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1.
Anim Genet ; 51(1): 3-13, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31637754

RESUMO

Telomeres are genetically conserved nucleoprotein complexes located at the ends of chromosomes that preserve genomic stability. In large mammals, somatic cell telomeres shorten with age, owing to the end replication problem and lack of telomere-lengthening events (e.g. telomerase and ALT activity). Therefore, telomere length reflects cellular replicative reserve and mitotic potential. Environmental insults can accelerate telomere attrition in response to cell division and DNA damage. As such, telomere shortening is considered one of the major hallmarks of ageing. Much effort has been dedicated to understanding the environmental perturbations that accelerate telomere attrition and therapeutic strategies to preserve or extend telomeres. As telomere dynamics seem to reflect cumulative cellular stress, telomere length could serve as a biomarker of animal welfare. The assessment of telomere dynamics (i.e. rate of shortening) in conjunction with telomere-regulating genes and telomerase activity in racehorses could monitor long-term animal health, yet it could also provide some unique opportunities to address particular limitations with the use of other animal models in telomere research. Considering the ongoing efforts to optimise the health and welfare of equine athletes, the purpose of this review is to discuss the potential utility of assessing telomere length in Thoroughbred racehorses. A brief review of telomere biology in large and small mammals will be provided, followed by discussion on the biological implications of telomere length and environmental (e.g. lifestyle) factors that accelerate or attenuate telomere attrition. Finally, the utility of quantifying telomere dynamics in horses will be offered with directions for future research.


Assuntos
Cavalos/genética , Encurtamento do Telômero , Telômero/ultraestrutura , Animais , Instabilidade Genômica , Humanos
2.
Ecol Lett ; 23(2): 381-398, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31773847

RESUMO

Animal response to stressors such as harsh environmental conditions and demanding biological processes requires energy generated through increased mitochondrial activity. This results in the production of reactive oxygen species (ROS). In vitro and some in vivo studies suggest that oxidative damage of DNA caused by ROS is responsible for telomere shortening. Since telomere length is correlated with survival in many vertebrates, telomere loss is hypothesised to trigger cellular ageing and/ or to reflect the harshness of the environment an individual has experienced. To improve our understanding of stress-induced telomere dynamics in non-human vertebrates, we analysed 109 relevant studies in a meta-analytical framework. Overall, the exposure to possible stressors was associated with shorter telomeres or higher telomere shortening rate (average effect size = -0.16 ± 0.03). This relationship was consistent for all phylogenetic classes and for all a priori-selected stressor categories. It was stronger in the case of pathogen infection, competition, reproductive effort and high activity level, which emphasises their importance in explaining intraspecific telomere length variability and, potentially, lifespan variability. Interestingly, the association between stressor exposure and telomeres in one hand, and oxidative stress in the other hand, covaried, suggesting the implication of oxidative stress in telomere dynamics.


Assuntos
Encurtamento do Telômero , Telômero , Animais , Senescência Celular , Filogenia , Vertebrados
3.
J Oral Pathol Med ; 49(1): 82-90, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31402483

RESUMO

BACKGROUND: Progressive telomere shortening with age or chronic inflammation may lead to genomic instability that characterizes the early stage of carcinogenesis. Certain risk factors, such as drinking alcoholic beverages or smoking, predispose the oral mucosa to squamous cell carcinoma. The ADH1B and ALDH2 genotypes can influence the risk of cancer due to alcohol drinking. In the present study, we analyzed chromosomal instability due to telomere shortening in the oral mucosa in relation to cancer risk factors. DESIGN: Using our quantitative fluorescence in situ hybridization (Q-FISH) technique, we estimated telomere lengths (TL) in the background mucosa from 23 cases of mucosal carcinoma, 12 cases of oral epithelial dysplasia, and 21 non-neoplasia cases. ALDH2 and ADH1B genotypes were determined using DNA extracted from paraffin sections. We analyzed TL in relation to alcohol drinking, smoking, and cancer multiplicity. RESULTS: Telomeres in the backgrounds of dysplasia and mucosal carcinoma were significantly shorter than in controls. In comparison with adult controls, telomeres were significantly (P = .038) shorter in the ADH1B less-active type (ADH1B*1/*1), but not (P = .841) in the ALDH2 inactive type (ALDH2*1/*2 or *2/*2). Cancer multiplicity and smoking had no significant relationship with TL. CONCLUSION: Telomeres in the oral epithelium are shorter in cases of oral dysplasia or mucosal carcinoma than in non-neoplasia. Unlike the esophageal epithelium of alcoholics, they are also shorter in individuals with the less-active rather than the active ADH1B gene. Telomeres in the oral epithelium may be directly affected by alcohol drinking.


Assuntos
Álcool Desidrogenase/genética , Aldeído-Desidrogenase Mitocondrial/genética , Encurtamento do Telômero , Adulto , Consumo de Bebidas Alcoólicas , Genótipo , Humanos , Hibridização in Situ Fluorescente , Polimorfismo Genético
4.
Environ Pollut ; 256: 113373, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672366

RESUMO

Comprehensively understanding the factors affecting physiology and fitness in urban wildlife requires concurrently considering multiple stressors. To this end, we simultaneously assessed how metal pollution and proximity to roads affect body condition and telomere shortening between days 8 and 15 of age in nestling great tits (Parus major), a common urban bird. We employed a repeated-measures sampling design to compare telomere shortening and body condition between nestlings from four urban study sites south of Antwerp, Belgium, which are located at different distances from a metal pollution point source. In addition, we explored associations between metal exposure and telomere dynamics on the individual level by measuring blood concentrations of five metals/metalloids, of which lead, copper and zinc were present at concentrations above the limit of detection. To assess whether roadway-associated stressors (e.g. noise and air pollution) might affect nestling condition and telomere shortening, we measured the proximity of nest boxes to roads. Metal exposure was not associated with nestling telomere length or body condition, despite elevated blood lead concentrations close to the metal pollution source (mean ±â€¯SE = 0.270 ±â€¯0.095 µg/g wet weight at the most polluted study site), suggesting that nestlings may have some capacity to detoxify metals. However, nestlings from nest boxes near roads exhibited more telomere shortening between days 8 and 15 of age, and shorter telomeres at day 15. Nestlings in poorer condition also had shorter telomeres, but proximity to the road was unrelated to body condition. Thus, nutritional stress is unlikely to mediate the relationship between proximity to roads and telomere length. Rather, proximity to roads could have affected telomere shortening by exposing nestlings to air or noise pollution. Our study highlights that traffic-related pollution, which is implicated in human health problems, might also affect urban wildlife.


Assuntos
Monitoramento Ambiental/métodos , Poluentes Ambientais/sangue , Metais Pesados/sangue , Ruído/efeitos adversos , Passeriformes/genética , Encurtamento do Telômero , Animais , Bélgica , Feminino , Masculino , Passeriformes/sangue
5.
Sci Total Environ ; 706: 135083, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841853

RESUMO

Stressors experience early in life by animals may have carry over impacts on life-traits over the life cycle. Accelerated telomere attrition induced by stress during development and growth could play a role in such delayed effects. Among stressors, exposure to chemicals may modify telomere dynamic but, to date, the trends evidenced between exposure and telomere shortening remains inconsistent. Moreover, the role of corticosterone as a possible mediator of chemical impact on telomere is not yet clearly established. Here, we investigated in wild populations of Red kite whether nestling exposure to metals and pesticides was related to corticosterone concentrations in feathers and telomere length measured in 47 individuals. Lead and mercury concentrations in blood ranged from 2.3 to 59.0 µg L-1 and to 1.4 to 115.7 µg L-1, respectively, and were below the toxicity thresholds proposed for wildlife. Rodenticides were detected in 30% of the chicks. Corticosterone increased with mercury and lead in interaction, showing a synergistic effect of these 2 non-essential metals on this stress hormone. Telomere length was not linked to metals and/or rodenticide exposure while it was related negatively to corticosterone. The relationship between telomere and corticosterone was modulated by nestling's age, which suggests that the rate of telomere shortening is higher when corticosterone increases. Our findings propose an effect of low exposure of Red Kite nestlings to mercury and lead mixture to raise baseline corticosterone in feathers. The relationships established suggest the hypothesis that telomere attrition could be an indirect consequence of metal exposure mediated by corticosterone.


Assuntos
Aves Predatórias , Animais , Corticosterona , Estresse Fisiológico , Telômero , Encurtamento do Telômero
6.
Nat Commun ; 10(1): 5688, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831736

RESUMO

Senescence is induced by various stimuli such as oncogene expression and telomere shortening, referred to as oncogene-induced senescence (OIS) and replicative senescence (RS), respectively, and accompanied by global transcriptional alterations and 3D genome reorganization. Here, we demonstrate that the human condensin II complex participates in senescence via gene regulation and reorganization of euchromatic A and heterochromatic B compartments. Both OIS and RS are accompanied by A-to-B and B-to-A compartmental transitions, the latter of which occur more frequently and are undergone by 14% (430 Mb) of the human genome. Mechanistically, condensin is enriched in A compartments and implicated in B-to-A transitions. The full activation of senescence genes (SASP genes and p53 targets) requires condensin; its depletion impairs senescence markers. This study describes that condensin reinforces euchromatic A compartments and promotes B-to-A transitions, both of which are coupled to optimal expression of senescence genes, thereby allowing condensin to contribute to senescent processes.


Assuntos
Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Senescência Celular/genética , Senescência Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/farmacologia , Proteínas de Ciclo Celular/genética , Linhagem Celular , Cromatina , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Genômica , Humanos , Proteínas Nucleares/genética , Oncogenes , Regiões Promotoras Genéticas , Encurtamento do Telômero , Proteína Supressora de Tumor p53/genética
7.
Environ Health Perspect ; 127(11): 117001, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31691586

RESUMO

BACKGROUND: Although studies have provided estimates of premature mortality to either heat or cold in adult populations, and fetal exposure to ambient temperature may be associated with life expectancy, the effects of temperature on aging in early life have not yet been studied. Telomere length (TL) is a marker of biological aging, and a short TL at birth may predict lifespan and disease susceptibility later in life. OBJECTIVES: We studied to what extent prenatal ambient temperature exposure is associated with newborn TL. METHODS: In the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort in Flanders, Belgium, we measured cord blood and placental TL in 1,103 mother-newborn pairs (singletons with ≥36wk of gestation) using a quantitative real-time polymerase chain reaction (qPCR) method. We associated newborn TL with average weekly exposure to ambient temperature using distributed lag nonlinear models (DLNMs) while controlling for potential confounders. Double-threshold DLNMs were used to estimate cold and heat thresholds and the linear associations between temperature and TL below the cold threshold and above the heat threshold. RESULTS: Prenatal temperature exposure above the heat threshold (19.5°C) was associated with shorter cord blood TL. The association with a 1°C increase in temperature was strongest at week 36 of gestation and resulted in a 3.29% [95% confidence interval (CI): -4.67, -1.88] shorter cord blood TL. Consistently, prenatal temperature exposure below the cold threshold (5.0°C) was associated with longer cord blood TL. The association with a 1°C decrease in temperature was strongest at week 10 of gestation with 0.72% (95% CI: 0.46, 0.97) longer cord blood TL. DISCUSSION: Our study supports potential effects of prenatal temperature exposure on longevity and disease susceptibility later in life. Future climate scenarios might jeopardize the potential molecular longevity of future generations from birth onward. https://doi.org/10.1289/EHP5153.


Assuntos
Envelhecimento/fisiologia , Temperatura Baixa , Sangue Fetal/fisiologia , Temperatura Alta , Exposição Materna , Placenta/fisiologia , Encurtamento do Telômero/fisiologia , Adulto , Bélgica , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Longevidade , Masculino , Gravidez , Adulto Jovem
8.
Adv Exp Med Biol ; 1192: 521-544, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31705512

RESUMO

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder, and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis, or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time, this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.


Assuntos
Senescência Celular/genética , Leucócitos/metabolismo , Transtornos Mentais/genética , Telomerase , Telômero/metabolismo , Idoso , Humanos , Transtornos Mentais/diagnóstico , Homeostase do Telômero , Encurtamento do Telômero
9.
Oecologia ; 191(4): 757-766, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31612326

RESUMO

In addition to direct mortality, predators can have indirect effects on prey populations by affecting prey behaviour or physiology. For example, predator presence can increase stress hormone levels, which can have physiological costs. Stress exposure accelerates the shortening of telomeres (i.e. the protective caps of chromosomes) and shorter telomeres have been linked to increased mortality risk. However, the effect of perceived predation risk on telomeres is not known. We investigated the effects of continuous predator threat (nesting Eurasian pygmy owl Glaucidium passerinum) on telomere dynamics of both adult and partially cross-fostered nestling pied flycatchers (Ficedula hypoleuca) in the wild. Females nesting at owl-inhabited sites showed impaired telomere maintenance between incubation and chick rearing compared to controls, and both males and females ended up with shorter telomeres at owl-inhabited sites in the end of chick rearing. On the contrary, both original and cross-fostered chicks reared in owl sites had consistently longer telomeres during growth than chicks reared at control sites. Thus, predation risk may cause a long-term cost in terms of telomeres for parents but not for their offspring. Predators may therefore affect telomere dynamics of their preys, which could have implications for their ageing rate and consequently for population dynamics.


Assuntos
Passeriformes , Aves Canoras , Animais , Feminino , Masculino , Comportamento Predatório , Telômero , Encurtamento do Telômero
10.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597307

RESUMO

Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication stress-induced DNA damage of telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) can be considered a common origin of senescence in vitro, with consequences on ageing in vivo. Unexpectedly, mtDNA and telDNA share common features indicative of a high degree of replicative stress, such as G-quadruplexes, D-loops, RNA:DNA heteroduplexes, epigenetic marks, or supercoiling. To avoid these stresses, both compartments use similar enzymatic strategies involving, for instance, endonucleases, topoisomerases, helicases, or primases. Surprisingly, many of these replication helpers are active at both telDNA and mtDNA (e.g., RNAse H1, FEN1, DNA2, RecQ helicases, Top2α, Top2ß, TOP3A, DNMT1/3a/3b, SIRT1). In addition, specialized telomeric proteins, such as TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component), or TIN2 (shelterin complex), shuttle from telomeres to mitochondria, and, by doing so, modulate mitochondrial metabolism and the production of ROS, in a feedback manner. Hence, mitochondria and telomeres use common weapons and cooperate to resist/prevent replication stresses, otherwise producing common consequences, namely senescence and ageing.


Assuntos
Replicação do DNA , DNA Mitocondrial/genética , Estresse Fisiológico/genética , Telômero/genética , Envelhecimento/genética , Animais , Senescência Celular/genética , Dano ao DNA , Epigênese Genética , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Estresse Oxidativo , Homeostase do Telômero , Encurtamento do Telômero
11.
PLoS Genet ; 15(9): e1008368, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31518356

RESUMO

Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.


Assuntos
Células-Tronco/metabolismo , Encurtamento do Telômero/fisiologia , Animais , Atrofia/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Proliferação de Células/genética , Células Epidérmicas/metabolismo , Epiderme/metabolismo , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Transdução de Sinais/genética , Proteínas Smad/metabolismo , Telômero/genética , Encurtamento do Telômero/genética , Transativadores/metabolismo
12.
Mol Med Rep ; 20(4): 3701-3708, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485647

RESUMO

Telomere length, a marker of cellular aging, decreases with age and it has been associated with aging­related diseases. Environmental factors, including diet and lifestyle factors, affect the rate of telomere shortening which can be reversed by telomerase. Telomerase activation by natural molecules has been suggested to be an anti­aging modulator that can play a role in the treatment of aging­related diseases. This study aimed to investigate the effect of natural compounds on telomerase activity in human peripheral blood mononuclear cells (PBMCs). The tested compounds included Centella asiatica extract formulation (08AGTLF), Astragalus extract formulation (Nutrient 4), TA­65 (containing Astragalus membranaceus extract), oleanolic acid (OA), maslinic acid (MA), and 3 multi­nutrient formulas (Nutrients 1, 2 and 3) at various concentrations. The mean absorbance values of telomerase activity measured following treatment with some of the above­mentioned formulations were statistically significantly higher compared to those of the untreated cells. In particular, in order of importance with respect to telomerase activation from highest to lowest, 08AGTLF, OA, Nutrient 4, TA­65, MA, Nutrient 3 and Nutrient 2, triggered statistically significant increase in telomerase activity compared to the untreated cells. 08AGTLF reached the highest levels of telomerase activity reported to date, at least to our knowledge, increasing telomerase activity by 8.8 folds compared to untreated cells, while Nutrient 4 and OA were also potent activators (4.3­fold and 5.9­fold increase, respectively). On the whole, this study indicates that the synergistic effect of nutrients and natural compounds can activate telomerase and produce more potent formulations. Human clinical studies using these formulations are required to evaluate their mode of action. This would reveal the health benefits of telomerase activation through natural molecules and would shed new light onto the treatment of aging­related diseases.


Assuntos
Senescência Celular/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Extratos Vegetais/farmacologia , Telomerase/metabolismo , Astrágalo (Planta)/química , Células Cultivadas , Descoberta de Drogas , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Ácido Oleanólico/farmacologia , Encurtamento do Telômero/efeitos dos fármacos , Triterpenos/farmacologia
13.
Genes Dev ; 33(19-20): 1381-1396, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31488579

RESUMO

Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature TR, consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8-null mice and found that heterozygotes, similar to human mutation carriers, had TR insufficiency but an otherwise preserved transcriptome. In contrast, Zcchc8-/- mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The Zcchc8-/- brain transcriptome was highly dysregulated, showing accumulation and 3' end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3' end maturation mechanism that vertebrate TR shares with replication-dependent histones.


Assuntos
Proteínas de Transporte/genética , Fibrose Pulmonar Idiopática/genética , Mutação com Perda de Função , Proteínas Nucleares/genética , RNA/metabolismo , Telomerase/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Linhagem Celular , Cílios/genética , Feminino , Ligação Genética , Células HCT116 , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genética , Linhagem , Processamento Pós-Transcricional do RNA/genética , Encurtamento do Telômero/genética
14.
Insect Biochem Mol Biol ; 115: 103241, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31536769

RESUMO

The attrition of telomeres, the ends of eukaryote chromosomes, and activity of telomerase, the enzyme that restores telomere length, play a role in the ageing process and act as indicators of biological age. A notable feature of advanced eusocial insects is the longevity of reproductive individuals (queens and kings) compared to those from non-reproductive castes (workers and soldiers) within a given species, with a proposed link towards upregulation of telomerase activity in the somatic tissues of reproductive individuals. Given this, eusocial insects provide excellent model systems for research into ageing. We tested telomerase activity and measured telomere length in Bombus terrestris, which is a primitively eusocial insect species with several distinct features compared to advanced social insects. In somatic tissues, telomerase activity was upregulated only in the fat bodies of pre-diapause queens, and this upregulation was linked to heightened DNA synthesis. Telomere length was shorter in old queens compared to that in younger queens or workers. We speculate that (1) the upregulation of telomerase activity, together with DNA synthesis, is the essential step for intensifying metabolic activity in the fat body to build up a sufficient energy reserve prior to diapause, and that (2) the lifespan differences between B. terrestris workers and queens are related to the long diapause period of the queen. A possible relationship between telomere length regulation and TOR, FOXO, and InR as cell signaling components, was tested.


Assuntos
Abelhas/enzimologia , Corpo Adiposo/enzimologia , Telomerase/metabolismo , Animais , DNA/biossíntese , Feminino , Encurtamento do Telômero
15.
Genetics ; 213(2): 411-429, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31391264

RESUMO

Telomeres progressively shorten at every round of DNA replication in the absence of telomerase. When they become critically short, telomeres trigger replicative senescence by activating a DNA damage response that is governed by the Mec1/ATR and Tel1/ATM protein kinases. While Mec1/ATR is known to block cell division when extended single-stranded DNA (ssDNA) accumulates at eroded telomeres, the molecular mechanism by which Tel1/ATM promotes senescence is still unclear. By characterizing a Tel1-hy184 mutant variant that compensates for the lack of Mec1 functions, we provide evidence that Tel1 promotes senescence by signaling to a Rad9-dependent checkpoint. Tel1-hy184 anticipates senescence onset in telomerase-negative cells, while the lack of Tel1 or the expression of a kinase-defective (kd) Tel1 variant delays it. Both Tel1-hy184 and Tel1-kd do not alter ssDNA generation at telomeric DNA ends. Furthermore, Rad9 and (only partially) Mec1 are responsible for the precocious senescence promoted by Tel1-hy184. This precocious senescence is mainly caused by the F1751I, D1985N, and E2133K amino acid substitutions, which are located in the FRAP-ATM-TRAPP domain of Tel1 and also increase Tel1 binding to DNA ends. Altogether, these results indicate that Tel1 induces replicative senescence by directly signaling dysfunctional telomeres to the checkpoint machinery.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas de Saccharomyces cerevisiae/genética , Encurtamento do Telômero/genética , Telômero/genética , Substituição de Aminoácidos/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Pontos de Checagem do Ciclo Celular/genética , Divisão Celular/genética , Senescência Celular/genética , Dano ao DNA/genética , Replicação do DNA/genética , DNA de Cadeia Simples/genética , Proteínas de Ligação a DNA/genética , Proteínas Mutantes/genética , Saccharomyces cerevisiae/genética , Telomerase/genética
16.
Nucleic Acids Res ; 47(17): 8927-8940, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31378812

RESUMO

The maintenance of telomere length is critical to longevity and survival. Specifically, the failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and, in turn, genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, we describe a novel role for CtIP. We show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. Our findings demonstrate a new role for CtIP as a protector of human telomere integrity.


Assuntos
Proteínas de Transporte/metabolismo , Quebras de DNA de Cadeia Dupla , Instabilidade Genômica , Proteínas Nucleares/metabolismo , Encurtamento do Telômero/genética , Telômero/metabolismo , Reparo do DNA por Junção de Extremidades , Replicação do DNA , DNA Circular/metabolismo , Humanos , Telômero/enzimologia , Proteínas de Ligação a Telômeros/metabolismo
17.
Georgian Med News ; (291): 58-63, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31418732

RESUMO

Aim - to determine the influence of different levels of lipid metabolism on the relative blood leukocytes telomeres length (RLTL), relative buccal epithelium cells telomeres length (RBTL) in hypertensive (H) individuals with type 2 diabetes mellitus (DM2T) and without DM2T. In 60 patients with H stage II (group 1), and 96 patients with H and DM2T (group 2) lipid metabolism indexes (total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C)), anthropometric parameters were measured. Relative telomeres length (RTL) was determined by a real time quantitative PCR. The most significant shortening of RLTL and RBTL were found in group 2. In both groups, the achievement of target blood lipid levels was accompanied by multidirectional changes in RTL. Analysis of variance revealed a significant effect of TC (p=0.036) on the RBTL, LDL -C (p=0.036) on the RBTL in group 1, and significant influence of TG (p = 0.049) on RBTL, TC (p=0.019) and HDL-C (p=0.032) on RLTL in group 2. Achieving target levels of lipid metabolism did not demonstrate the expected significant effect on the elongation of the relative length of telomeres, both with isolated hypertension and with a combined course of hypertension and DM2T.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Hipertensão/complicações , Hipertensão/metabolismo , Metabolismo dos Lipídeos , Telômero/metabolismo , HDL-Colesterol , LDL-Colesterol , Diabetes Mellitus Tipo 2/genética , Humanos , Hipertensão/genética , Telômero/genética , Encurtamento do Telômero , Triglicerídeos
18.
Genetics ; 213(2): 431-447, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405990

RESUMO

A subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant "alternative lengthening of telomeres" pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 ortholog, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that upregulation of telomere-engaged TERRA, or altered recruitment of shelterin components, can support telomerase-independent telomere maintenance.


Assuntos
Proteínas de Schizosaccharomyces pombe/genética , Homeostase do Telômero/genética , Encurtamento do Telômero/genética , Proteínas de Ligação a Telômeros/genética , Telômero/genética , DNA Fúngico/química , DNA Fúngico/genética , Proteínas de Ligação a DNA/genética , RNA Fúngico/química , RNA Fúngico/genética , Reparo de DNA por Recombinação/genética , Schizosaccharomyces/genética , Telomerase/genética
19.
Int J Mol Sci ; 20(13)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266154

RESUMO

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.


Assuntos
Envelhecimento/genética , Encurtamento do Telômero , Telômero/genética , Animais , Feminino , Longevidade , Masculino , Camundongos , Ratos-Toupeira , Especificidade de Órgãos , Spalax , Especificidade da Espécie
20.
Oncogene ; 38(34): 6172-6183, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285550

RESUMO

Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.


Assuntos
Neoplasias/genética , Neoplasias/metabolismo , Telomerase/metabolismo , Transformação Celular Neoplásica/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias/patologia , Regiões Promotoras Genéticas , Telomerase/genética , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero/genética , Encurtamento do Telômero/genética , Transcrição Genética
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