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2.
Cell Metab ; 32(1): 31-43, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32640245

RESUMO

For centuries, people believed that bats possessed sinister powers. Bats are thought to be ancestral hosts to many deadly viruses affecting humans including Ebola, rabies, and most recently SARS-CoV-2 coronavirus. However, bats themselves tolerate these viruses without ill effects. The second power that bats have is their longevity. Bats live much longer than similar-sized land mammals. Here we review how bats' ability to control inflammation may be contributing to their longevity. The underlying mechanisms may hold clues to developing new treatments for age-related diseases. Now may be the time to use science to exploit the secret powers of bats for human benefit.


Assuntos
Envelhecimento/fisiologia , Betacoronavirus/imunologia , Quirópteros/fisiologia , Longevidade/fisiologia , Envelhecimento/imunologia , Animais , Quirópteros/imunologia , Quirópteros/virologia , Infecções por Coronavirus/imunologia , Humanos , Inflamação/imunologia , Pandemias , Pneumonia Viral/imunologia , Homeostase do Telômero/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-32604805

RESUMO

Telomere length in early life has been recently associated with biological aging and development of negative consequences in later adult life. A relevant area of research has emerged to understand the factors that impact telomere length in children. We conducted a bibliometric analysis to track research output and identify global trends and gaps in the knowledge of telomere length in children. Bibliographic data were retrieved from the Web of Science database and then analyzed by using Bibliometrix R package. A total of 840 publications were yielded from 1991 to 2019. The references were prominently published in journals, with 20 high ranked journals contributing to 30% of literature on telomere length in children. The USA was the most productive country (35.7%), followed by Europe (12.1%), and Asia (11.9%). A knowledge map of telomere length in children through keyword analyses revealed that there were two potential main lines of research based on two different approaches: genomic research and epidemiological research. This study shows that telomere length in children is a topic of research that has gained significant relevance in the last decade. This bibliometric study may be helpful in identifying research trends and finding research hot spots and gaps in this research field.


Assuntos
Bibliometria , Homeostase do Telômero , Encurtamento do Telômero , Telômero , Ásia , Criança , Europa (Continente) , Humanos , Publicações , Estados Unidos
4.
Am J Physiol Endocrinol Metab ; 319(2): E447-E454, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32691630

RESUMO

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence, and preserves telomere health in skeletal muscle in older compared with younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies (n = 34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS), and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence-associated ß-galactosidase (SA-ß-Gal) staining, and quantitative (q)RT-PCR. Independently of the endurance training status, TIF levels (+35%, P < 0.001) and the percentage of SA-ß-Gal-positive cells (+30%, P < 0.05) were higher in cultured satellite cells of older compared with younger subjects. p16 (4- to 5-fold) and p21 (2-fold) mRNA levels in skeletal muscle were higher with age but unchanged by the training status. Aging induced higher CD68 mRNA levels in human skeletal muscle (+102%, P = 0.009). Independently of age, both trained groups had lower IL-8 mRNA levels (-70%, P = 0.011) and tended to have lower TNF-α mRNA levels (-40%, P = 0.10) compared with the sedentary subjects. All together, we found that the endurance training status did not slow down senescence in skeletal muscle and satellite cells in older compared with younger subjects despite reduced inflammation in skeletal muscle. These findings highlight that the link between senescence and inflammation can be disrupted in skeletal muscle.


Assuntos
Envelhecimento/fisiologia , Treino Aeróbico , Inflamação/prevenção & controle , Músculo Esquelético/fisiologia , Resistência Física/fisiologia , Homeostase do Telômero/fisiologia , Idoso , Senescência Celular/genética , Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Humanos , Masculino , Músculo Esquelético/química , Músculo Esquelético/citologia , RNA Mensageiro/análise , Células Satélites de Músculo Esquelético/fisiologia , Células Satélites de Músculo Esquelético/ultraestrutura , Telômero/fisiologia , Telômero/ultraestrutura , Adulto Jovem , beta-Galactosidase/análise
5.
Mol Cell ; 79(1): 115-126.e6, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32497497

RESUMO

Extension of telomeres is a critical step in the immortalization of cancer cells. This complex reaction requires proper spatiotemporal coordination of telomerase and telomeres and remains poorly understood at the cellular level. To understand how cancer cells execute this process, we combine CRISPR genome editing and MS2 RNA tagging to image single molecules of telomerase RNA (hTR). Real-time dynamics and photoactivation experiments of hTR in Cajal bodies (CBs) reveal that hTERT controls the exit of hTR from CBs. Single-molecule tracking of hTR at telomeres shows that TPP1-mediated recruitment results in short telomere-telomerase scanning interactions, and then base pairing between hTR and telomere ssDNA promotes long interactions required for stable telomerase retention. Interestingly, POT1 OB-fold mutations that result in abnormally long telomeres in cancers act by enhancing this retention step. In summary, single-molecule imaging unveils the life cycle of telomerase RNA and provides a framework to reveal how cancer-associated mutations mechanistically drive defects in telomere homeostasis.


Assuntos
Corpos Enovelados/metabolismo , DNA de Cadeia Simples/metabolismo , RNA/metabolismo , Imagem Individual de Molécula/métodos , Telomerase/metabolismo , Homeostase do Telômero , Telômero/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , DNA de Cadeia Simples/genética , Edição de Genes , Células HeLa , Humanos , Mutação , RNA/genética , Telomerase/genética , Telômero/genética , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
6.
Medicine (Baltimore) ; 99(23): e20551, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502020

RESUMO

This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to gastric carcinoma (GC) and investigate the association between genetic polymorphisms in the telomere length related genes and GC risk.RTL was measured using the real-time quantitative polymerase chain reaction from 1000 patients and 1100 healthy controls. Genotyping was performed using the Agena MassARRAY platform. The statistical analysis was performed using the chi-square/ Welch T tests, Mann-Whitney U test, and logistic regression analysis.The association analysis of telomere length and GC showed that the RTL in the case group was shorter than in the controls, and the shorter RTL was associated with an increased risk of GC. The association analysis between telomere length related genes polymorphisms and genetic susceptibility to GC indicated that: In the allele models and genetic models, TERT (rs10069690, rs2242652 and rs2853676) and TN1F1 (rs7708392 and rs10036748) were significantly associated with an increased risk of GC. In addition, the haplotype 'Grs10069690Crs2242652" of TERT and the haplotype 'Grs7708392Trs10036748" of TNIP1 were associated with an increased risk of GCOur results suggested that shorter RTL was associated with an increased risk of GC; The association analysis have identified that the TERT (rs10069690, rs2242652 and rs2853676) and TN1P1 (rs7708392 and rs10036748) were associated with GC risk.


Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Neoplasias Gástricas/genética , Telomerase/genética , Telômero/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Homeostase do Telômero
7.
Science ; 368(6495): 1081-1085, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32499435

RESUMO

The CTC1-STN1-TEN1 (CST) complex is essential for telomere maintenance and resolution of stalled replication forks genome-wide. Here, we report the 3.0-angstrom cryo-electron microscopy structure of human CST bound to telomeric single-stranded DNA (ssDNA), which assembles as a decameric supercomplex. The atomic model of the 134-kilodalton CTC1 subunit, built almost entirely de novo, reveals the overall architecture of CST and the DNA-binding anchor site. The carboxyl-terminal domain of STN1 interacts with CTC1 at two separate docking sites, allowing allosteric mediation of CST decamer assembly. Furthermore, ssDNA appears to staple two monomers to nucleate decamer assembly. CTC1 has stronger structural similarity to Replication Protein A than the expected similarity to yeast Cdc13. The decameric structure suggests that CST can organize ssDNA analogously to the nucleosome's organization of double-stranded DNA.


Assuntos
Complexos Multiproteicos/química , Homeostase do Telômero , Proteínas de Ligação a Telômeros/química , Telômero/química , Microscopia Crioeletrônica , DNA de Cadeia Simples/química , Células HEK293 , Humanos , Ligação Proteica , Domínios Proteicos , Multimerização Proteica , Proteína de Replicação A/química
8.
Nucleic Acids Res ; 48(13): 7239-7251, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32542379

RESUMO

Telomeres cap the ends of eukaryotic chromosomes and distinguish them from broken DNA ends to suppress DNA damage response, cell cycle arrest and genomic instability. Telomeres are elongated by telomerase to compensate for incomplete replication and nuclease degradation and to extend the proliferation potential of germ and stem cells and most cancers. However, telomeres in somatic cells gradually shorten with age, ultimately leading to cellular senescence. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and diverse symptoms including bone marrow failure, immunodeficiency, and neurodevelopmental defects. HHS is caused by germline mutations in telomerase subunits, factors essential for its biogenesis and recruitment to telomeres, and in the helicase RTEL1. While diverse phenotypes were associated with RTEL1 deficiency, the telomeric role of RTEL1 affected in HHS is yet unknown. Inducible ectopic expression of wild-type RTEL1 in patient fibroblasts rescued the cells, enabled telomerase-dependent telomere elongation and suppressed the abnormal cellular phenotypes, while silencing its expression resulted in gradual telomere shortening. Our observations reveal an essential role of the RTEL1 C-terminus in facilitating telomerase action at the telomeric 3' overhang. Thus, the common etiology for HHS is the compromised telomerase action, resulting in telomere shortening and reduced lifespan of telomerase positive cells.


Assuntos
DNA Helicases/metabolismo , Disceratose Congênita/genética , Retardo do Crescimento Fetal/genética , Deficiência Intelectual/genética , Microcefalia/genética , Homeostase do Telômero , Células Cultivadas , DNA Helicases/química , DNA Helicases/genética , Fibroblastos/metabolismo , Humanos , Domínios Proteicos , Telomerase/genética , Telomerase/metabolismo , Encurtamento do Telômero
9.
Nucleic Acids Res ; 48(11): 6019-6031, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32379321

RESUMO

ALT tumor cells often contain abundant DNA damage foci at telomeres and rely on the alternative lengthening of telomeres (ALT) mechanism to maintain their telomeres. How the telomere chromatin is regulated and maintained in these cells remains largely unknown. In this study, we present evidence that heterochromatin protein 1 binding protein 3 (HP1BP3) can localize to telomeres and is particularly enriched on telomeres in ALT cells. HP1BP3 inhibition led to preferential growth inhibition of ALT cells, which was accompanied by telomere chromatin decompaction, increased presence of C-circles, more pronounced ALT-associated phenotypes and elongated telomeres. Furthermore, HP1BP3 appeared to participate in regulating telomere histone H3K9me3 epigenetic marks. Taken together, our data suggest that HP1BP3 functions on telomeres to maintain telomere chromatin and represents a novel target for inhibiting ALT cancer cells.


Assuntos
Proliferação de Células , Montagem e Desmontagem da Cromatina , Heterocromatina/metabolismo , Histonas/metabolismo , Telômero/metabolismo , Linhagem Celular Tumoral , Dano ao DNA , Eucromatina/genética , Eucromatina/metabolismo , Técnicas de Silenciamento de Genes , Heterocromatina/genética , Código das Histonas , Histonas/química , Humanos , Metilação , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Multimerização Proteica , Homeostase do Telômero
10.
PLoS Genet ; 16(5): e1008816, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32469862

RESUMO

Alternative lengthening of telomeres (ALT) in human cells is a conserved process that is often activated in telomerase-deficient human cancers. This process exploits components of the recombination machinery to extend telomere ends, thus allowing for increased proliferative potential. Human MUS81 (Mus81 in Saccharomyces cerevisiae) is the catalytic subunit of structure-selective endonucleases involved in recombination and has been implicated in the ALT mechanism. However, it is unclear whether MUS81 activity at the telomere is specific to ALT cells or if it is required for more general aspects of telomere stability. In this study, we use S. cerevisiae to evaluate the contribution of the conserved Mus81-Mms4 endonuclease in telomerase-deficient yeast cells that maintain their telomeres by mechanisms akin to human ALT. Similar to human cells, we find that yeast Mus81 readily localizes to telomeres and its activity is important for viability after initial loss of telomerase. Interestingly, our analysis reveals that yeast Mus81 is not required for the survival of cells undergoing recombination-mediated telomere lengthening, i.e. for ALT itself. Rather we infer from genetic analysis that Mus81-Mms4 facilitates telomere replication during times of telomere instability. Furthermore, combining mus81 mutants with mutants of a yeast telomere replication factor, Rrm3, reveals that the two proteins function in parallel to promote normal growth during times of telomere stress. Combined with previous reports, our data can be interpreted in a consistent model in which both yeast and human MUS81-dependent nucleases participate in the recovery of stalled replication forks within telomeric DNA. Furthermore, this process becomes crucial under conditions of additional replication stress, such as telomere replication in telomerase-deficient cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Endonucleases Flap/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Telomerase/deficiência , Replicação do DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Endonucleases Flap/genética , Viabilidade Microbiana , Recombinação Genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Telômero/metabolismo , Homeostase do Telômero
11.
Occup Environ Med ; 77(7): 488-495, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32385190

RESUMO

OBJECTIVES: Exposure to high-molecular-weight polycyclic aromatic hydrocarbons (PAHs) may cause cancer in chimney sweeps and creosote-exposed workers, however, knowledge about exposure to low-molecular-weight PAHs in relation to cancer risk is limited. In this study, we aimed to investigate occupational exposure to the low-molecular-weight PAHs phenanthrene and fluorene in relation to different cancer biomarkers. METHODS: We recruited 151 chimney sweeps, 19 creosote-exposed workers and 152 unexposed workers (controls), all men. We measured monohydroxylated metabolites of phenanthrene and fluorene in urine using liquid chromatography coupled to tandem mass spectrometry. We measured, in peripheral blood, the cancer biomarkers telomere length and mitochondrial DNA copy number using quantitative PCR; and DNA methylation of F2RL3 and AHRR using pyrosequencing. RESULTS: Median PAH metabolite concentrations were higher among chimney sweeps (up to 3 times) and creosote-exposed workers (up to 353 times), compared with controls (p<0.001; adjusted for age and smoking). ∑OH-fluorene (sum of 2-hydroxyfluorene and 3-hydroxyfluorene) showed inverse associations with percentage DNA methylation of F2RL3 and AHRR in chimney sweeps (B (95% CI)=-2.7 (-3.9 to -1.5) for F2RL3_cg03636183, and -7.1 (-9.6 to -4.7) for AHRR_cg05575921: adjusted for age and smoking), but not in creosote-exposed workers. In addition, ∑OH-fluorene showed a 42% mediation effect on the inverse association between being a chimney sweep and DNA methylation of AHRR CpG2. CONCLUSIONS: Chimney sweeps and creosote-exposed workers were occupationally exposed to low-molecular-weight PAHs. Increasing fluorene exposure, among chimney sweeps, was associated with lower DNA methylation of F2RL3 and AHRR, markers for increased lung cancer risk. These findings warrant further investigation of fluorene exposure and toxicity.


Assuntos
Epigênese Genética , Fluorenos/efeitos adversos , Exposição Ocupacional/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Adulto , Idoso , Biomarcadores Tumorais/sangue , Creosoto/efeitos adversos , Estudos Transversais , Metilação de DNA , DNA Mitocondrial , Fluorenos/metabolismo , Fluorenos/urina , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/análise , Fenantrenos/metabolismo , Fenantrenos/urina , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Homeostase do Telômero
12.
PLoS Genet ; 16(4): e1008733, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32287268

RESUMO

In budding yeast, Cdc13, Stn1, and Ten1 form the telomere-binding heterotrimer CST complex. Here we investigate the role of Cdc13/CST in maintaining genome stability by using a Chr VII disome system that can generate recombinants, chromosome loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise from problems in or near a telomere. We found that, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes that are then the source for additional chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or chromosome loss). We observed that genome instability arises from a defect in Cdc13's function during DNA replication, not Cdc13's putative post-replication telomere capping function. The molecular nature of the initial unstable chromosomes formed by a Cdc13-defect involves ssDNA and does not involve homologous recombination nor non-homologous end joining; we speculate the original unstable chromosome may be a one-ended double strand break. This system defines a link between Cdc13's function during DNA replication and genome stability in the form of unstable chromosomes, that then progress to form other chromosome changes.


Assuntos
Instabilidade Genômica , Proteínas de Saccharomyces cerevisiae/metabolismo , Homeostase do Telômero , Proteínas de Ligação a Telômeros/metabolismo , Cromossomos Fúngicos/genética , Quebras de DNA de Cadeia Dupla , Replicação do DNA , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Recombinação Genética , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Ligação a Telômeros/genética
13.
Proc Natl Acad Sci U S A ; 117(16): 8924-8933, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32265285

RESUMO

Adaptation to environmental changes is crucial for cell fitness. In Saccharomyces cerevisiae, variations in external osmolarity trigger the activation of the stress-activated protein kinase Hog1 (high-osmolarity glycerol 1), which regulates gene expression, metabolism, and cell-cycle progression. The activation of this kinase leads to the regulation of G1, S, and G2 phases of the cell cycle to prevent genome instability and promote cell survival. Here we show that Hog1 delays mitotic exit when cells are stressed during metaphase. Hog1 phosphorylates the nucleolar protein Net1, altering its affinity for the phosphatase Cdc14, whose activity is essential for mitotic exit and completion of the cell cycle. The untimely release of Cdc14 from the nucleolus upon activation of Hog1 is linked to a defect in ribosomal DNA (rDNA) and telomere segregation, and it ultimately delays cell division. A mutant of Net1 that cannot be phosphorylated by Hog1 displays reduced viability upon osmostress. Thus, Hog1 contributes to maximizing cell survival upon stress by regulating mitotic exit.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Segregação de Cromossomos/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mitose/fisiologia , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Ciclo Celular/genética , DNA Ribossômico/metabolismo , Mutação , Proteínas Nucleares/genética , Pressão Osmótica/fisiologia , Fosforilação/genética , Proteínas Tirosina Fosfatases/metabolismo , Saccharomyces cerevisiae/fisiologia , Proteínas de Saccharomyces cerevisiae/genética , Homeostase do Telômero/fisiologia
14.
Arch Environ Contam Toxicol ; 79(1): 122-130, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32300848

RESUMO

Exposure to polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) through food, water, and air occurred during the life, which may change telomere length (TL) in peripheral blood leukocytes. The present study was designed to investigate the association between TL and serum levels of PCBs and OCPs in Tehran male's population. Whole blood samples were randomly taken from 300 adult males, aged between 25 and 40 years. TL was determined by real-time PCR to measure the number of the telomere (T) repeats to the number of a single-copy gene (S). We applied the multivariate linear regression model to compare the effect of each lipid adjusted serum levels of PCBs and OCPs congener on the TL, with adjustment for age, body mass index, education, smoking, and food patterns. Each doubling of the nondioxin-like PCBs, dioxin-like PCBs, and OCPs levels were associated with 1.9% [95% confidence interval (CI) - 0.70 to 5.40%], 2.5% (95% CI 0.30-8.3%), and - 2.4% (95% CI - 0.70 to - 6.2%) variation in the TL, respectively. The percent difference in the TL with exposure to nondioxin-like PCBs, dioxin-like PCBs, and OCPs for participants with older than age 37 years were 6.45% (95% CI 2.81-16.50%), 4.52% (95% CI 1.60-10.54%), and - 7.44% (95% CI - 1.55 to - 15.51%), respectively. Exposures to nondioxin-like PCBs (except for PCB 28 and 52) with high chlorine in structure and dioxin-like PCBs were related to longer TLs. Conversely, serum levels of OCPs can be associated with oxidative stress and systemic inflammation that lead to telomere shortening.


Assuntos
Hidrocarbonetos Clorados/sangue , Leucócitos/efeitos dos fármacos , Praguicidas/sangue , Bifenilos Policlorados/sangue , Homeostase do Telômero/efeitos dos fármacos , Telômero/efeitos dos fármacos , Adulto , Fatores Etários , Humanos , Hidrocarbonetos Clorados/toxicidade , Irã (Geográfico) , Leucócitos/patologia , Lipídeos/sangue , Masculino , Praguicidas/toxicidade , Bifenilos Policlorados/toxicidade , Distribuição Aleatória , Inquéritos e Questionários
15.
J Cancer Res Clin Oncol ; 146(7): 1671-1676, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32333143

RESUMO

BACKGROUND: DNA topoisomerase and telomerase enzymes are popular targets of several anti-tumor drugs. Smooth proceeding of telomeric recombination requires Topoisomerase II (Top2), which is involved in telomere-telomere recombination through functioning in relaxation of positive supercoils among the cells adopting telomerase-independent Alternative lengthening of telomere (ALT) pathway. Most of the inhibitors reported so far have been designed to targetsolely telomerase-positive cells, which can potentially lead to therapeutic failure because tumor cells treated with telomerase inhibitors can activate the ALT pathway for telomere maintenance. Knowing that ALT cells are more sensitive against a Top2 inhibitor, ICRF-93 agent, compared to telomerase-positive cells, we analyzed two selected ellipticine derivatives that we recently reported as TopII-targeting compounds, to assess their effects on the formation of DNA breaks and suppression of ALT pathway. METHODS: Cell viability, Comet, C-Circle assays, dot blot, immunofluorescence staining, and telomere fluorescence in situ hybridization (FISH) staining were used for determining the effect of the compounds on ALT status of tumor cells. RESULTS AND CONCLUSIONS: Treatment of ALT cells with ellipticine derivatives resulted in the formation of DNA breaks and suppression of ALT-associated phenotypes in vitro. Our results will contribute to the development of therapeutic strategies combining telomerase and ALT pathway inhibitors.


Assuntos
Antineoplásicos/farmacologia , Elipticinas/farmacologia , Telomerase/genética , Homeostase do Telômero/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Linhagem Celular , Elipticinas/química , Imunofluorescência , Humanos , Hibridização in Situ Fluorescente
16.
Psychiatry Res ; 286: 112865, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114208

RESUMO

Bipolar disorder (BD) may be associated with accelerated cellular aging. However, previous studies on telomere length (TL), an important biomarker of cellular aging, have yielded mixed results in BD. We aimed to evaluate the hypothesis that BD is associated with telomere shortening and whether this is counteracted by long-term lithium treatment. We also sought to determine whether long-term lithium treatment is associated with increased expression of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. We determined TL and TERT expression in 100 BD I patients and 100 healthy controls. We also genotyped three single nucleotide polymorphisms associated with TL. TERT expression was significantly increased in BD I patients currently on lithium treatment. TERT expression was also significantly positively correlated with duration of lithium treatment in patients treated for 24 months or more. However, we did not find any significant effect of lithium treatment on TL. Neither did we find significant differences in TL between BD patients and controls. We suggest that long-term lithium treatment is associated with an increase in the expression of TERT. We hypothesize that an increase in TERT expression may contribute to lithium's mood stabilizing and neuroprotective properties by improving mitochondrial function and decreasing oxidative stress.


Assuntos
Envelhecimento/metabolismo , Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Senescência Celular/genética , Compostos de Lítio/uso terapêutico , Lítio/uso terapêutico , Telomerase/metabolismo , Adulto , Envelhecimento/genética , Transtorno Bipolar/sangue , Senescência Celular/efeitos dos fármacos , Feminino , Humanos , Compostos de Lítio/farmacologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo Real , Telomerase/efeitos dos fármacos , Telomerase/genética , Telômero/efeitos dos fármacos , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero/genética , Encurtamento do Telômero/efeitos dos fármacos , Encurtamento do Telômero/genética
17.
Am J Respir Cell Mol Biol ; 62(6): 692-698, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32208105

RESUMO

Type II alveolar epithelial cells (AEC2s) play an essential role in the function and maintenance of the pulmonary epithelium. Several transgenic mice have been developed to study the function of these cells in vivo by using the human SFTPC promoter to drive expression of Cre recombinase. The precise activity of each of these transgenic alleles has not been studied, and previous reports suggest that their activity can depend on breeding strategies. We bred mice with a conditional allele of the essential telomere capping protein TRF2 with two different SFTPC-Cre-transgenic strains and observed opposite phenotypes (100% lethality vs. 100% viability). We characterized the Cre recombinase activity in these two transgenic lines and found that the contrasting phenotypes were driven by difference in embryonic expression of the two transgenes, likely due to position effects or differences in the transgenic constructs. We also tested if SFTPC-Cre activity was dependent on maternal or paternal inheritance. When paternally inherited, both SFTPC-Cre alleles produced offspring with constitutive reporter activity independent of the inheritance of the Cre allele, suggesting that Cre recombinase was expressed in the male germline before meiosis. Immunohistochemical analysis of the testis showed reporter activity during spermatogenesis. Analysis of single-cell RNA sequencing data from murine and human testis demonstrated SFTPC expression uniquely during human spermatogenesis, suggesting that use of the human promoter in these constructs is responsible for male germline activity. Our data highlight the importance of careful analysis of transgenic allele activity and identify an SFTPC-Cre allele that is useful for panepithelial targeting in the mouse.


Assuntos
Integrases/genética , Regiões Promotoras Genéticas/genética , Proteína C Associada a Surfactante Pulmonar/genética , Transgenes , Alelos , Células Epiteliais Alveolares/metabolismo , Animais , Linhagem da Célula , Senescência Celular , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Genes Reporter , Estudos de Associação Genética , Humanos , Integrases/biossíntese , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Proteínas Recombinantes/metabolismo , Análise de Célula Única , Espermatogênese , Homeostase do Telômero/genética , Proteína 2 de Ligação a Repetições Teloméricas/biossíntese , Proteína 2 de Ligação a Repetições Teloméricas/genética , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
18.
Nutr Metab Cardiovasc Dis ; 30(4): 694-700, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32007334

RESUMO

BACKGROUND AND AIMS: In lifestyle intervention studies, we demonstrated that changes in telomere length (TL) were associated with changes in anthropometric indices. Therefore, our new hypothesis is that TL could be a predictor of changes in anthropometric or metabolic measures in children with abdominal obesity. The aim of the study was to evaluate the association between anthropometric and biochemical measurements with TL before and after an 8-week lifestyle intervention in children with abdominal obesity (7-16 years old). METHODS AND RESULTS: We assessed anthropometric and biochemical outcomes at baseline and after 8-week lifestyle intervention in 106 children with abdominal obesity (11.30 ± 2.49 years old, 63% girls). TL was measured by monochrome multiplex real-time quantitative PCR. After the lifestyle intervention, anthropometric parameters and glucose metabolism indicators significantly improved in the participants. TL did not change after the intervention in participants. Significant negative correlations between baseline TL and anthropometric measures (BMI, body weight and waist circumference) were observed. Furthermore, baseline TL was a predictor for changes in blood glucose levels after the lifestyle intervention. CONCLUSIONS: An inverse correlation between TL and obesity traits was observed in children with abdominal obesity. Interestingly, we found that baseline TL could predict changes in blood glucose levels. CLINICAL TRIAL: NCT03147261. Registered 10 May 2017.


Assuntos
Adiposidade , Glicemia/metabolismo , Estilo de Vida Saudável , Obesidade Abdominal/terapia , Obesidade Pediátrica/terapia , Comportamento de Redução do Risco , Homeostase do Telômero , Encurtamento do Telômero , Adolescente , Fatores Etários , Biomarcadores/sangue , Índice de Massa Corporal , Restrição Calórica , Criança , Dieta Saudável , Dieta Mediterrânea , Exercício Físico , Feminino , Humanos , Masculino , Obesidade Abdominal/sangue , Obesidade Abdominal/genética , Obesidade Abdominal/fisiopatologia , Obesidade Pediátrica/sangue , Obesidade Pediátrica/genética , Obesidade Pediátrica/fisiopatologia , Espanha , Fatores de Tempo , Resultado do Tratamento , Circunferência da Cintura , Perda de Peso
20.
PLoS One ; 15(2): e0228887, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040538

RESUMO

BACKGROUND: Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm and inherited variation in telomere maintenance genes. METHODS: We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets. RESULTS: The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004). CONCLUSIONS: Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.


Assuntos
Segunda Neoplasia Primária/genética , Proteínas de Ligação a Telômeros/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Sobreviventes de Câncer , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Humanos , Incidência , Íntrons , Estudos Longitudinais , Masculino , Segunda Neoplasia Primária/epidemiologia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Fatores de Risco , Homeostase do Telômero/genética , Neoplasias da Glândula Tireoide/epidemiologia
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