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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)...
April 25, 2018: Nature
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
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
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
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
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
Sofia Henriksson, Hanif Rassoolzadeh, Elisabeth Hedström, Christos Coucoravas, Alexander Julner, Michael Goldstein, Gabriela Imreh, Boris Zhivotovsky, Michael B Kastan, Thomas Helleday, Marianne Farnebo
The WD40 domain-containing protein WRAP53β (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53β as an essential regulator of DNA double-strand break (DSB) repair. WRAP53β rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53β targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage...
December 15, 2014: Genes & Development
Adam Freund, Franklin L Zhong, Andrew S Venteicher, Zhaojing Meng, Timothy D Veenstra, Judith Frydman, Steven E Artandi
Telomere maintenance by telomerase is impaired in the stem cell disease dyskeratosis congenita and during human aging. Telomerase depends upon a complex pathway for enzyme assembly, localization in Cajal bodies, and association with telomeres. Here, we identify the chaperonin CCT/TRiC as a critical regulator of telomerase trafficking using a high-content genome-wide siRNA screen in human cells for factors required for Cajal body localization. We find that TRiC is required for folding the telomerase cofactor TCAB1, which controls trafficking of telomerase and small Cajal body RNAs (scaRNAs)...
December 4, 2014: Cell
Ping Yuan, Zhitian Wang, Wang Lv, Hui Pan, Yunhai Yang, Xiaoshuai Yuan, Jian Hu
Telomerase Cajal body protein 1 (TCAB1) is a telomerase holoenzyme, which is markedly enriched in Cajal bodies (CBs) and facilitates the recruitment of telomerase to CBs in the S phase of the cell cycle. This recruitment is dependent on TCAB1 binding to a telomerase RNA component. The majority of cancer cells are able to grow indefinitely due to telomerase and its mechanism of trafficking to telomeres. In the present study, a certain level of TCAB1 expression in A549 human lung cells was identified and TCAB1 knockdown exhibited a potent antiproliferative effect on these cells, which was coupled with a decrease in the cell density and activity of the cellular enzymes...
September 2014: Oncology Letters
Chong-kui Sun, Xiao-bo Luo, Ya-ping Gou, Ling Hu, Kun Wang, Chao Li, Zhen-ting Xiang, Ping Zhang, Xiang-li Kong, Chao-liang Zhang, Qin Yang, Jing Li, Li-ying Xiao, Yan Li, Qian-ming Chen
BACKGROUND: WRAP53, including α, β and γ isoforms, plays an important role not only in the stability of p53 mRNA, but also in the assembly and trafficking of the telomerase holoenzyme. It has been considered an oncogene and is thought to promote the survival of cancer cells. The aim of this study was to detect the role of TCAB1 (except WRAP53α) in the occurrence and development of head and neck carcinomas. METHODS: Immunohistochemistry was used to detect the TCAB1 expression in clinical specimen sections and performed western blotting to check the TCAB1 expression levels in cell lines...
2014: Molecular Cancer
Ji Hoon Lee, Yang Sin Lee, Sun Ah Jeong, Prabhat Khadka, Jürgen Roth, In Kwon Chung
The maintenance of human telomeres requires the ribonucleoprotein enzyme telomerase, which is composed of telomerase reverse transcriptase (TERT), telomerase RNA component, and several additional proteins for assembly and activity. Telomere elongation by telomerase in human cancer cells involves multiple steps including telomerase RNA biogenesis, holoenzyme assembly, intranuclear trafficking, and telomerase recruitment to telomeres. Although telomerase has been shown to accumulate in Cajal bodies for association with telomeric chromatin, it is unclear where and how the assembly and trafficking of catalytically active telomerase is regulated in the context of nuclear architecture...
February 2014: Histochemistry and Cell Biology
Deniz Aslan, Rustu F Akata, Harriet Holme, Tom Vulliamy, Inderjeet Dokal
The aim of this study is to present the limbal stem cell deficiency (LSCD) cases with features resembling dyskeratosis congenita (DC), a heritable disease of stem cells principally caused by telomerase deficiency. The clinical, laboratory and molecular findings of four cases are presented. A complete systemic examination was performed in a standardized manner for each patient. Laboratory measurements included investigations of the tests used for screening DC. All eight known disease-causing genes in DC (DKC1, TERC, TERT, NOP10, NHP2, TINF2, C16orf57, and TCAB1) were screened for mutations...
December 2012: International Ophthalmology
J Lewis Stern, Katherine G Zyner, Hilda A Pickett, Scott B Cohen, Tracy M Bryan
The ability of most cancer cells to grow indefinitely relies on the enzyme telomerase and its recruitment to telomeres. In human cells, recruitment depends on the Cajal body RNA chaperone TCAB1 binding to the RNA subunit of telomerase (hTR) and is also thought to rely on an N-terminal domain of the catalytic subunit, hTERT. We demonstrate that coilin, an essential structural component of Cajal bodies, is required for endogenous telomerase recruitment to telomeres but that overexpression of telomerase can compensate for Cajal body absence...
July 2012: Molecular and Cellular Biology
Inderjeet Dokal
Dyskeratosis congenita (DC) is a multisystem inherited syndrome exhibiting marked clinical and genetic heterogeneity. In its classic form, it is characterized by mucocutaneous abnormalities, BM failure, and a predisposition to cancer. BM failure is the principal cause of premature mortality. Studies over the last 15 years have led to significant advances, with 8 DC genes (DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, and TCAB1) having been characterized. Seven of these are important in telomere maintenance either because they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and TCAB1) or the shelterin complex (TINF2)...
2011: Hematology—the Education Program of the American Society of Hematology
Shahinaz M Gadalla, Hormuzd A Katki, Fatma M Shebl, Neelam Giri, Blanche P Alter, Sharon A Savage
The regulation of telomere length (TL) is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. Epigenetic regulation may also be important in telomere maintenance. Specifically, methylation at subtelomeres is associated with changes in TL in vitro and in mouse models. Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by exceedingly short telomeres and mutations in telomere biology genes. To understand the interaction between methylation and TL in humans, we measured LINE-1, pericentromeric (NBL2), and subtelomeric (D4Z4) methylation in peripheral blood DNA derived from 40 patients with DC and 51 mutation-negative relatives...
February 2012: Aging Cell
Luis F Z Batista, Matthew F Pech, Franklin L Zhong, Ha Nam Nguyen, Kathleen T Xie, Arthur J Zaug, Sharon M Crary, Jinkuk Choi, Vittorio Sebastiano, Athena Cherry, Neelam Giri, Marius Wernig, Blanche P Alter, Thomas R Cech, Sharon A Savage, Renee A Reijo Pera, Steven E Artandi
The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of dyskeratosis congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of dyskeratosis congenita...
May 22, 2011: Nature
Franklin Zhong, Sharon A Savage, Marina Shkreli, Neelam Giri, Lea Jessop, Timothy Myers, Renee Chen, Blanche P Alter, Steven E Artandi
Dyskeratosis congenita (DC) is a genetic disorder of defective tissue maintenance and cancer predisposition caused by short telomeres and impaired stem cell function. Telomerase mutations are thought to precipitate DC by reducing either the catalytic activity or the overall levels of the telomerase complex. However, the underlying genetic mutations and the mechanisms of telomere shortening remain unknown for as many as 50% of DC patients, who lack mutations in genes controlling telomere homeostasis. Here, we show that disruption of telomerase trafficking accounts for unknown cases of DC...
January 1, 2011: Genes & Development
Emily D Egan, Kathleen Collins
The H/ACA motif of human telomerase RNA (hTR) directs specific pathways of endogenous telomerase holoenzyme assembly, function, and regulation. Similarities between hTR and other H/ACA RNAs have been established, but differences have not been explored even though unique features of hTR H/ACA RNP assembly give rise to telomerase deficiency in human disease. Here, we define hTR H/ACA RNA and RNP architecture using RNA accumulation, RNP affinity purification, and primer extension activity assays. First, we evaluate alternative folding models for the hTR H/ACA motif 5' hairpin...
June 2010: Molecular and Cellular Biology
Andrew S Venteicher, Steven E Artandi
Telomerase supports the proliferation of progenitor cells and tumor cells by adding telomere repeats to chromosome ends. The low abundance and restricted expression pattern of telomerase have limited our knowledge of this important enzyme. A new telomerase protein, TCAB1, sheds light on the pathway that governs telomerase holoenzyme assembly and function in vivo. TCAB1 is a component of active telomerase and is required for the telomerase holoenzyme to accumulate in Cajal bodies and to elongate telomeres. These findings provide important new insights into how telomerase functions in cancer and in stem cell biology...
May 1, 2009: Cell Cycle
Andrew S Venteicher, Eladio B Abreu, Zhaojing Meng, Kelly E McCann, Rebecca M Terns, Timothy D Veenstra, Michael P Terns, Steven E Artandi
Telomerase is a ribonucleoprotein (RNP) complex that synthesizes telomere repeats in tissue progenitor cells and cancer cells. Active human telomerase consists of at least three principal subunits, including the telomerase reverse transcriptase, the telomerase RNA (TERC), and dyskerin. Here, we identify a holoenzyme subunit, TCAB1 (telomerase Cajal body protein 1), that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. TCAB1 associates with active telomerase enzyme, established telomerase components, and small Cajal body RNAs that are involved in modifying splicing RNAs...
January 30, 2009: Science
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