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1.
Sci Rep ; 13(1): 25, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36646720

RESUMO

Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-ß1 (TGF-ß1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-ß expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-ß expression in vivo, the blockade of TGF-ß-induced myofibroblast differentiation, and the reduction of TGF-ß-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.


Assuntos
Fumar Cigarros , Doença Pulmonar Obstrutiva Crônica , Telomerase , Camundongos , Animais , Catalase/metabolismo , Telomerase/metabolismo , Remodelação das Vias Aéreas , Fumar Cigarros/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Fibroblastos/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Colágeno/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fibrose
2.
Curr Opin Oncol ; 35(2): 100-106, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36700456

RESUMO

PURPOSE OF REVIEW: Checkpoint inhibitors (CPIs) have revolutionized treatment outcomes for patients with malignant melanoma. Long-term follow-up shows that a substantial subset of patients who exhibit clinical responses achieve extended overall survival. Nevertheless, most patients do not achieve durable benefit from CPIs, and improvements are urgently needed. The clinical efficacy of CPIs depends on highly variable preexisting spontaneous T-cell immune responses. Cancer vaccines represent an independent treatment modality uniquely capable of expanding the repertoire of tumor-specific T cells in cancer patients and thus have the capacity to compensate for the variability in spontaneous T-cell responses. Vaccines are, therefore, considered attractive components in a CPI-combination strategy. RECENT FINDINGS: Here we discuss recent results obtained through therapeutic vaccination against telomerase human telomerase reverse transcriptase (hTERT). Recent publications on translational research and clinical results from phase I trials indicate that vaccination against telomerase in combination with CPIs provides relevant immune responses, negligible added toxicity, and signals of clinical efficacy. CONCLUSION: In the near future, randomized data from clinical trials involving therapeutic cancer vaccines and checkpoint inhibitors will be available. Positive readout may spark broad development and allow cancer vaccines to find their place in the clinic as an important component in multiple future CPI combinations.


Assuntos
Vacinas Anticâncer , Melanoma , Neoplasias Cutâneas , Telomerase , Humanos , Telomerase/metabolismo , Vacinas Anticâncer/uso terapêutico , Melanoma/tratamento farmacológico , Vacinação
3.
DNA Repair (Amst) ; 122: 103446, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36603239

RESUMO

Understanding how benign nevi can progress to invasive and metastatic Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USAelanoma is critical for developing interventions and therapeutics for this most deadly form of skin cancer. UV-induced mutations in the telomerase TERT gene promoter occur in the majority of melanomas but fail to prevent telomere shortening despite telomerase upregulation. This suggests additional "hits" are required to enable telomere maintenance. A new study in Science identified somatic variants in the promoter of the gene that encodes telomere shelterin protein TPP1 in human melanomas. These variants show mutational signatures of UV-induced DNA damage and upregulate TPP1 expression, which synergizes with telomerase to lengthen telomeres. This study provides evidence that TPP1 promoter variants are a critical second hit to prevent telomere shortening and promote immortalization of melanoma cells.


Assuntos
Melanoma , Telomerase , Humanos , Telomerase/genética , Telomerase/metabolismo , Raios Ultravioleta/efeitos adversos , Telômero/metabolismo , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Melanoma/genética , Mutação
4.
Chem Commun (Camb) ; 59(9): 1181-1184, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36628652

RESUMO

We develop a new strategy for single-molecule monitoring of telomerase based on proximity ligation-transcription circuit-powered exponential amplifications. This strategy exhibits high sensitivity with a detection limit of 0.1 aM for the synthetic telomerase product TPC4 in vitro and 1 HeLa cell in vivo. Moreover, it can screen potential inhibitors, discriminate telomerase from interferents, and distinguish cancer cells from normal cells.


Assuntos
Telomerase , Humanos , Células HeLa , Telomerase/metabolismo
5.
Anal Chem ; 95(2): 1498-1504, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36598384

RESUMO

Simultaneous imaging and especially visualizing the association of survivin mRNA and telomerase in living cells are of great value for the diagnosis and prognosis of cancer because their co-expression facilitates the development of cancer and identifies patients at high risk of tumor-related death. The challenge is to develop methods that enable visualizing the association of multiplex targets and avoid the distorted signals due to the different delivery efficiency of probes. Herein, we engineered a DNA triangular prism nanomachine (DTPN) for simultaneous multicolor imaging of survivin mRNA and telomerase and visualizing their association in living cells. Two recognizing probes targeted survivin mRNA and telomerase, and the reporter probe was assembled on the DTP in equal amounts, ensuring the same delivery efficiency of the probes to the living cells. The results showed that this DTPN could quantify intracellular survivin mRNA expression and telomerase activity. Moreover, it also enabled us to visualize the effect of the down-regulation of one target on the expression of another target under different drug stimulations. The results implied that our DTPN provided a promising platform for cancer diagnosis, prognosis, drug screening, and related biological research.


Assuntos
Telomerase , Humanos , Survivina/genética , Survivina/metabolismo , RNA Mensageiro/genética , Telomerase/genética , Telomerase/metabolismo , DNA/genética , Regulação para Baixo
6.
J Am Chem Soc ; 145(2): 1108-1117, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36622303

RESUMO

Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. In this study, using the principle of distance-dependent magnetic resonance tuning, we constructed a telomerase-activated magnetic resonance imaging probe (TAMP) by connecting superparamagnetic ferroferric oxide nanoparticles (SPFONs) and paramagnetic Gd-DOTA (Gd(III) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) complexes via telomerase-responsive DNA motifs. Upon telomerase-catalyzed extension of the primer in TAMP, Gd-DOTA-conjugated oligonucleotides can be liberated from the surface of SPFONs through a DNA strand displacement reaction, restoring the T1 signal of the Gd-DOTA for a direct readout of the telomerase activity. Here we show that, by tracking telomerase activity, this probe provides consistent monitoring of tumor growth kinetics during progression and in response to drug treatment and enables in situ screening of telomerase inhibitors in whole-animal models. This study provides an alternative toolkit for cancer diagnosis, treatment response assessment, and anticancer drug screening.


Assuntos
Telomerase , Animais , Linhagem Celular Tumoral , Telomerase/metabolismo , Cinética , Imageamento por Ressonância Magnética
7.
Neoplasia ; 36: 100863, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36528911

RESUMO

Gastric cancer is one of most lethal diseases across the world. However, the underlying mechanism of gastric cancer carcinogenesis and development is still not fully known. Forkhead box M1 (FOXM1) belongs to the FOX family and has crucial roles in transactivation of multiple oncogenes in several cancer types, including gastric cancer. Recent studies have also shown the non-transcriptional function of FOXM1 via protein-protein interactions. Human telomerase reverse transcriptase (hTERT) is the core subunit of telomerase that facilitates cancer initiation and progression by maintaining cell immortalization, promoting cell proliferation and inhibiting cell apoptosis. However, the relationship between FOXM1 and hTERT in gastric cancer is still unclear. In our study, we found that FOXM1 and hTERT were convergent to the cell cycle-related pathways and they were positively related with advanced gastric cancer stages and poor outcomes. Simultaneous high levels of FOXM1 and hTERT predicted the worst prognosis. FOXM1 could increase hTERT protein rather than mRNA levels in a non-transcriptional manner. Mechanistically, FOXM1 interrupted the interaction between the E3 ligase MKRN1 and hTERT and decreased hTERT protein degradation. Further studies revealed that FOXM1 interacted with hTERT through its DNA-binding domain (DBD) region. Finally, we found that hTERT played important roles in FOXM1-mediated activation of the Wnt/ß-catenin pathway to promote gastric cancer cell proliferation. Taken together, we found a novel non-classical function of FOXM1 to increase hTERT protein stability. Targeting the FOXM1-hTERT pathway may be a potential therapeutic strategy in treating gastric cancer.


Assuntos
Neoplasias Gástricas , Telomerase , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Prognóstico , Estabilidade Proteica , Neoplasias Gástricas/metabolismo , Telomerase/genética , Telomerase/metabolismo
8.
Nucleic Acids Res ; 51(1): 420-433, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36546771

RESUMO

In contrast to the catalytic subunit of telomerase, its RNA subunit (TR) is highly divergent in size, sequence and biogenesis pathways across eukaryotes. Current views on TR evolution assume a common origin of TRs transcribed with RNA polymerase II in Opisthokonta (the supergroup including Animalia and Fungi) and Trypanosomida on one hand, and TRs transcribed with RNA polymerase III under the control of type 3 promoter, found in TSAR and Archaeplastida supergroups (including e.g. ciliates and Viridiplantae taxa, respectively). Here, we focus on unknown TRs in one of the largest Animalia order - Hymenoptera (Arthropoda) with more than 300 available representative genomes. Using a combination of bioinformatic and experimental approaches, we identify their TRs. In contrast to the presumed type of TRs (H/ACA box snoRNAs transcribed with RNA Polymerase II) corresponding to their phylogenetic position, we find here short TRs of the snRNA type, likely transcribed with RNA polymerase III under the control of the type 3 promoter. The newly described insect TRs thus question the hitherto assumed monophyletic origin of TRs across Animalia and point to an evolutionary switch in TR type and biogenesis that was associated with the divergence of Arthropods.


Assuntos
Himenópteros , Telomerase , Animais , Telomerase/genética , Telomerase/metabolismo , Himenópteros/genética , Filogenia , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Conformação de Ácido Nucleico , RNA/genética , Plantas/genética , Eucariotos/genética
9.
Angew Chem Int Ed Engl ; 62(6): e202213884, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36478372

RESUMO

DNA nanomachines have been engineered into diverse personalized devices for diagnostic imaging of biomarkers; however, the regeneration of DNA nanomachines in living cells remains challenging. Here, we report an ingenious DNA nanomachine that can implement telomerase (TE)-activated regeneration in living cells. Upon apurinic/apyrimidinic endonuclease 1 (APE1)-responsive initiation of the nanomachine, the walker of the nanomachine moves along tracks regenerated by TE, generating multiply amplified signals through which APE1 can be imaged in situ. Additionally, augmentation of the signal due to the regeneration of the nanomachines could reveal differential expression of TE in different cell lines. To the best of our knowledge, this is the first proof-of-concept demonstration of the use of biomarkers to assist in the regeneration of nanomachines in living cells. This study offers a new paradigm for the development of more applicable and efficient DNA nanomachines.


Assuntos
Telomerase , Telomerase/metabolismo , DNA/metabolismo , Linhagem Celular , Reparo do DNA , Regeneração
10.
Cells ; 11(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36497103

RESUMO

Telomere shortening is well known to be associated with ageing. Age is the most decisive risk factor for age-related macular degeneration (AMD) development. The older the individual, the higher the AMD risk. For this reason, we aimed to find any associations between telomere length, distribution of genetic variants in telomere-related genes (TERT, TERT-CLPTM1, TRF1, TRF2, and TNKS2), and serum TERF-1 and TERF2 levels on AMD development. METHODS: Our study enrolled 342 patients with AMD and 177 healthy controls. Samples of DNA from peripheral blood leukocytes were extracted by DNA salting-out method. The genotyping of TERT rs2736098, rs401681 in TERT-CLPTM1 locus, TRF1 rs1545827, rs10107605, TNKS2 rs10509637, rs10509639, and TRF2 rs251796 and relative leukocyte telomere length (T/S) measurement were carried out using the real-time polymerase chain reaction method. Serum TERF-1 and TERF2 levels were measured by enzymatic immunoassay (ELISA). RESULTS: We found longer telomeres in early AMD patients compared to the control group. Additionally, we revealed that minor allele C at TRF1 rs10107605 was associated with decreases the odds of both early and exudative AMD. Each minor allele G at TRF2 rs251796 and TRF1 rs1545827 C/T genotype and C/T+T/T genotypes, compared to the C/C genotype, increases the odds of having shorter telomeres. Furthermore, we found elevated TERF1 serum levels in the early AMD group compared to the control group. CONCLUSIONS: In conclusion, these results suggest that relative leukocyte telomere length and genetic variants of TRF1 and TRF2 play a role in AMD development. Additionally, TERF1 is likely to be associated with early AMD.


Assuntos
Degeneração Macular , Tanquirases , Telomerase , Humanos , Proteína 1 de Ligação a Repetições Teloméricas/genética , Proteína 1 de Ligação a Repetições Teloméricas/metabolismo , Telomerase/genética , Telomerase/metabolismo , Leucócitos/metabolismo , Degeneração Macular/genética , DNA
11.
Nucleic Acids Res ; 50(22): 12829-12843, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36513120

RESUMO

Cancer cells achieve immortality by employing either homology-directed repair (HDR) or the telomerase enzyme to maintain telomeres. ALT (alternative lengthening of telomeres) refers to the subset of cancer cells that employ HDR. Many ALT features are conserved from yeast to human cells, with the yeast equivalent being referred to as survivors. The non-coding RNA TERRA, and its ability to form RNA-DNA hybrids, has been implicated in ALT/survivor maintenance by promoting HDR. It is not understood which telomeres in ALT/survivors engage in HDR, nor is it clear which telomeres upregulate TERRA. Using yeast survivors as a model for ALT, we demonstrate that HDR only occurs at telomeres when they become critically short. Moreover, TERRA levels steadily increase as telomeres shorten and decrease again following HDR-mediated recombination. We observe that survivors undergo cycles of senescence, in a similar manner to non-survivors following telomerase loss, which we refer to as survivor associated senescence (SAS). Similar to 'normal' senescence, we report that RNA-DNA hybrids slow the rate of SAS, likely through the elongation of critically short telomeres, however decreasing the rate of telomere shortening may contribute to this effect. In summary, TERRA RNA-DNA hybrids regulate telomere dysfunction-induced senescence before and after survivor formation.


Assuntos
RNA Longo não Codificante , Saccharomyces cerevisiae , Telomerase , Encurtamento do Telômero , Humanos , RNA Longo não Codificante/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo
12.
Expert Rev Mol Diagn ; 22(11): 997-1008, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36503370

RESUMO

INTRODUCTION: The reactivation of telomerase represents a key moment in the carcinogenesis process. Mutations in the central promoter region of the telomerase reverse transcriptase (TERT) gene cause telomerase reactivation in approximately 90% of solid tumors. In some of these, its prognostic and predictive role in response to treatments has already been demonstrated, in others (such as tumors of the genitourinary tract like urothelial carcinoma) data are controversial and the research is still ongoing. In the future, TERT promoter mutations and telomerase activity could have diagnostic, prognostic, and therapeutic applications in many types of cancer. AREAS COVERED: We performed a review the literature with the aim of describing the current evidence on the prognostic and predictive role of TERT promoter mutations. In some tumor types, TERT promoter mutations have been associated with a worse prognosis and could have a potential value as biomarkers to guide therapeutic decisions. Mutations in TERT promoter seems to make the tumor particularly immunogenic and more responsive to immunotherapy, although data is controversial. EXPERT OPINION: We described the role of TERT promoter mutations in solid tumors with a particular focus in genitourinary cancers, considering their frequency in this tract.


Assuntos
Carcinoma de Células de Transição , Telomerase , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Mutação , Regiões Promotoras Genéticas , Telomerase/genética , Telomerase/metabolismo , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
13.
Anal Chem ; 94(51): 18092-18098, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36519804

RESUMO

Telomerase is a highly valuable cancer diagnosis biomarker and a promising cancer therapy target. So far, most telomerase assays are limited by the involvement of tedious procedures, multiple enzymes, and complicated reaction schemes. Sensitive monitoring of low-abundant telomerase in living cells remains a challenge. Herein, we demonstrate an entropy-driven catalytic assembly of quantum dot (QD) sensors for accurate detection and imaging of telomerase activity in living cells. In this sensor, target telomerase specifically catalyzes extension of telomerase primer, and the extended primer subsequently acts as a catalyst to continuously initiate entropy-driven catalytic reaction, generating a large number of fluorophore- and biotin-labeled DNAs that can be self-assembled on the QD surface to induce an efficient Föster resonance energy transfer signal. The proposed sensor requires a single step for both recognition and amplification of the telomerase signal, eliminating the use of either protein enzymes or laborious procedures. Taking advantage of the inherent superiority of single-molecule fluorescence detection and high amplification efficiency of the entropy-driven reaction, this sensor demonstrates single-cell sensitivity for the in vitro assay. Moreover, it is capable of screening the telomerase inhibitor, discriminating different tumor cells from normal ones, and even real-time imaging telomerase in living cells, providing a novel platform for telomerase-associated cancer diagnosis and drug screening.


Assuntos
Pontos Quânticos , Telomerase , Telomerase/metabolismo , Entropia , Linhagem Celular Tumoral , DNA , Biomarcadores Tumorais
14.
Clin Epigenetics ; 14(1): 178, 2022 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-36529814

RESUMO

BACKGROUND: Breast cancer (BC) is the most frequently diagnosed cancer and a leading cause of death among women worldwide. Early BC is potentially curable, but the mortality rates still observed among BC patients demonstrate the urgent need of novel and more effective diagnostic and therapeutic options. Limitless self-renewal is a hallmark of cancer, governed by telomere maintenance. In around 95% of BC cases, this process is achieved by telomerase reactivation through upregulation of the human telomerase reverse transcriptase (hTERT). The hypermethylation of a specific region within the hTERT promoter, termed TERT hypermethylated oncological region (THOR) has been associated with increased hTERT expression in cancer. However, its biological role and clinical potential in BC have never been studied to the best of our knowledge. Therefore, we aimed to investigate the role of THOR as a biomarker and explore the functional impact of THOR methylation status in hTERT upregulation in BC. RESULTS: THOR methylation status in BC was assessed by pyrosequencing on discovery and validation cohorts. We found that THOR is significantly hypermethylated in malignant breast tissue when compared to benign tissue (40.23% vs. 12.81%, P < 0.0001), differentiating malignant tumor from normal tissue from the earliest stage of disease. Using a reporter assay, the addition of unmethylated THOR significantly reduced luciferase activity by an average 1.8-fold when compared to the hTERT core promoter alone (P < 0.01). To further investigate its biological impact on hTERT transcription, targeted THOR demethylation was performed using novel technology based on CRISPR-dCas9 system and significant THOR demethylation was achieved. Cells previously demethylated on THOR region did not develop a histologic cancer phenotype in in vivo assays. Additional studies are required to validate these observations and to unravel the causality between THOR hypermethylation and hTERT upregulation in BC. CONCLUSIONS: THOR hypermethylation is an important epigenetic mark in breast tumorigenesis, representing a promising biomarker and therapeutic target in BC. We revealed that THOR acts as a repressive regulatory element of hTERT and that its hypermethylation is a relevant mechanism for hTERT upregulation in BC.


Assuntos
Neoplasias da Mama , Telomerase , Humanos , Feminino , Telomerase/genética , Telomerase/metabolismo , Metilação de DNA , Neoplasias da Mama/genética , Epigênese Genética , Biomarcadores/metabolismo
15.
Expert Rev Mol Med ; 25: e4, 2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36503597

RESUMO

Ageing is characterised by the accumulation of molecular and cellular damage through time, leading to a decline in physical and mental abilities. Currently, society has experienced a rapid increase in life expectancy, which has led to an increase in age-associated diseases. Therefore, it is crucial to study the process of ageing to guarantee the best conditions in the final stages of life. In recent years, interest has increased in a myokine known as irisin, which is secreted during physical exercise. This polypeptide hormone is produced by various organs, mainly muscle, and once it is released into the blood, it performs a wide variety of functions that are involved in metabolic control and may be relevant during some of the diseases associated with ageing. The aim of this review is to highlight the recent studies of irisin, such as its mechanism of expression, blood release, distribution, tissue target and participation in various cellular metabolic reactions and the relationship with key anti-ageing pathways such as adenosine monophosphate-activated protein kinase, silent information regulator T 1, autophagy and telomerase. In conclusion, irisin is a key player during the ageing process and it could be a novel target molecule for the therapeutic approach to boost longevity pathways. However, more research will be necessary to use this promising hormone for this gain.


Assuntos
Proteínas Quinases Ativadas por AMP , Telomerase , Humanos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Telomerase/genética , Telomerase/metabolismo , Longevidade , Sirtuína 1/metabolismo , Autofagia
16.
Int J Mol Sci ; 23(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36499514

RESUMO

A growing number of studies have evidenced non-telomeric functions of "telomerase". Almost all of them, however, investigated the non-canonical effects of the catalytic subunit TERT, and not the telomerase ribonucleoprotein holoenzyme. These functions mainly comprise signal transduction, gene regulation and the increase of anti-oxidative systems. Although less studied, TERC (the RNA component of telomerase) has also been shown to be involved in gene regulation, as well as other functions. All this has led to the publication of many reviews on the subject, which, however, are often disseminating personal interpretations of experimental studies of other researchers as original proofs. Indeed, while some functions such as gene regulation seem ascertained, especially because mechanistic findings have been provided, other ones remain dubious and/or are contradicted by other direct or indirect evidence (e.g., telomerase activity at double-strand break site, RNA polymerase activity of TERT, translation of TERC, mitochondrion-processed TERC). In a critical study of the primary evidence so far obtained, we show those functions for which there is consensus, those showing contradictory results and those needing confirmation. The resulting picture, together with some usually neglected aspects, seems to indicate a link between TERT and TERC functions and cellular stemness and gives possible directions for future research.


Assuntos
Telomerase , Telomerase/metabolismo , RNA/genética , Regulação da Expressão Gênica , Mitocôndrias/metabolismo , Emoções , Telômero/metabolismo
17.
Genes Dev ; 36(17-18): 951-953, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36347559

RESUMO

Although telomeres are essential for chromosome stability, they represent fragile structures in our genome. Telomere shortening occurs during aging in cells lacking telomerase due to the end replication problem. In addition, recent work uncovered that the bulk of telomeric DNA poses severe hurdles for the semiconservative DNA replication machinery, requiring the assistance of an increasing number of specialized factors that prevent accidental telomere loss or damage events. In this issue of Genes & Development, Yang and colleagues (pp. 956-969) discover that TFIIH, a basic component of the PolII transcription initiation and nucleotide excision repair machinery, facilitates telomere replication. TFIIH is recruited to telomeres by the shelterin component TRF1, taking on at telomeres a moonlighting function.


Assuntos
Telomerase , Proteína 1 de Ligação a Repetições Teloméricas , Telômero/genética , Telômero/metabolismo , Encurtamento do Telômero , Proteínas de Ligação a Telômeros/metabolismo , Telomerase/metabolismo , Complexo Shelterina
18.
Biochem Biophys Res Commun ; 636(Pt 2): 40-47, 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36343489

RESUMO

Telomerase is activated in pluripotent stem cells and the majority of tumors and is postulated to be necessary for the acquisition of self-renewal and long-term proliferation. Placental mesenchymal stem cells (PMSCs) are very promising in regenerative medicine owing to their great capacity for self-renewal and differentiation potential. Although telomerase activity in the placenta is naturally low, it remains unclear whether telomerase activity is required for the properties of PMSCs. We herein isolated and identified a PMSC line carrying compound heterozygote variations in hTERT (DC-PMSCs) that lost telomerase activity, showed a typical surface phenotype of MSCs, and was able to differentiate into multiple cell lineages. DC-PMSCs showed accelerated telomere erosion, advanced senescence, and diminished migratory and invasive capabilities. RNA-seq identified 361 differentially expressed genes between DC-PMSCs and control groups, most of which were enriched in extracellular matrix, ECM, and related pathways. Knockdown of telomerase subunit genes in PMSCs confirmed the phenotype and attenuated the expression of extracellular matrix components and matrix metalloproteases. Our results suggest that low telomerase activity is not essential for the properties of MSCs, but that it is required for community maintenance and for the migration of PMSCs.


Assuntos
Células-Tronco Mesenquimais , Telomerase , Feminino , Gravidez , Humanos , Telomerase/genética , Telomerase/metabolismo , Placenta/metabolismo , Proliferação de Células/genética , Diferenciação Celular/genética
19.
Expert Opin Ther Targets ; 26(9): 767-780, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36369706

RESUMO

INTRODUCTION: The expression of telomerase reverse transcriptase (TERT) in liver is restricted to rare cells, that are able to replace senescent hepatocytes and regenerate tissue in response to hepatic damage, while becoming extinguished in differentiated progeny cells. TERT gene is permanently activated in liver neoplasms from the very early stage of the hepatocarcinogenesis mainly through the accumulation of genetic alterations, virus-related insertional mutagenesis and somatic mutations in the TERT promoter region. Several lines of evidence suggest that telomerase, beyond the canonical function of telomeres elongation, has multiple oncogenic activities in cancer cells and may represent a promising therapeutic target in hepatocellular carcinoma (HCC). AREAS COVERED: We review the mechanisms of activation of telomerase in HCC, the canonical and non-canonical functions of TERT as well as experimental strategies to directly target telomerase or to inhibit pathways associated with telomerase activity. EXPERT OPINION: TERT holoenzyme and telomerase components represent promising therapeutic targets in the treatment of liver malignancies. Several chemical agents and natural products known to alter telomerase activity are under evaluation for their potency to inhibit telomeres attrition in cirrhosis and TERT function in liver cancer. Therefore, this review outlines the current strategies pursued to suppress the multiple mechanisms of the major telomerase components in liver cancer.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Telomerase , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Telomerase/genética , Telomerase/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Telômero/metabolismo
20.
Clin Transl Med ; 12(11): e1111, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36394204

RESUMO

BACKGROUND: Telomerase is a ribonucleoprotein complex consisting of a catalytic component telomerase reverse transcriptase (TERT), internal RNA template and other co-factors, and its essential function is to synthesize telomeric DNA, repetitive TTAGGG sequences at the termini of linear chromosomes. Telomerase is silent in normal human follicular thyroid cells, primarily due to the TERT gene being tightly repressed. During the development and progression of thyroid carcinomas (TCs), TERT induction and telomerase activation is in general required to maintain telomere length, thereby conferring TC cells with immortal and aggressive phenotypes. METHODS: The genomic alterations of the TERT loci including TERT promoter's gain-of-function mutations, copy number gain, fusion and rearrangements, have recently been identified in TCs as mechanisms to induce TERT expression and to activate telomerase. Importantly, numerous studies have consistently shown that TERT promoter mutations and TERT expression occur in all TC subtypes, and are robustly associated with TC malignancy, aggressiveness, treatment failure and poor outcomes. Therefore, the assessment of TERT promoter mutations and TERT expression is highly valuable in TC diagnostics, prognosis, treatment decision, and follow-up design. In addition, the TERT promoter is frequently hypermethylated in TC cells and tumors, which is required to activate TERT transcription and telomerase. Dysregulation of other components in the telomerase complex similarly upregulate telomerase. Moreover, shortened telomeres lead to altered gene expression and metabolism, thereby actively promoting TC aggressiveness. Here we summarize recent findings in TCs to provide the landscape of TC-featured telomere/telomerase biology and discuss underlying implications in TC precision medicine. CONCLUSION: Mechanistic insights into telomerase activation and TERT induction in TCs are important both biologically and clinically. The TERT gene aberration and expression-based molecular classification of TCs is proposed, and for such a purpose, the standardization of the assay and evaluation system is required. Moreover, the TERT-based system and 2022 WHO TC classification may be combined to improve TC care.


Assuntos
Telomerase , Neoplasias da Glândula Tireoide , Humanos , Telomerase/genética , Telomerase/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero/genética , Biologia
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