keyword
https://read.qxmd.com/read/37879098/the-c-terminal-extension-of-dyskerin-is-a-dyskeratosis-congenita-mutational-hotspot-that-modulates-interaction-with-telomerase-rna-and-subcellular-localization
#1
JOURNAL ARTICLE
Jian Qin, Alexandre Garus, Chantal Autexier
Dyskerin is a component of the human telomerase complex and is involved in stabilizing the human telomerase RNA (hTR). Many mutations in the DKC1 gene encoding dyskerin are found in X-linked dyskeratosis congenita (X-DC), a premature aging disorder and other related diseases. The C-terminal extension (CTE) of dyskerin contributes to its interaction with the molecular chaperone SHQ1 during the early stage of telomerase biogenesis. Disease mutations in this region were proposed to disrupt dyskerin-SHQ1 interaction and destabilize dyskerin, reducing hTR levels indirectly...
October 25, 2023: Human Molecular Genetics
https://read.qxmd.com/read/37750664/selenomethionine-suppresses-head-and-neck-squamous-cell-carcinoma-progression-through-topbp1-atr-and-tcab1-signaling
#2
JOURNAL ARTICLE
Bo Zhang, Xiaodong Wei, Jiwu Li
OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) is a histological type of cancer originating from the head and neck. Selenium complexes have been considered as a potential treatment for HNSCC. Therefore, the present work focused on probing the mechanism of L-selenomethionine (SeMet) in HNSCC treatment. METHODS: MTT and colony formation assays were carried out to analyze the survival rate and proliferation of HNSCC cells, respectively. TUNEL staining was performed to examine apoptosis of HNSCC cells...
September 11, 2023: Histology and Histopathology
https://read.qxmd.com/read/37267110/tcab1-prevents-nucleolar-accumulation-of-the-telomerase-rna-to-facilitate-telomerase-assembly
#3
JOURNAL ARTICLE
Basma M Klump, Gloria I Perez, Eric M Patrick, Kate Adams-Boone, Scott B Cohen, Li Han, Kefei Yu, Jens C Schmidt
Localization of a variety of RNAs to non-membrane-bound cellular compartments such as nucleoli and Cajal bodies is critical for their stability and function. The molecular mechanisms that underly the recruitment and exclusion of RNAs from these phase-separated organelles is incompletely understood. Telomerase is a ribonucleoprotein composed of the reverse transcriptase protein telomerase reverse transcriptase (TERT), the telomerase RNA (TR), and several auxiliary proteins, including TCAB1. Here we show that in the absence of TCAB1, a large fraction of TR is tightly bound to the nucleolus, while TERT is largely excluded from the nucleolus, reducing telomerase assembly...
June 1, 2023: Cell Reports
https://read.qxmd.com/read/36937416/case-report-a-novel-mutation-in-rtel1-gene-in-dyskeratosis-congenita
#4
Haider Nisar, Memoona Khan, Qamar Un Nisa Chaudhry, Raheel Iftikhar, Tariq Ghafoor
Dyskeratosis congenita (DKC), also known as Zinsser-Cole-Engman syndrome, is a telomeropathy typically presenting as a triad of leukoplakia, nail dystrophy, and reticular hyperpigmentation. Reported genetic mutations linked to DKC include DKC1 , TINF2 , TERC , TERT , C16orf57 , NOLA2 , NOLA3 , WRAP53/TCAB1 , and RTEL1 . Homozygous, compound heterozygous, and heterozygous mutations in RTEL1 ( RTEL1 , regulator of telomere elongation helicase 1) gene on chromosome 20q13 are known to cause autosomal dominant as well as recessive DKC...
2023: Frontiers in Oncology
https://read.qxmd.com/read/36354684/the-role-of-wrap53-in-cell-homeostasis-and-carcinogenesis-onset
#5
REVIEW
Renan Brito Gadelha, Caio Bezerra Machado, Flávia Melo Cunha de Pinho Pessoa, Laudreísa da Costa Pantoja, Igor Valentim Barreto, Rodrigo Monteiro Ribeiro, Manoel Odorico de Moraes Filho, Maria Elisabete Amaral de Moraes, André Salim Khayat, Caroline Aquino Moreira-Nunes
The WD repeat containing antisense to TP53 ( WRAP53 ) gene codifies an antisense transcript for tumor protein p53 ( TP53 ), stabilization (WRAP53α), and a functional protein (WRAP53β, WDR79, or TCAB1). The WRAP53β protein functions as a scaffolding protein that is important for telomerase localization, telomere assembly, Cajal body integrity, and DNA double-strand break repair. WRAP53β is one of many proteins known for containing WD40 domains, which are responsible for mediating a variety of cell interactions...
November 4, 2022: Current Issues in Molecular Biology
https://read.qxmd.com/read/36249522/-de-novo-tinf2-c-845g-a-pathogenic-variant-in-patient-with-dyskeratosis-congenita
#6
S A Kocheva, M Gjorgjievska, K Martinova, Z Antevska-Trajkova, A Jovanovska, D Plaseska-Karanfilska
Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous, multisystem inherited syndrome with a very high risk for bone marrow failure (BMF) and cancer predisposition. The classical clinical form of DC is characterized by abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. Bone marrow failure is considered to be an important and major complication of DC and the leading cause of death which develops in around 85% of cases. A number of genes involved in telomere maintenance are associated with DC, such as genes that encode the components of the telomerase complex ( TERT , DKC1 , TERC , NOP 10, and NHP 2), T-loop assembly protein ( RTEL1 ), telomere capping ( CTC1 ), telomere shelterin complex ( TINF2 ), and telomerase trafficking protein ( TCAB1 )...
November 2021: Balkan Journal of Medical Genetics: BJMG
https://read.qxmd.com/read/36239411/genomic-epigenomic-and-transcriptomic-signatures-for-telomerase-complex-components-a-pan-cancer-analysis
#7
JOURNAL ARTICLE
Jing Wang, Mingkai Dai, Xiangling Xing, Xing Wang, Xin Qin, Tao Huang, Zhiqing Fang, Yidong Fan, Dawei Xu
Telomerase activation is required for malignant transformation. Recent advances in high throughput technologies have enabled the generation of complex data sets, thus providing alternative approaches to exploring telomerase biology more comprehensively, which has proven to be challenging due to the need for laborious assays required to test for telomerase activity. To solve these issues, several groups have analyzed TCGA pan-cancer tumor datasets by investigating telomerase reverse transcriptase (TERT), the catalytic subunit for telomerase activity, or its surrogates...
October 14, 2022: Molecular Oncology
https://read.qxmd.com/read/36116037/next-generation-sequencing-errors-due-to-genetic-variation-in-wrap53-encoding-tcab1-on-chromosome-17
#8
JOURNAL ARTICLE
Sharon A Savage, Kristine Jones, Kedest Teshome, Adriana Lori, Lisa J McReynolds, Marena R Niewisch
Next generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate by Sanger sequencing. This error occurs because rs755116516 G>-/GG/GGG (Chr17:7,606,714) is polymorphic and variants at this site challenge the ability of NGS to accurately call the correct number of nucleotides in a homopolymer run...
September 18, 2022: Human Mutation
https://read.qxmd.com/read/33482595/molecular-mechanisms-of-telomere-biology-disorders
#9
REVIEW
Sherilyn Grill, Jayakrishnan Nandakumar
Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere...
January 2021: Journal of Biological Chemistry
https://read.qxmd.com/read/33413389/suppression-of-tcab1-expression-induced-cellular-senescence-by-lessening-proteasomal-degradation-of-p21-in-cancer-cells
#10
JOURNAL ARTICLE
Jing Niu, Rui-Qi Gao, Meng-Tian Cui, Chen-Guang Zhang, Shen-Tao Li, Shan Cheng, Wei Ding
BACKGROUND: TCAB1, a.k.a. WRAP53β or WDR79, is an important molecule for the maintenance of Cajal bodies and critically involved in telomere elongation and DNA repair. Upregulation of TCAB1 were discovered in a variety types of cancers. However, the function of TCAB1 in tumor cell senescence remains absent. METHODS: The TCAB1 knockdown cell lines were constructed. The expression levels of TCAB1, p21, p16 and p53 were detected by qRT-PCR and western blotting. Staining of senescence-associated β-galactosidase was used to detect senescent cells...
January 7, 2021: Cancer Cell International
https://read.qxmd.com/read/33184060/molecular-mechanisms-of-telomere-biology-disorders
#11
REVIEW
Sherilyn Grill, Jayakrishnan Nandakumar
Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita (DC), pulmonary fibrosis (PF) and aplastic anemia (AA), is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere...
November 12, 2020: Journal of Biological Chemistry
https://read.qxmd.com/read/32303682/biallelic-mutations-in-wrap53-result-in-dysfunctional-telomeres-cajal-bodies-and-dna-repair-thereby-causing-hoyeraal-hreidarsson-syndrome
#12
JOURNAL ARTICLE
Sofie Bergstrand, Stefanie Böhm, Helena Malmgren, Anna Norberg, Mikael Sundin, Ann Nordgren, Marianne Farnebo
Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded...
April 17, 2020: Cell Death & Disease
https://read.qxmd.com/read/31664887/nopp140-mediated-concentration-of-telomerase-in-cajal-bodies-regulates-telomere-length
#13
JOURNAL ARTICLE
Jonathan Bizarro, Amit Bhardwaj, Susan Smith, U Thomas Meier
Cajal bodies (CBs) are nuclear organelles concentrating two kinds of RNA--protein complexes (RNPs), spliceosomal small nuclear (sn), and small CB-specific (sca)RNPs. Whereas the CB marker protein coilin is responsible for retaining snRNPs, the tether for scaRNPs is not known. Here we show that Nopp140, an intrinsically disordered CB phosphoprotein, is required to recruit and retain all scaRNPs in CBs. Knockdown (KD) of Nopp140 releases all scaRNPs leading to an unprecedented reduction in size of CB granules, hallmarks of CB ultrastructure...
December 15, 2019: Molecular Biology of the Cell
https://read.qxmd.com/read/29804836/an-activity-switch-in-human-telomerase-based-on-rna-conformation-and-shaped-by-tcab1
#14
JOURNAL ARTICLE
Lu Chen, Caitlin M Roake, Adam Freund, Pedro J Batista, Siqi Tian, Yi A Yin, Chandresh R Gajera, Shengda Lin, Byron Lee, Matthew F Pech, Andrew S Venteicher, Rhiju Das, Howard Y Chang, Steven E Artandi
Ribonucleoprotein enzymes require dynamic conformations of their RNA constituents for regulated catalysis. Human telomerase employs a non-coding RNA (hTR) with a bipartite arrangement of domains-a template-containing core and a distal three-way junction (CR4/5) that stimulates catalysis through unknown means. Here, we show that telomerase activity unexpectedly depends upon the holoenzyme protein TCAB1, which in turn controls conformation of CR4/5. Cells lacking TCAB1 exhibit a marked reduction in telomerase catalysis without affecting enzyme assembly...
June 28, 2018: Cell
https://read.qxmd.com/read/29695869/cryo-em-structure-of-substrate-bound-human-telomerase-holoenzyme
#15
JOURNAL ARTICLE
Thi Hoang Duong Nguyen, Jane Tam, Robert A Wu, Basil J Greber, Daniel Toso, Eva Nogales, Kathleen Collins
The enzyme telomerase adds telomeric repeats to chromosome ends to balance the loss of telomeres during genome replication. Telomerase regulation has been implicated in cancer, other human diseases, and ageing, but progress towards clinical manipulation of telomerase has been hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of the substrate-bound human telomerase holoenzyme at subnanometre resolution, showing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP)...
May 2018: Nature
https://read.qxmd.com/read/28607398/epstein-barr-virus-induced-up-regulation-of-tcab1-is-involved-in-the-dna-damage-response-in-nasopharyngeal-carcinoma
#16
JOURNAL ARTICLE
Kun Wang, Yichen Ge, Chao Ni, Bomiao Cui, Jintao Du, Bo Zhang, Xiaoyu Hu, Jiao Chen, Liying Xiao, Chongkui Sun, Yan Li
Telomerase Cajal body protein 1 (TCAB1), which is involved in Cajal body maintenance, telomere elongation and ribonucleoprotein biogenesis, has been linked to cancer predisposition, including nasopharyngeal carcinoma (NPC), due to its oncogenic properties. However, there are no specific reports to date on the functional relevance of TCAB1 and Epstein-Barr virus (EBV), which is considered to be a risk factor for NPC. In this study, we first examined NPC clinical tissues and found a notable overexpression of TCAB1 in EBV-positive specimens...
June 12, 2017: Scientific Reports
https://read.qxmd.com/read/28502804/wdr79-tcab1-plays-a-conserved-role-in-the-control-of-locomotion-and-ameliorates-phenotypic-defects-in-sma-models
#17
JOURNAL ARTICLE
Maria Laura Di Giorgio, Alessandro Esposito, Paolo Maccallini, Emanuela Micheli, Francesca Bavasso, Ivan Gallotta, Fiammetta Vernì, Fabian Feiguin, Stefano Cacchione, Brian D McCabe, Elia Di Schiavi, Grazia Daniela Raffa
SMN (Survival Motor Neuron) deficiency is the predominant cause of spinal muscular atrophy (SMA), a severe neurodegenerative disorder that can lead to progressive paralysis and death. Although SMN is required in every cell for proper RNA metabolism, the reason why its loss is especially critical in the motor system is still unclear. SMA genetic models have been employed to identify several modifiers that can ameliorate the deficits induced by SMN depletion. Here we focus on WDR79/TCAB1, a protein important for the biogenesis of several RNA species that has been shown to physically interact with SMN in human cells...
September 2017: Neurobiology of Disease
https://read.qxmd.com/read/27525856/association-between-the-wrap53-gene-rs2287499-c-g-polymorphism-and-cancer-risk-a-meta-analysis
#18
REVIEW
H Y Cao, S Wang, Z Y Zhang, J Y Lou
The TP53 5'-untranslated region flanking the gene WRAP53 (also known as WDR79 and TCAB1) has been hypothesized to be associated with cancer risk due to its critical function in regulating p53 levels. In this review, we analyzed the association between the WRAP53 gene rs2287499 C>G polymorphism and risk of cancer using five case-control studies, comprising seven datasets. All analyses were performed using RevMan software. In the overall analysis, no significant association between rs2287499 and risk of cancer was found...
July 25, 2016: Genetics and Molecular Research: GMR
https://read.qxmd.com/read/27525486/minimized-human-telomerase-maintains-telomeres-and-resolves-endogenous-roles-of-h-aca-proteins-tcab1-and-cajal-bodies
#19
JOURNAL ARTICLE
Jacob M Vogan, Xiaozhu Zhang, Daniel T Youmans, Samuel G Regalado, Joshua Z Johnson, Dirk Hockemeyer, Kathleen Collins
We dissected the importance of human telomerase biogenesis and trafficking pathways for telomere maintenance. Biological stability of human telomerase RNA (hTR) relies on H/ACA proteins, but other eukaryotes use other RNP assembly pathways. To investigate additional rationale for human telomerase assembly as H/ACA RNP, we developed a minimized cellular hTR. Remarkably, with only binding sites for telomerase reverse transcriptase (TERT), minimized hTR assembled biologically active enzyme. TERT overexpression was required for cellular interaction with minimized hTR, indicating that H/ACA RNP assembly enhances endogenous hTR-TERT interaction...
August 15, 2016: ELife
https://read.qxmd.com/read/26170453/dynamics-of-human-telomerase-holoenzyme-assembly-and-subunit-exchange-across-the-cell-cycle
#20
JOURNAL ARTICLE
Jacob M Vogan, Kathleen Collins
Human telomerase acts on telomeres during the genome synthesis phase of the cell cycle, accompanied by its concentration in Cajal bodies and transient colocalization with telomeres. Whether the regulation of human telomerase holoenzyme assembly contributes to the cell cycle restriction of telomerase function is unknown. We investigated the steady-state levels, assembly, and exchange dynamics of human telomerase subunits with quantitative in vivo cross-linking and other methods. We determined the physical association of telomerase subunits in cells blocked or progressing through the cell cycle as synchronized by multiple protocols...
August 28, 2015: Journal of Biological Chemistry
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