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1.
Biochem Med (Zagreb) ; 29(3): 030501, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31379458

RESUMO

The complex process of biological aging, as an intrinsic feature of living beings, is the result of genetic and, to a greater extent, environmental factors and time. For many of the changes taking place in the body during aging, three factors are important: inflammation, immune aging and senescence (cellular aging, biological aging). Senescence is an irreversible form of long-term cell-cycle arrest, caused by excessive intracellular or extracellular stress or damage. The purpose of this cell-cycles arrest is to limit the proliferation of damaged cells, to eliminate accumulated harmful factors and to disable potential malignant cell transformation. As the biological age does not have to be in accordance with the chronological age, it is important to find specific hallmarks and biomarkers that could objectively determine the rate of age of a person. These biomarkers might be a valuable measure of physiological, i.e. biological age. Biomarkers should meet several criteria. For example, they have to predict the rate of aging, monitor a basic process that underlies the aging process, be able to be tested repeatedly without harming the person. In addition, biomarkers have to be indicators of biological processes, pathogenic processes or pharmacological responses to therapeutic intervention. It is considered that the telomere length is the weak biomarker (with poor predictive accuracy), and there is currently no reliable biomarker that meets all the necessary criteria.


Assuntos
Envelhecimento , Senescência Celular , Biomarcadores/metabolismo , Dano ao DNA , Humanos , Sistema Imunitário/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Homeostase do Telômero
2.
High Blood Press Cardiovasc Prev ; 26(4): 321-329, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31325087

RESUMO

Cardiovascular disease (CVD) remains the leading cause of morbility and mortality worldwide. The identification of common cardiovascular risk factors has led to the development of effective treatments that enabled a significant reduction of the global cardiovascular disease burden. However, a significant proportion of cardiovascular risk remains unexplained by these risk factors leaving many individuals at risk of cardiovascular events despite good control of the risk factors. Recent randomized clinical trials and Mendelian randomization studies have suggested that inflammation explains a significant proportion of the residual cardiovascular risk in subjects with good control of risk factors. An accelerated process of vascular ageing is increasingly recognized as a potential mechanism by which inflammation might increase the risk of CVD. In turn, cellular ageing represents an important source of inflammation within the vascular wall, potentially creating a vicious cycle that might promote progression of atherosclerosis, independently from the individual cardiovascular risk factor burden. In this review, we summarise current evidence suggesting a role for biological ageing in CVD and how inflammation might act as a key mediator of this association.


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Telômero/metabolismo , Fatores Etários , Envelhecimento/genética , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Senescência Celular , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Medição de Risco , Fatores de Risco , Transdução de Sinais , Telômero/genética , Telômero/patologia , Homeostase do Telômero , Encurtamento do Telômero , Fatores de Tempo
3.
DNA Cell Biol ; 38(9): 955-961, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31361513

RESUMO

The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Envelhecimento/genética , Encéfalo/metabolismo , Proteínas Nucleares/genética , Proteína Nuclear Ligada ao X/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/crescimento & desenvolvimento , Humanos , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Homeostase do Telômero , Proteína Nuclear Ligada ao X/metabolismo
4.
Genes Dev ; 33(13-14): 814-827, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171703

RESUMO

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitotic DNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to Saccharomyces cerevisiae type II ALT survivors.


Assuntos
Núcleo Celular/metabolismo , DNA/biossíntese , Leucemia Promielocítica Aguda/fisiopatologia , Mitose , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , RecQ Helicases/metabolismo , Homeostase do Telômero/genética , Motivos de Aminoácidos , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Leucemia Promielocítica Aguda/genética , Fenótipo , Transporte Proteico , Proteína SUMO-1/metabolismo , Telômero/genética , Telômero/metabolismo
5.
Nat Commun ; 10(1): 2491, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171785

RESUMO

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10-8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10-7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10-4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Reparo do DNA/genética , Leucócitos/metabolismo , Homeostase do Telômero/genética , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Respiratórias/genética , Singapura , Adulto Jovem
6.
Plant Cell Rep ; 38(9): 1081-1097, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31134349

RESUMO

KEY MESSAGE: Duplicate POT1 genes must rapidly diverge or be inactivated. Protection of telomeres 1 (POT1) encodes a conserved telomere binding protein implicated in both chromosome end protection and telomere length maintenance. Most organisms harbor a single POT1 gene, but in the few lineages where the POT1 family has expanded, the duplicate genes have diversified. Arabidopsis thaliana bears three POT1-like loci, POT1a, POT1b and POT1c. POT1a retains the ancestral function of telomerase regulation, while POT1b is implicated in chromosome end protection. Here we examine the function and evolution of the third POT1 paralog, POT1c. POT1c is a new gene, unique to A. thaliana, and was derived from a duplication event involving the POT1a locus and a neighboring gene encoding ribosomal protein S17. The duplicate S17 locus (dS17) is highly conserved across A. thaliana accessions, while POT1c is highly divergent, harboring multiple deletions within the gene body and two transposable elements within the promoter. The POT1c locus is transcribed at very low to non-detectable levels under standard growth conditions. In addition, no discernable molecular or developmental defects are associated with plants bearing a CRISPR mutation in the POT1c locus. However, forced expression of POT1c leads to decreased telomerase enzyme activity and shortened telomeres. Evolutionary reconstruction indicates that transposons invaded the POT1c promoter soon after the locus was formed, permanently silencing the gene. Altogether, these findings argue that POT1 dosage is critically important for viability and duplicate gene copies are retained only upon functional divergence.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Dosagem de Genes , Homeostase do Telômero/genética , Proteínas de Ligação a Telômeros/metabolismo , Telômero/genética , Arabidopsis/enzimologia , Arabidopsis/fisiologia , Proteínas de Arabidopsis/genética , Elementos de DNA Transponíveis/genética , Evolução Molecular , Duplicação Gênica , Mutação , Regiões Promotoras Genéticas/genética , Telomerase/genética , Telomerase/metabolismo , Proteínas de Ligação a Telômeros/genética
7.
Nat Commun ; 10(1): 2253, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138795

RESUMO

Telomerase negative immortal cancer cells elongate telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. While sustained telomeric replicative stress is required to maintain ALT, it might also lead to cell death when excessive. Here, we show that the ATPase/translocase activity of FANCM keeps telomeric replicative stress in check specifically in ALT cells. When FANCM is depleted in ALT cells, telomeres become dysfunctional, and cells stop proliferating and die. FANCM depletion also increases ALT-associated marks and de novo synthesis of telomeric DNA. Depletion of the BLM helicase reduces the telomeric replication stress and cell proliferation defects induced by FANCM inactivation. Finally, FANCM unwinds telomeric R-loops in vitro and suppresses their accumulation in cells. Overexpression of RNaseH1 completely abolishes the replication stress remaining in cells codepleted for FANCM and BLM. Thus, FANCM allows controlled ALT activity and ALT cell proliferation by limiting the toxicity of uncontrolled BLM and telomeric R-loops.


Assuntos
DNA Helicases/genética , Replicação do DNA/genética , RecQ Helicases/genética , Homeostase do Telômero/genética , Telômero/metabolismo , Morte Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , DNA Helicases/metabolismo , Células HEK293 , Células HeLa , Humanos , RecQ Helicases/metabolismo , Ribonuclease H/genética , Ribonuclease H/metabolismo
8.
Nat Commun ; 10(1): 2252, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138797

RESUMO

The collapse of stalled replication forks is a major driver of genomic instability. Several committed mechanisms exist to resolve replication stress. These pathways are particularly pertinent at telomeres. Cancer cells that use Alternative Lengthening of Telomeres (ALT) display heightened levels of telomere-specific replication stress, and co-opt stalled replication forks as substrates for break-induced telomere synthesis. FANCM is a DNA translocase that can form independent functional interactions with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex. Here, we demonstrate that FANCM depletion provokes ALT activity, evident by increased break-induced telomere synthesis, and the induction of ALT biomarkers. FANCM-mediated attenuation of ALT requires its inherent DNA translocase activity and interaction with the BTR complex, but does not require the FA core complex, indicative of FANCM functioning to restrain excessive ALT activity by ameliorating replication stress at telomeres. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells.


Assuntos
Proteínas de Transporte/metabolismo , DNA Helicases/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , RecQ Helicases/metabolismo , Homeostase do Telômero , Telômero/metabolismo , Linhagem Celular Tumoral , Replicação do DNA , Células HCT116 , Células HEK293 , Células HeLa , Humanos
9.
Trials ; 20(1): 202, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961631

RESUMO

BACKGROUND: To date, surgeons and physicians have found positive results treating metabolic syndrome with surgical and non-surgical weight loss therapies. The purpose of this study was to evaluate changes in telomere length in patients with metabolic syndrome after weight loss. METHODS/DESIGN: This study is a three-arm randomized controlled trial. The first group is composed of patients who have undergone stapleless bypass surgery (one anastomosis gastric bypass with an obstructive stapleless pouch and anastomosis (LOAGB-OSPAN)). The second group of patients underwent standard gastric bypass surgery (laparoscopic mini-gastric bypass-one anastomosis gastric bypass (LMGB-OAGB). The patients in the third group received non-surgical weight loss therapy, including a hypocaloric diet with energy restriction (- 500 kcal/day). The aim is to compare changes-telomere length, body mass index, comorbidities, and quality of life-in patients with metabolic syndrome after weight loss. DISCUSSION: To the best of our knowledge, this is the first randomized study to simultaneously compare the effects of surgical and non-surgical weight loss on changes in telomere length. It could provide a solution to the growing problem of metabolic syndrome. Normalization of the body mass index results in improvements in the health of patients with metabolic syndrome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03667469 . Registered on 11 September 2018.


Assuntos
Restrição Calórica , Dieta Redutora , Derivação Gástrica/métodos , Laparoscopia , Expectativa de Vida , Síndrome Metabólica/terapia , Obesidade/terapia , Perda de Peso , Adolescente , Adulto , Índice de Massa Corporal , Restrição Calórica/efeitos adversos , Comorbidade , Dieta Redutora/efeitos adversos , Feminino , Derivação Gástrica/efeitos adversos , Humanos , Cazaquistão , Laparoscopia/efeitos adversos , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/fisiopatologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Homeostase do Telômero , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Science ; 364(6436)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30975860

RESUMO

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.


Assuntos
Adaptação Fisiológica , Astronautas , Voo Espacial , Imunidade Adaptativa , Peso Corporal , Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Dano ao DNA , Metilação de DNA , Microbioma Gastrointestinal , Instabilidade Genômica , Humanos , Masculino , Homeostase do Telômero , Fatores de Tempo , Estados Unidos , United States National Aeronautics and Space Administration
11.
Res Vet Sci ; 124: 328-333, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31035221

RESUMO

Telomeres are short and repetitive sequences at the ends of linear chromosomes which shorten with every cell-division in vitro. Telomere length (TL) is reported to decrease with age and stress. The domesticated water buffalo (Bubalus bubalis) is the second most important milk producing animal worldwide. The productive lifespan of water buffalo cows is reported to be longer than that of dairy cows (Bos taurus). With this background, we aimed to compare TL in leukocytes obtained from blood samples from water buffaloes across different ages. In addition, we tested the suitability of assessing TL in DNA derived from nasal and vaginal epithelial cells via swabs as potential non-invasive alternatives to blood sampling Samples were collected from 20 calves (3 months of age), 20 heifers (2 years old), 20 cows (1st lactation, 3 years old), and 13 cows (3rd lactation, about 5 years old). We found that TL in leukocytes from water buffalo calves, heifers, and from cows in their first lactation was not different, but shorter telomeres were observed in cows in their third lactation. The results thus support an age-dependent decrease of TL in water buffaloes. Leukocyte TL was weakly correlated with TL measured in DNA from nasal epithelial cells (r = 0.327; P = .025), but not with TL from vaginal epithelial cells. Due to the poor correlation between epithelial cell and leukocyte TL and to the difficulties with collecting nasal swabs, we conclude that they are no suitable alternatives to blood samples for telomere studies in water buffaloes.


Assuntos
Búfalos/fisiologia , Células Epiteliais/fisiologia , Leucócitos/fisiologia , Mucosa Nasal/fisiologia , Encurtamento do Telômero , Vagina/fisiologia , Animais , Feminino , Homeostase do Telômero
12.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013622

RESUMO

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.


Assuntos
Quadruplex G , Proteínas de Neoplasias/química , Telomerase/química , Homeostase do Telômero , Telômero/química , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Ressonância Magnética Nuclear Biomolecular , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Telômero/metabolismo
13.
Cell Biochem Funct ; 37(4): 273-280, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31012504

RESUMO

Telomerase is a good target for new anticancer drug development because it is present in over 85% of human tumours. However, despite chronic therapy is a condition for anti-telomerase approach, the effects of long-term treatment with telomerase inhibitors remain not well understood. In this work, it was evaluated the effects of long-term treatment of human MDA-MB-231 breast cancer cells with the telomerase inhibitor MST-312. Cells were treated for 72 hours or 140 days, and it was accessed their viability, proliferation rate, morphology, telomeric DNA content, and resistance mechanism. The drug had a clear short-term effect, including chemosensitizing cells for docetaxel and irinotecan, but the chronic exposition led to selection of long telomeres clones, changing characteristics of original cell line. This effect was confirmed in a clonal culture with homogenous karyotype. MRP-1 expression and alternative lengthening of telomeres (ALT) were discarded as additional mechanisms of resistance. This data suggest that, considering the intra-tumour heterogeneity (ITH), what is already a big challenge for treatment of cancer, chronic exposition to telomerase inhibitors can promote tumour adaptations with potential clinical repercussion, drawing attention to ongoing clinical trials and pointing important considerations most times neglected on studies about use of these inhibitors on cancer therapy. SIGNIFICANCE OF THE STUDY: Antitumour action of telomerase inhibitors is well known, but it depends on a long-term exposition because cells will undergo telomere erosion only after many duplication cycles. Recently, the frustrating results of clinical trials with these inhibitors aroused the interest of the scientific community to understand the mechanisms of resistance to anti-telomerase therapy. In this study, we conducted an 18-week experiment to show that telomerase inhibition can lead to cell adaptations and selection of long-telomeres clones, leading to acquisition of resistance. However, we also showed that this inhibitor can sensitize cells to the chemotherapeutic drugs docetaxel and irinotecan.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Telomerase/antagonistas & inibidores , Homeostase do Telômero/efeitos dos fármacos , Antineoplásicos/química , Benzamidas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Relação Estrutura-Atividade , Telomerase/metabolismo , Células Tumorais Cultivadas
14.
BMC Med ; 17(1): 77, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971237

RESUMO

BACKGROUND: The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants. METHOD: In a mother-child cohort in northern Argentina (n = 169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log2-transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D3). RESULTS: Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2-0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n = 98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n = 88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony. CONCLUSIONS: Elevated exposure to boron, lithium, arsenic, and antimony was associated with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations.


Assuntos
Antioxidantes/administração & dosagem , Exposição Ambiental/análise , Exposição Materna , Fenômenos Fisiológicos da Nutrição Materna , Metais Pesados/toxicidade , Homeostase do Telômero/fisiologia , Telômero/fisiologia , Adolescente , Adulto , Argentina/epidemiologia , Criança , Estudos de Coortes , Dieta , Exposição Ambiental/prevenção & controle , Feminino , Sangue Fetal/efeitos dos fármacos , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Exposição Materna/estatística & dados numéricos , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/genética , Metais Pesados/análise , Metais Pesados/sangue , Metais Pesados/urina , Mães , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Telômero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Adulto Jovem
15.
PLoS Genet ; 15(4): e1008039, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30970016

RESUMO

The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.


Assuntos
Sarcoma Experimental/etiologia , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X/deficiência , Proteína Nuclear Ligada ao X/genética , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Sistemas CRISPR-Cas , Carcinogênese/genética , Carcinogênese/metabolismo , Modelos Animais de Doenças , Eritropoese , Feminino , Técnicas de Inativação de Genes , Globinas/genética , Humanos , Mutação com Perda de Função , Masculino , Neurofibromina 1/deficiência , Neurofibromina 1/genética , Sarcoma Experimental/genética , Sarcoma Experimental/metabolismo , Homeostase do Telômero/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
16.
Medicine (Baltimore) ; 98(14): e14932, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946316

RESUMO

Telomeres are transcribed into long, noncoding telomeric repeat-containing RNAs (TERRA) that have been implicated in the regulation of telomerase, the enzyme that lengthens telomeres, in heterochromatin formation at telomeres, and in telomere stability. This study aimed to evaluate the correlation between TERRA expression and long-term oncologic outcomes in colorectal cancer (CRC).We evaluated 18p TERRA expression and telomere length using quantitative real-time PCR in 60 patients who underwent surgical resection for CRC between June 2008 and November 2010.Patients were grouped according to 18p TERRA expression, with 29 (48.3%) and 31 (51.7%) patients in the low and high TERRA expression groups, respectively. The median follow-up period was 80 months (range 2-103). The 18p TERRA expression was marginally significantly associated with preoperative carcinoembryonic antigen (CEA; P = .082) and was significantly associated with telomere length (P < .05). Multivariate analysis revealed that preoperative CEA (hazard ratio [HR], 2.728; 95% confidence interval [CI], 0.832-8.944, P = .098) and 18p TERRA expression (HR, 0.113; 95% CI, 0.011-1.126, P = .071) were marginally significant independent prognostic factors for overall survival (OS), whereas preoperative CEA (HR, 4.254; 95% CI, 1.394-12.985, P = .011) and 18p TERRA expression (HR, 0.108; 95% CI, 0.011-1.037, P = .054) were significant independent prognostic factors for disease-free survival (DFS). According to our prognostic model with 2 prognostic factors, the OS and DFS rate increased to 76.2% and 80.63%, respectively, in patients with high 18p TERRA expression and CEA levels ≤5 (P = .178, P = .057, respectively).18p TERRA expression was marginally significantly associated with preoperative CEA and significantly associated with telomere length, rendering it a potential prognostic factor for long-term oncologic outcomes in CRC.


Assuntos
Neoplasias Colorretais/cirurgia , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno Carcinoembrionário/metabolismo , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Oncologia , Pessoa de Meia-Idade , Período Pré-Operatório , Prognóstico , Estudos Prospectivos , Homeostase do Telômero
17.
Lipids Health Dis ; 18(1): 80, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935416

RESUMO

BACKGROUND: Evidence regarding the correlation between lipoproteins and telomere length in US adults is limited. We aimed to investigate whether lipoproteins was associated with telomere length using US National Health and Nutrition Examination Survey (NHANES) database. METHODS: A total of 6468 selected participants were identified in the NHANES Data Base (1999-2002). The independent and dependent variables were lipoproteins and telomere length, respectively. The covariates included demographic data, dietary data, physical examination data, and comorbidities. RESULTS: In fully-adjusted model, we found that 0.1 differences of telomere length were positively associated with HDL-C [0.19 (95% CI 0.07, 0.31)], while the associations between LDL-C [0.19 (95% CI -0.27, 0.65)], TG [- 1.00 (95% CI -2.09, 0.07) and telomere length were not detected. By nonlinearity test, only the relationship between HDL-C and telomere length was nonlinear. The inflection point we got was 1.25. On the left side of the inflection point (telomere length ≤ 1.25), a difference in 0.1 of telomere length was associated with 0.50 difference in HDL-C. CONCLUSION: After adjusting for demographic data, dietary data, physical examination data, and comorbidities, telomere length is not associated with LDL-C and TG, but is positively associated with HDL-C when telomere length is less than 1.25.


Assuntos
Hiperlipoproteinemia Tipo II/epidemiologia , Lipoproteínas/genética , Homeostase do Telômero/genética , Telômero/genética , Adulto , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dieta , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/patologia , Leucócitos/citologia , Leucócitos/metabolismo , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Fatores de Risco , Triglicerídeos/sangue
18.
Int J Mol Sci ; 20(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30870992

RESUMO

Mammalian telomere lengths are primarily regulated by telomerase, consisting of a reverse transcriptase protein (TERT) and an RNA subunit (TERC). We previously reported the generation of mouse Terc+/- and Terc-/- embryonic stem cells (ntESCs) by somatic cell nuclear transfer. In the present work, we investigated the germ layer development competence of Terc-/-, Terc+/- and wild-type (Terc+/+) ntESCs. The telomere lengths are longest in wild-type but shortest in Terc-/- ntESCs, and correlate reversely with the population doubling time. Interestingly, while in vitro embryoid body (EB) differentiation assay reveals EB size difference among ntESCs of different genotypes, the more stringent in vivo teratoma assay demonstrates that Terc-/- ntESCs are severely defective in differentiating into the mesodermal lineage cartilage. Consistently, in a directed in vitro chondrocyte differentiation assay, the Terc-/- cells failed in forming Collagen II expressing cells. These findings underscore the significance in maintaining proper telomere lengths in stem cells and their derivatives for regenerative medicine.


Assuntos
Diferenciação Celular/fisiologia , Núcleo Celular/fisiologia , Condrócitos/fisiologia , Células-Tronco Embrionárias Murinas/fisiologia , RNA/genética , Telomerase/genética , Animais , Cartilagem/fisiologia , Diferenciação Celular/genética , Núcleo Celular/genética , Células Cultivadas , Condrogênese/genética , Condrogênese/fisiologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Transferência Nuclear , Telômero/genética , Homeostase do Telômero/genética , Homeostase do Telômero/fisiologia
19.
J Neurooncol ; 142(3): 435-444, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830680

RESUMO

PURPOSE: Elongation of telomeres is necessary for tumor cell immortalization and senescence escape; neoplastic cells use to alternative pathways to elongate telomeres: telomerase reactivation or a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Telomerase and ALT pathway has been explored in adult and pediatric gliomas and medulloblastomas (MDBs); however, these mechanisms were not previously investigated in MDBs metastatic at the onset. Therefore, we analyzed the activation of telomerase and ALT pathway in a homogenous cohort of 43 pediatric metastatic medulloblastomas, to investigate whether telomere elongation could play a role in the biology of metastatic MDB. METHODS: We evaluated telomeres length via telomere-specific fluorescence in situ hybridization (Telo-FISH); we assessed nuclear expression of ATRX by immunohistochemistry (IHC). H3F3A and TERT promoter mutations were analyzed by pyrosequencing, while UTSS methylation status was analyzed via methylation-specific-PCR (MS-PCR). RESULTS: H3F3A mutations were absent in all MDBs, 30% of samples showed ATRX nuclear loss, 18.2% of cases were characterized by TERT promoter mutations, while 60.9% harboured TERT promoter hyper-methylation in the UTSS region. Elongation of telomeres was found in 42.8% of cases. Metastatic MDBs control telomere elongation via telomerase activation (10.7%), induced by TERT promoter mutations in association with UTSS hyper-methylation, and ALT mechanism (32.1%), triggered by ATRX inactivation. Among non-metastatic MDBs, only 5.9% (1/17) showed ATRX nuclear loss with activation of ALT. CONCLUSIONS: Our metastatic cases frequently activate ALT pathway, suggesting that it is a common process for senescence escape in primary metastatic medulloblastomas. Furthermore, the activation of mechanisms for telomere elongation is not restricted to certain molecular subgroups in this high-risk group of MDBs.


Assuntos
Neoplasias Cerebelares/secundário , Meduloblastoma/patologia , Mutação , Regiões Promotoras Genéticas , Telomerase/metabolismo , Homeostase do Telômero , Telômero/genética , Adolescente , Adulto , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , Prognóstico , Telomerase/genética , Adulto Jovem
20.
Nat Commun ; 10(1): 1001, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824709

RESUMO

In vertebrates, the telomere repeat containing long, non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres. This results in the formation of R-loop structures, replication stress and telomere instability, but also contributes to alternative lengthening of telomeres (ALT). Here, we identify the TERRA binding proteins NONO and SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. NONO and SFPQ act as heterodimers to suppress fragility and homologous recombination at telomeres, respectively. Combining increased telomere fragility with unleashing telomere recombination upon NONO/SFPQ loss of function causes massive recombination events, involving 35% of telomeres in ALT cells. Our data identify the RNA binding proteins SFPQ and NONO as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids.


Assuntos
DNA/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Hibridização de Ácido Nucleico , Fatores de Transcrição de Octâmero/metabolismo , Fator de Processamento Associado a PTB/metabolismo , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Telômero/metabolismo , Animais , Linhagem Celular Tumoral , Replicação do DNA , Recombinação Homóloga , Humanos , Camundongos , RNA não Traduzido , Homeostase do Telômero , Proteínas de Ligação a Telômeros/metabolismo
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