesis and function is poorly understood. Our aim was to find the role of telomere-associated proteins and telomere structures in TERRA transcription. We silenced four [two shelterin (TRF1, TRF2) and two non-shelterin (PARP-1, SLX4)] telomere-associated genes using siRNA and verified depletion in protein level...
November 13, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29130457/gene-dosage-reductions-of-trf1-and-or-tin2-induce-telomere-dna-damage-and-lymphoma-formation-in-aging-mice
#5
K Hartmann, A Illing, F Leithäuser, A Baisantry, L Quintanilla-Martinez, K L Rudolph
This corrects the article DOI: 10.1038/leu.2015.173.
November 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29126443/ubiquitin-c-terminal-hydrolase-isozyme-l1-is-associated-with-shelterin-complex-at-interstitial-telomeric-sites
#6
Aleksandar Ilic, Sumin Lu, Vikram Bhatia, Farhana Begum, Thomas Klonisch, Prasoon Agarwal, Wayne Xu, James R Davie
BACKGROUND: Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells and has been associated with various diseases, including many cancers. It is a multifunctional protein involved in deubiquitination, ubiquitination and ubiquitin homeostasis, but its specific roles are disputed and still generally undetermined. RESULTS: Herein, we demonstrate that UCHL1 is associated with genomic DNA in certain prostate cancer cell lines, including DU 145 cells derived from a brain metastatic site, and in HEK293T embryonic kidney cells with a neuronal lineage...
November 10, 2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/29097657/modulation-of-telomere-protection-by-the-pi3k-akt-pathway
#7
Marinela Méndez-Pertuz, Paula Martínez, Carmen Blanco-Aparicio, Elena Gómez-Casero, Ana Belen García, Jorge Martínez-Torrecuadrada, Marta Palafox, Javier Cortés, Violeta Serra, Joaquin Pastor, Maria A Blasco
Telomeres and the insulin/PI3K pathway are considered hallmarks of aging and cancer. Here, we describe a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. PI3K and AKT chemical inhibitors reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identify the PI3Kα isoform as responsible for this TRF1 inhibition. TRF1 is phosphorylated at different residues by AKT and these modifications regulate TRF1 protein stability and TRF1 binding to telomeric DNA in vitro and are important for in vivo TRF1 telomere location and cell viability...
November 2, 2017: Nature Communications
https://www.readbyqxmd.com/read/29083416/telomeric-terb1-trf1-interaction-is-crucial-for-male-meiosis
#8
Juanjuan Long, Chenhui Huang, Yanyan Chen, Ying Zhang, Shaohua Shi, Ligang Wu, Yie Liu, Chengyu Liu, Jian Wu, Ming Lei
During meiotic prophase, the meiosis-specific telomere-binding protein TERB1 regulates chromosome movement required for homologous pairing and recombination by interacting with the telomeric shelterin subunit TRF1. Here, we report the crystal structure of the TRF1-binding motif of human TERB1 in complex with the TRFH domain of TRF1. Notably, specific disruption of the TERB1-TRF1 interaction by a point mutation in the mouse Terb1 gene results in infertility only in males. We find that this mutation causes an arrest in the zygotene-early pachytene stage and mild telomere abnormalities of autosomes but unpaired X and Y chromosomes in pachytene, leading to massive spermatocyte apoptosis...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29083414/dissecting-the-telomere-inner-nuclear-membrane-interface-formed-in-meiosis
#9
Devon F Pendlebury, Yasuhiro Fujiwara, Valerie M Tesmer, Eric M Smith, Hiroki Shibuya, Yoshinori Watanabe, Jayakrishnan Nandakumar
Tethering telomeres to the inner nuclear membrane (INM) allows homologous chromosome pairing during meiosis. The meiosis-specific protein TERB1 binds the telomeric protein TRF1 to establish telomere-INM connectivity and is essential for mouse fertility. Here we solve the structure of the human TRF1-TERB1 interface to reveal the structural basis for telomere-INM linkage. Disruption of this interface abrogates binding and compromises telomere-INM attachment in mice. An embedded CDK-phosphorylation site within the TRF1-binding region of TERB1 provides a mechanism for cap exchange, a late-pachytene phenomenon involving the dissociation of the TRF1-TERB1 complex...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28978030/genetic-profile-and-biological-implication-of-pin2-trf1-interacting-telomerase-inhibitor-1-pinx1-in-human-cancers-an-analysis-using-the-cancer-genome-atlas
#10
Wei-Juan Huang, Mei Li, Xiao-Han Jin, Xiao-Jia Huang, Wei Zhao, Xiao-Peng Tian
Pin2/TRF1-interacting telomere inhibitor 1 (PinX1) was originally identified as a telomerase inhibitor, involved in maintaining telomerase activity, telomere length, and chromosomal stability. However, research has shown that PinX1 can have opposing molecular status in its expression patterns in several other tumor types. We thus investigated the genetic profile and biological implication of PinX1 in several human cancers using the cBioportal database. Our results showed that PinX1 deletion accounted for the most alterations, with the frequency of its deletion regularly occurring in pathological types of carcinosarcoma and adenocarcinoma...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28977920/chiral-platinum-ii-4-2-3-dihydroxypropyl-formamide-oxo-aporphine-foa-complexes-promote-tumor-cells-apoptosis-by-directly-targeting-g-quadruplex-dna-in-vitro-and-in-vivo
#11
Qi-Pin Qin, Jiao-Lan Qin, Ming Chen, Yu-Lan Li, Ting Meng, Jie Zhou, Hong Liang, Zhen-Feng Chen
Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(-)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28955502/systematic-analysis-of-human-telomeric-dysfunction-using-inducible-telosome-shelterin-crispr-cas9-knockout-cells
#12
Hyeung Kim, Feng Li, Quanyuan He, Tingting Deng, Jun Xu, Feng Jin, Cristian Coarfa, Nagireddy Putluri, Dan Liu, Zhou Songyang
CRISPR/Cas9 technology enables efficient loss-of-function analysis of human genes using somatic cells. Studies of essential genes, however, require conditional knockout (KO) cells. Here, we describe the generation of inducible CRISPR KO human cell lines for the subunits of the telosome/shelterin complex, TRF1, TRF2, RAP1, TIN2, TPP1 and POT1, which directly interact with telomeres or can bind to telomeres through association with other subunits. Homozygous inactivation of several subunits is lethal in mice, and most loss-of-function studies of human telomere regulators have relied on RNA interference-mediated gene knockdown, which suffers its own limitations...
2017: Cell Discovery
https://www.readbyqxmd.com/read/28944611/gene-therapy-with-the-trf1-telomere-gene-rescues-decreased-trf1-levels-with-aging-and-prolongs-mouse-health-span
#13
Aksinya Derevyanko, Kurt Whittemore, Ralph P Schneider, Verónica Jiménez, Fàtima Bosch, Maria A Blasco
The shelterin complex protects telomeres by preventing them from being degraded and recognized as double-strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 expression in both adult (1-year-old) and old (2-year-old) mice using gene therapy can delay age-associated pathologies...
September 24, 2017: Aging Cell
https://www.readbyqxmd.com/read/28870734/curcusone-c-induces-telomeric-dna-damage-response-in-cancer-cells-through-inhibition-of-telomeric-repeat-factor-2
#14
Mingxue Wang, Jiaojiao Cao, Jian-Yong Zhu, Jun Qiu, Yan Zhang, Bing Shu, Tian-Miao Ou, Jia-Heng Tan, Lian-Quan Gu, Zhi-Shu Huang, Sheng Yin, Ding Li
Telomeric repeat factor 2 (known as TRF2 or TERF2) is a key component of telomere protection protein complex named as Shelterin. TRF2 helps the folding of telomere to form T-loop structure and the suppression of ATM-dependent DNA damage response activation. TRF2 has been recognized as a potentially new therapeutic target for cancer treatment. In our routine screening of small molecule libraries, we found that Curcusone C had significant effect in disrupting the binding between TRF2 and telomeric DNA, with potent antitumor activity against cancer cells...
September 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28862757/the-ccctc-binding-factor-ctcf-forkhead-box-protein-m1-axis-regulates-tumour-growth-and-metastasis-in-hepatocellular-carcinoma
#15
Bin Zhang, Yajing Zhang, Xiaoping Zou, Anthony Wh Chan, Rui Zhang, Terence Kin-Wah Lee, Hang Liu, Eunice Yuen-Ting Lau, Nicole Pui-Yu Ho, Paul Bs Lai, Yue-Sun Cheung, Ka-Fai To, Hoi Kin Wong, Kwong Wai Choy, Vincent W Keng, Larry Mc Chow, Kenrick Ky Chan, Alfred S Cheng, Ben Cb Ko
CCCTC-binding factor (CTCF) is a DNA-binding protein that interacts with a large number of highly divergent target sequences throughout the genome. It is implicated in a variety of functions, including chromatin organization and transcriptional control. The functional role of CTCF in tumour pathogenesis remains elusive. We showed that CTCF is frequently upregulated in a subset of primary hepatocellular carcinomas (HCCs) as compared with non-tumoural liver. Overexpression of CTCF was associated with shorter disease-free survival of patients...
September 1, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28854357/neil3-repairs-telomere-damage-during-s-phase-to-secure-chromosome-segregation-at-mitosis
#16
Jia Zhou, Jany Chan, Marie Lambelé, Timur Yusufzai, Jason Stumpff, Patricia L Opresko, Markus Thali, Susan S Wallace
Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner...
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28808664/expression-of-telomere-repeat-binding-factor-1-and-trf2-in-prostate-cancer-and-correlation-with-clinical-parameters
#17
Wei Chen, Yong Wang, Fei Li, Wei Lin, Yong Liang, Zhiwei Ma
OBJECTIVE: The objective of this study was to investigate the expression of telomere repeat binding factor 1 (TRF1) and TRF2 in prostate cancer and their relationships with clinicopathological features. METHODS: In total 50 prostate cancer tissues and paired benign prostate hyperplasia tissues were analyzed. The telomere-binding proteins TRF1 and TRF2 were measured using immunohistochemical method. Correlation analyses were used to evaluate the association between immunohistochemical score and clinical parameters...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28753579/inhibitors-of-telomerase-and-poly-adp-ribose-polymerases-synergize-to-limit-the-lifespan-of-pancreatic-cancer-cells
#18
Katrina M Burchett, Asserewou Etekpo, Surinder K Batra, Ying Yan, Michel M Ouellette
Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 and L3.6pl. In both lines, chronic exposure to GRN163L led to an initial shortening of telomeres followed by a stabilization of extremely short telomeres. In AsPC1 cells, telomere attrition eventually led to the induction of crisis and the loss of the treated population...
July 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28700353/chiral-platinum-ii-4-2-3-dihydroxypropyl-formamide-oxo-aporphine-foa-complexes-promote-tumor-cells-apoptosis-by-directly-targeting-g-quadruplex-dna-in-vitro-and-in-vivo
#19
Qi-Pin Qin, Jiao-Lan Qin, Ming Chen, Yu-Lan Li, Ting Meng, Jie Zhou, Hong Liang, Zhen-Feng Chen
Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(-)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28698207/strict-tropism-for-cd71-cd234-human-reticulocytes-limits-the-zoonotic-potential-of-plasmodium-cynomolgi
#20
Varakorn Kosaisavee, Rossarin Suwanarusk, Adeline C Y Chua, Dennis E Kyle, Benoit Malleret, Rou Zhang, Mallika Imwong, Rawiwan Imerbsin, Ratawan Ubalee, Hugo Sámano-Sánchez, Bryan K S Yeung, Jessica J Y Ong, Eric Lombardini, François Nosten, Kevin S W Tan, Pablo Bifani, Georges Snounou, Laurent Rénia, Bruce Russell
Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date, only a single case of naturally acquired P cynomolgi has been found in humans. In this study, we show that whereas P cynomolgi merozoites invade monkey red blood cells indiscriminately in vitro, in humans, they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234)...
September 14, 2017: Blood
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