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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/29602239/inflammatory-factor-receptor-toll-like-receptor-4-controls-telomeres-through-heterochromatin-protein-1-isoforms-in-liver-cancer-stem-cell
#2
Qidi Zheng, Jie Xu, Zhuojia Lin, Yanan Lu, Xiaoru Xin, Xiaonan Li, Yuxin Yang, Qiuyu Meng, Chen Wang, Wujun Xiong, Dongdong Lu
Toll-like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone-lysine N-methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9-heterochromatin protein 1-telomere repeat binding factor 2 (H3K9me3-HP1-TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer-associated 1 (CUDR)...
March 30, 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29596531/insights-into-dna-substrate-selection-by-apobec3g-from-structural-biochemical-and-functional-studies
#3
Samantha J Ziegler, Chang Liu, Mark Landau, Olga Buzovetsky, Belete A Desimmie, Qi Zhao, Tomoaki Sasaki, Ryan C Burdick, Vinay K Pathak, Karen S Anderson, Yong Xiong
Human apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (A3) proteins are a family of cytidine deaminases that catalyze the conversion of deoxycytidine (dC) to deoxyuridine (dU) in single-stranded DNA (ssDNA). A3 proteins act in the innate immune response to viral infection by mutating the viral ssDNA. One of the most well-studied human A3 family members is A3G, which is a potent inhibitor of HIV-1. Each A3 protein prefers a specific substrate sequence for catalysis-for example, A3G deaminates the third dC in the CCCA sequence motif...
2018: PloS One
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
#4
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
#5
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
#6
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/29546066/time-dependent-effects-of-pot1-knockdown-on-proliferation-tumorigenicity-and-hdaci-response-of-sk-ov3-ovarian-cancer-cells
#7
Hua Zhou, Abdul Mondal, Aleksandra Dakic, Lama Alhawas, Xuefeng Liu, Zhixu He
The roles of protection of telomeres 1 (POT1) in human ovarian cancer have not been fully elucidated. Here, we investigated the impact of POT1 knockdown (POT1-KD) on in vitro cell proliferation, tumorigenesis, and histone deacetylase inhibitor (HDACi) response in human ovarian cancer-derived SK-OV3 cells. The POT1 gene was knocked down by infection with POT1 lenti-shRNA. POT1, c-Myc, and hTERT mRNA levels and relative telomere length were determined by qRT-PCR; POT1 protein levels were determined by western blot...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29523635/germline-variants-in-the-pot1-gene-in-high-risk-melanoma-patients-in-austria
#8
Christoph Müller, Milica Krunic, Judith Wendt, Arndt von Haeseler, Ichiro Okamoto
Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n=163) or with a positive family history (n=133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced...
March 9, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29522136/human-rtel1-stabilizes-long-g-overhangs-allowing-telomerase-dependent-over-extension
#9
Rosa M Porreca, Galina Glousker, Aya Awad, Maria I Matilla Fernandez, Anne Gibaud, Christian Naucke, Scott B Cohen, Tracy M Bryan, Yehuda Tzfati, Irena Draskovic, Arturo Londoño-Vallejo
Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase...
March 7, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29458554/genetic-shifts-in-methicillin-resistant-staphylococcus-aureus-epidemic-clones-and-toxin-gene-profiles-in-japan-comparative-analysis-among-pre-epidemic-epidemic-and-post-epidemic-phases
#10
Shunsuke Osaka, Katsuko Okuzumi, Shota Koide, Kiyoko Tamai, Tomoaki Sato, Koichi Tanimoto, Haruyoshi Tomita, Masahiro Suzuki, Yukiko Nagano, Keigo Shibayama, Yoshichika Arakawa, Noriyuki Nagano
PURPOSE: The decline in methicillin-resistant Staphylococcus aureus (MRSA) isolation rates has become a general observation worldwide, including Japan. We hypothesized that some genetic shift in MRSA might cause this phenomenon, and therefore we investigated the genetic profiles among MRSA clinical isolates obtained from three different epidemic phases in Japan. METHODOLOGY: A total of 353 MRSA isolates were selected from 202 medical facilities in 1990 (pre-epidemic phase), 2004 (epidemic phase) and 2016 (post-epidemic phase)...
February 2, 2018: Journal of Medical Microbiology
https://www.readbyqxmd.com/read/29410177/mutation-in-fission-yeast-phosphatidylinositol-4-kinase-pik1-is-synthetically-lethal-with-defect-in-telomere-protection-protein-pot1
#11
Asami Sugihara, Luan Cao Nguyen, Hossain Mohammad Shamim, Tetsushi Iida, Mai Nakase, Kaoru Takegawa, Mitsuhisa Senda, Shohei Jida, Masaru Ueno
Fission yeast Pik1p is one of three phosphatidylinositol 4-kinases associated with the Golgi complex, but its function is not fully understood. Deletion of pot1+ causes telomere degradation and chromosome circularization. We searched for the gene which becomes synthetically lethal with pot1Δ. We obtained a novel pik1 mutant, pik1-1, which is synthetically lethal with pot1Δ. We found phosphoinositol 4-phosphate in the Golgi was reduced in pik1-1. To investigate the mechanism of the lethality of the pot1Δ pik1-1 double mutant, we constructed the nmt-pot1-aid pik1-1 strain, where Pot1 function becomes low by drugs, which leads to telomere loss and chromosome circularization, and found pik1-1 mutation does not affect telomere resection and chromosome circularization...
February 2, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29344158/construction-of-the-pot1-promoter-report-gene-vector-and-the-effect-and-underlying-mechanism-of-the-pot1-promoter-in-regulating-telomerase-and-telomere-length
#12
Liang Zeng, Yue-Li Wang, Fa Wang, Shi-Quan Cui, Liang Hu, Di-Nan Huang, Gan Hou
By using human genomic DNA as a template to clone protection of telomere 1 (POT1) promoter gene segments and construct the POT1 promoter luciferase report gene vector (pGL3-Control-POT1-promoter), the association between POT1, and the regulation of telomerase and telomere length was investigated. In the present study, two recombinant luciferase report gene vectors were constructed, which included different regions of the POT1 promoter. The plasmids were transformed into DH5α and the positive clones were obtained...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29298360/chromosome-passenger-complex-is-required-for-the-survival-of-cells-with-ring-chromosomes-in-fission-yeast
#13
Ahmed G K Habib, Kanako Sugiura, Masaru Ueno
Ring chromosomes are circular chromosomal abnormalities that have been reported in association with some genetic disorders and cancers. In Schizosaccharomyces pombe, lack of function of protection of telomere 1 (Pot1) or telomerase catalytic subunit (Trt1) results in survivors with circular chromosomes. Hitherto, it is poorly understood how cells with circular chromosomes survive and how circular chromosomes are maintained. Fission yeast Cut17/Bir1, Ark1, Pic1, and Nbl1 is a conserved chromosome passenger complex (CPC) functioning mainly throughout mitosis...
2018: PloS One
https://www.readbyqxmd.com/read/29227966/pot1-inhibits-the-efficiency-but-promotes-the-fidelity-of-nonhomologous-end-joining-at-non-telomeric-dna-regions
#14
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/29203363/mechanism-of-action-of-g-quadruplex-forming-oligonucleotide-homologous-to-the-telomere-overhang-in-melanoma
#15
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/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/29149597/structural-basis-for-shelterin-bridge-assembly
#18
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/29121084/fission-yeast-strains-with-circular-chromosomes-require-the-9-1-1-checkpoint-complex-for-the-viability-in-response-to-the-anti-cancer-drug-5-fluorodeoxyuridine
#19
Hossain Mohammad Shamim, Yukako Minami, Daiki Tanaka, Shinobu Ukimori, Johanne M Murray, Masaru Ueno
Thymidine kinase converts 5-fluorodeoxyuridine to 5-fluorodeoxyuridine monophosphate, which causes disruption of deoxynucleotide triphosphate ratios. The fission yeast Schizosaccharomyces pombe does not express endogenous thymidine kinase but 5-fluorodeoxyuridine inhibits growth when exogenous thymidine kinase is expressed. Unexpectedly, we found that 5-fluorodeoxyuridine causes S phase arrest even without thymidine kinase expression. DNA damage checkpoint proteins such as the 9-1-1 complex were required for viability in the presence of 5-fluorodeoxyuridine...
2017: PloS One
https://www.readbyqxmd.com/read/29057866/reconstitution-of-human-shelterin-complexes-reveals-unexpected-stoichiometry-and-dual-pathways-to-enhance-telomerase-processivity
#20
Ci Ji Lim, Arthur J Zaug, Hee Jin Kim, Thomas R Cech
The human shelterin proteins associate with telomeric DNA to confer telomere protection and length regulation. They are thought to form higher-order protein complexes for their functions, but studies of shelterin proteins have been mostly limited to pairs of proteins. Here we co-express various human shelterin proteins and find that they form defined multi-subunit complexes. A complex harboring both TRF2 and POT1 has the strongest binding affinity to telomeric DNA substrates comprised of double-stranded DNA with a 3' single-stranded extension...
October 20, 2017: Nature Communications
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