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https://www.readbyqxmd.com/read/28986560/the-telomere-binding-protein-pot1-maintains-haematopoietic-stem-cell-activity-with-age
#1
Kentaro Hosokawa, Ben D MacArthur, Yoshiko Matsumoto Ikushima, Hirofumi Toyama, Yoshikazu Masuhiro, Shigemasa Hanazawa, Toshio Suda, Fumio Arai
Repeated cell divisions and aging impair stem cell function. However, the mechanisms by which this occurs are not fully understood. Here we show that protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, improves haematopoietic stem cell (HSC) activity during aging. Pot1a is highly expressed in young HSCs, but declines with age. In mouse HSCs, Pot1a knockdown increases DNA damage response (DDR) and inhibits self-renewal. Conversely, Pot1a overexpression or treatment with POT1a protein prevents DDR, maintained self-renewal activity and rejuvenated aged HSCs upon ex vivo culture...
October 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28981887/molecular-mechanisms-by-which-oxidative-dna-damage-promotes-telomerase-activity
#2
Hui-Ting Lee, Arindam Bose, Chun-Ying Lee, Patricia L Opresko, Sua Myong
Telomeres are highly susceptible to oxidative DNA damage, which if left unrepaired can lead to dysregulation of telomere length homeostasis. Here we employed single molecule FRET, single molecule pull-down and biochemical analysis to investigate how the most common oxidative DNA lesions, 8-oxoguanine (8oxoG) and thymine glycol (Tg), regulate the structural properties of telomeric DNA and telomerase extension activity. In contrast to 8oxoG which disrupts the telomeric DNA structure, Tg exhibits substantially reduced perturbation of G-quadruplex folding...
September 18, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28955502/systematic-analysis-of-human-telomeric-dysfunction-using-inducible-telosome-shelterin-crispr-cas9-knockout-cells
#3
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/28922845/pot1-mediated-%C3%AE-integration-strategy-for-high-copy-stable-expression-of-heterologous-proteins-in-saccharomyces-cerevisiae
#4
Xiaofei Song, Quanli Liu, Jiwei Mao, Yuzhen Wu, Yuanzi Li, Kai Gao, Xiuming Zhang, Yanling Bai, Haijin Xu, Mingqiang Qiao
In biotechnological industry, increased expression cassette stability and copy number serve as important means of maintaining consistently high production levels of heterologous proteins in Saccharomyces cerevisiae. In this study, we combined δ sequences for site-specific integration with TPI1 gene from Schizosaccharomyces pombe (POT1) as a selection marker to realize high-copy integration and stable expression of heterologous proteins in S. cerevisiae. With the newly developed POT1 platform, a 32-copy integration of enhanced green fluorescent protein (EGFP) expression cassette was obtained in a single round and was stably maintained after 100 generations of growth in a rich complex medium...
September 1, 2017: FEMS Yeast Research
https://www.readbyqxmd.com/read/28853721/the-wide-spectrum-of-pot1-gene-variants-correlates-with-multiple-cancer-types
#5
Oriol Calvete, Pablo Garcia-Pavia, Fernando Domínguez, Gaelle Bougeard, Kristin Kunze, Andreas Braeuninger, Alex Teule, Adriana Lasa, Teresa Ramón Y Cajal, Gemma Llort, Victoria Fernández, Conxi Lázaro, Miguel Urioste, Javier Benitez
The POT1 protein binds and protects telomeres. Germline variants in the POT1 gene have recently been shown to be associated with risk of developing tumors in different tissues such as familial chronic lymphocytic leukemia, colorectal, glioma and melanoma tumors. Recently, we uncovered a variant in the POT1 gene (p.R117C) as causative of familial cardiac angiosarcomas (CAS) in Li-Fraumeni-like (LFL) syndrome families. Our in silico studies predicted that this protein had lost the ability to interact with TPP1 and single-stranded DNA...
November 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28811689/expression-of-telomere-binding-proteins-rap1-and-pot1-in-renal-cell-carcinoma-and-their-correlation-with-clinicopathological-parameters
#6
Deeksha Pal, Shrawan Kumar Singh, Nandita Kakkar, Rajendra Prasad
Telomere stability is indispensable for continuous proliferation of cells. Telomere structure is maintained by group of six proteins termed as shelterin. RAP1 and POT1 proteins are significant members of shelterin complex. Expression of RAP1 and POT1 are crucial for telomere maintenance and hence uncontrolled division of cells. Notably, expression of RAP1 and POT1 is unknown in renal cell carcinoma (RCC). In view of these facts, the present study was initiated to investigate the expression of RAP1 and POT1 in RCC and their relationships with clinicopathological features...
July 2017: Indian Journal of Clinical Biochemistry: IJCB
https://www.readbyqxmd.com/read/28686874/telomere-protection-by-tpp1-pot1-requires-tethering-to-tin2
#7
Kaori K Takai, Tatsuya Kibe, Jill R Donigian, David Frescas, Titia de Lange
No abstract text is available yet for this article.
July 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28643740/telomere-length-variation-and-expression-analysis-of-shelterin-complex-genes-during-gallbladder-carcinogenesis
#8
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/28485764/%C3%A3-kad-kunskap-om-familj%C3%A3-rt-melanom-och-de-bakom%C3%A2-liggande-generna
#9
Hildur Helgadottir, Kari Nielsen, Veronica Höiom
Increased knowledge on familial melanoma and the underlying genetics Approximately 5-10 % of all melanoma patients have close relatives with melanoma. 5-20% of melanoma families have germline mutations in the CDKN2A gene. Swedish CDKN2A mutation carriers have a young median age of onset of melanoma, increased risks of multiple primary melanoma and of tobacco-associated cancers in respiratory and upper digestive tissues, and also worse survival compared to non-carriers. In up to 80% of melanoma families no high risk melanoma associated germline mutations are found...
May 9, 2017: Läkartidningen
https://www.readbyqxmd.com/read/28459507/molecular-recognition-of-a-carboxy-pyridostatin-toward-g-quadruplex-structures-why-does-it-prefer-rna
#10
Roberta Rocca, Carmine Talarico, Federica Moraca, Giosuè Costa, Isabella Romeo, Francesco Ortuso, Stefano Alcaro, Anna Artese
The pyridostatin (PDS) represents the lead compound of a family of G-quadruplex (G4) stabilizing synthetic small molecules based on a N,N'-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold. Its mechanism of action involves the induction of telomere dysfunction by competing for binding with telomere-associated proteins, such as human POT1. Recently, through a template-directed "in situ" click chemistry approach, a PDS derivative, the carboxypyridostatin (cPDS), was discovered. It has the peculiarity to exhibit high molecular specificity for RNA over DNA G4, while PDS is a good generic RNA and DNA G4-interacting small molecule...
April 29, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28425274/profile-of-pot1-as-telomerase-shelterin-component-discriminatesbetween-cervical-cancer-and-normal-cervical-cells
#11
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/28404540/abnormal-mrna-expression-levels-of-telomere-binding-proteins-represent-biomarkers-in-myelodysplastic-syndromes-a-case-control-study
#12
Baoshan Liu, Rongdi Yan, Jie Zhang, Bin Wang, Hu Sun, Xing Cui
OBJECTIVE: As evidence was shown that abnormal shortening of telomeres begins to accumulate in myelodysplastic syndrome (MDS) patients, this study was conducted to determine the relationship between the mRNA expression levels of telomere-binding proteins (TRF1/TRF2/TIN2/TPP1/POT1/RAP1) and the risk level in MDS. MATERIALS AND METHODS: There were 40 patients with MDS and 40 normal controls in this study. Methods including telomere content assays and quantitative reverse transcription-polymerase chain reaction were used to examine the mRNA levels of TRF1/TRF2/TIN2/TPP1/POT1/RAP1 in patients with MDS...
August 2, 2017: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
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/28283772/identification-genetic-testing-and-management-of-hereditary-melanoma
#17
Sancy A Leachman, Olivia M Lucero, Jone E Sampson, Pamela Cassidy, William Bruno, Paola Queirolo, Paola Ghiorzo
Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal "rule of twos and threes," but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: "melanoma dominant" and "melanoma subordinate...
March 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28216226/nbs1-phosphorylation-status-dictates-repair-choice-of-dysfunctional-telomeres
#18
Rekha Rai, Chunyi Hu, Cayla Broton, Yong Chen, Ming Lei, Sandy Chang
Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. The crystal structure of the TRF2-NBS1 complex at 3.0 Å resolution shows that the NBS1 429YQLSP433 motif interacts specifically with the TRF2(TRFH) domain...
March 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28146043/characterization-of-melanoma-susceptibility-genes-in-high-risk-patients-from-central-italy
#19
Cristina Pellegrini, Maria Giovanna Maturo, Claudia Martorelli, Mariano Suppa, Ambra Antonini, Dimitra Kostaki, Lucilla Verna, Maria Teresa Landi, Ketty Peris, Maria Concetta Fargnoli
Genetic susceptibility to cutaneous melanoma has been investigated in Italian high-risk melanoma patients from different geographical regions. CDKN2A, CDK4, and MC1R genes have been screened in most studies, MITF and POT1 were screened in only one study, and none analyzed the TERT promoter. We carried out a mutational analysis of CDKN2A, CDK4 exon 2, POT1 p.S270N, MITF exon 10, MC1R, and the TERT promoter in 106 high-risk patients with familial melanoma (FM) and sporadic multiple primary melanoma (spMPM) from Central Italy and evaluated mutations according to the clinicopathological characteristics of patients and lesions...
June 2017: Melanoma Research
https://www.readbyqxmd.com/read/27959900/genomic-profile-of-chronic-lymphocytic-leukemia-in-korea-identified-by-targeted-sequencing
#20
Jung-Ah Kim, Byungjin Hwang, Si Nae Park, Sunghoon Huh, Kyongok Im, Sungbin Choi, Hye Yoon Chung, JooRyung Huh, Eul-Ju Seo, Je-Hwan Lee, Duhee Bang, Dong Soon Lee
Chronic lymphocytic leukemia (CLL) is extremely rare in Asian countries and there has been one report on genetic changes for 5 genes (TP53, SF3B1, NOTCH1, MYD88, and BIRC3) by Sanger sequencing in Chinese CLL. Yet studies of CLL in Asian countries using Next generation sequencing have not been reported. We aimed to characterize the genomic profiles of Korean CLL and to find out ethnic differences in somatic mutations with prognostic implications. We performed targeted sequencing for 87 gene panel using next-generation sequencing along with G-banding and fluorescent in situ hybridization (FISH) for chromosome 12, 13q14...
2016: PloS One
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