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1.
J Frailty Aging ; 10(1): 2-9, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33331615

RESUMO

Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Evidences from various organisms suggests that several factors influence telomere length regulation, such as telomere binding proteins, telomere capping proteins, telomerase, and DNA replication enzymes. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. In this study, our main goal is investigating the relationship between telomerase enzyme and vitamin D. Findings of this study suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases. Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. Significant Low levels of telomerase activity create short telomeres, which in turn signal exit from the cell cycle resulting in cell senescence and apoptosis. In follow-up examination, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were depleted. Increasing 25-hydroxyvitamin D levels in patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.


Assuntos
Senescência Celular/fisiologia , Telômero/metabolismo , Vitamina D/sangue , Vitamina D/metabolismo , Envelhecimento/sangue , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Humanos , Telomerase/genética , Telomerase/metabolismo , Telômero/genética
2.
Elife ; 92020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33350935

RESUMO

HOAP is a telomere-binding protein that has a conserved role in Drosophila, but it also needs to evolve quickly to restrict telomeric retrotransposons.


Assuntos
Proteínas de Drosophila , Telômero , Animais , Proteínas Cromossômicas não Histona/metabolismo , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Retroelementos , Telômero/genética , Telômero/metabolismo
3.
BMC Evol Biol ; 20(1): 160, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33261558

RESUMO

BACKGROUND: Life history theory predicts that during the lifespan of an organism, resources are allocated to either growth, somatic maintenance or reproduction. Resource allocation trade-offs determine the evolution and ecology of different life history strategies and define an organisms' position along a fast-slow continuum in interspecific comparisons. Labord's chameleon (Furcifer labordi) from the seasonal dry forests of Madagascar is the tetrapod species with the shortest reported lifespan (4-9 months). Previous investigations revealed that their lifespan is to some degree dependent on environmental factors, such as the amount of rainfall and the length of the vegetation period. However, the intrinsic mechanisms shaping such a fast life history remain unknown. Environmental stressors are known to increase the secretion of glucocorticoids in other vertebrates, which, in turn, can shorten telomeres via oxidative stress. To investigate to what extent age-related changes in these molecular and cellular mechanisms contribute to the relatively short lifetime of F. labordi, we assessed the effects of stressors indirectly via leukocyte profiles (H/L ratio) and quantified relative telomere length from blood samples in a wild population in Kirindy Forest. We compared our findings with the sympatric, but longer-lived sister species F. cf. nicosiai, which exhibit the same annual timing of reproductive events, and with wild-caught F. labordi that were singly housed under ambient conditions. RESULTS: We found that H/L ratios were consistently higher in wild F. labordi compared to F. cf. nicosiai. Moreover, F. labordi already exhibited relatively short telomeres during the mating season when they were 3-4 months old, and telomeres further shortened during their post-reproductive lives. At the beginning of their active season, telomere length was relatively longer in F. cf. nicosiai, but undergoing rapid shortening towards the southern winter, when both species gradually die off. Captive F. labordi showed comparatively longer lifespans and lower H/L ratios than their wild counterparts. CONCLUSION: We suggest that environmental stress and the corresponding accelerated telomere attrition have profound effects on the lifespan of F. labordi in the wild, and identify physiological mechanisms potentially driving their relatively early senescence and mortality.


Assuntos
Leucócitos/metabolismo , Lagartos/genética , Longevidade , Estresse Fisiológico/genética , Encurtamento do Telômero , Telômero , Animais , Longevidade/genética , Madagáscar , Telômero/genética , Encurtamento do Telômero/genética
4.
Nucleic Acids Res ; 48(22): 12697-12710, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33264397

RESUMO

Break-induced replication (BIR) is a mechanism used to heal one-ended DNA double-strand breaks, such as those formed at collapsed replication forks or eroded telomeres. Instead of utilizing a canonical replication fork, BIR is driven by a migrating D-loop and is associated with a high frequency of mutagenesis. Here we show that when BIR encounters an interstitial telomere sequence (ITS), the machinery frequently terminates, resulting in the formation of an ectopic telomere. The primary mechanism to convert the ITS to a functional telomere is by telomerase-catalyzed addition of telomeric repeats with homology-directed repair serving as a back-up mechanism. Termination of BIR and creation of an ectopic telomere is promoted by Mph1/FANCM helicase, which has the capacity to disassemble D-loops. Other sequences that have the potential to seed new telomeres but lack the unique features of a natural telomere sequence, do not terminate BIR at a significant frequency in wild-type cells. However, these sequences can form ectopic telomeres if BIR is made less processive. Our results support a model in which features of the ITS itself, such as the propensity to form secondary structures and telomeric protein binding, pose a challenge to BIR and increase the vulnerability of the D-loop to dissociation by helicases, thereby promoting ectopic telomere formation.


Assuntos
RNA Helicases DEAD-box/genética , Replicação do DNA/genética , Recombinação Genética , Proteínas de Saccharomyces cerevisiae/genética , Telômero/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , DNA Helicases/genética , DNA Polimerase III/genética , Reparo do DNA/genética , Saccharomyces cerevisiae/genética , Telomerase/genética
5.
Nucleic Acids Res ; 48(22): 12792-12803, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33270890

RESUMO

Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C.


Assuntos
Adenosina Trifosfatases/genética , Histona Acetiltransferases/genética , Proteínas de Saccharomyces cerevisiae/genética , Homeostase do Telômero/genética , Cromatina/genética , Proteínas de Ligação a DNA/genética , Regulação Fúngica da Expressão Gênica/genética , Histonas/genética , Humanos , Complexos Multiproteicos/genética , Saccharomyces cerevisiae/genética , Telomerase/genética , Telômero/genética , Proteínas de Ligação a Telômeros/genética
6.
Cytogenet Genome Res ; 160(10): 610-624, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33207346

RESUMO

Agamid lizards (Squamata: Agamidae) are karyotypically heterogeneous. Among the 101 species currently described from Australia, all are from the subfamily Amphibolurinae. This group is, with some exceptions, karyotypically conserved, and all species involving heterogametic sex show female heterogamety. Here, we describe the chromosomes of 2 additional Australian agamid lizards, Tympanocryptis lineata and Rankinia diemensis. These species are phylogenetically and cytogenetically sisters to the well-characterised Pogona vitticeps, but their sex chromosomes and other chromosomal characteristics are unknown. In this study, we applied advanced molecular cytogenetic techniques, such as fluorescence in situ hybridisation (FISH) and cross-species gene mapping, to characterise chromosomes and to identify sex chromosomes in these species. Our data suggest that both species have a conserved karyotype with P. vitticeps but with subtle rearrangements in the chromosomal landscapes. We could identify that T. lineata possesses a female heterogametic system (ZZ/ZW) with a pair of sex microchromosomes, while R. diemensis may have heterogametic sex chromosomes, but this requires further investigations. Our study shows the pattern of chromosomal rearrangements between closely related species, explaining the speciation within Australian agamid lizards of similar karyotypes.


Assuntos
Cromossomos/genética , Rearranjo Gênico/genética , Cariótipo , Lagartos/genética , Animais , Bandeamento Cromossômico , Mapeamento Cromossômico , Cromossomos Artificiais Bacterianos/genética , Células Clonais , Metilação de DNA/genética , Geografia , Repetições de Microssatélites/genética , Especificidade da Espécie , Telômero/genética
7.
Nat Commun ; 11(1): 5861, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203878

RESUMO

Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1-TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Microcefalia/genética , Telômero/genética , Proteína 2 de Ligação a Repetições Teloméricas/metabolismo , Aminopeptidases/genética , Aminopeptidases/metabolismo , Animais , Sítios de Ligação , Calorimetria , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Dano ao DNA , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Fibroblastos , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Mutação , Domínios e Motivos de Interação entre Proteínas , Serina Proteases/genética , Serina Proteases/metabolismo , Telômero/metabolismo , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Proteína 2 de Ligação a Repetições Teloméricas/química , Proteína 2 de Ligação a Repetições Teloméricas/genética
8.
PLoS Genet ; 16(10): e1009078, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33090998

RESUMO

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10-15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (ß = 0.004, 95% CI = 0.002-0.007, P = 6.61×10-4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential.


Assuntos
Evolução Clonal/genética , Neoplasias/sangue , Homeostase do Telômero/genética , Telômero/genética , Adulto , Idoso , Divisão Celular/genética , Variações do Número de Cópias de DNA/genética , Feminino , Genética Populacional , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Reino Unido/epidemiologia
9.
PLoS One ; 15(10): e0241363, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33125425

RESUMO

INTRODUCTION: We examined whether abuse in childhood and/or adolescence was associated with shorter telomere length in a pooled analysis of 3,232 participants from five diverse cohorts. We also assessed whether religion or spirituality (R/S) could buffer deleterious effects of abuse. METHODS: Physical and sexual abuse in childhood (age <12) and adolescence (age 12-18) was assessed using the Revised Conflict Tactics Scale and questions from a 1995 Gallup survey. We measured relative leukocyte telomere lengths (RTL) using quantitative real time polymerase chain reaction. We used generalized estimating equations to assess associations of physical and sexual abuse with log-transformed RTL z-scores. Analyses were conducted in each cohort, overall, and stratified by extent of religiosity or spirituality and religious coping in adulthood. We pooled study-specific estimates using random-effects models and assessed between-study heterogeneity. RESULTS: Compared to no abuse, severe sexual abuse was associated with lower RTL z-scores, in childhood: -15.6%, 95% CI: -25.9, -4.9; p-trend = 0.04; p-heterogeneity = 0.58 and in adolescence: -16.5%, 95% CI: -28.1, -3.0; p-trend = 0.08; p-heterogeneity = 0.68. Sexual abuse experienced in both childhood and adolescence was associated with 11.3% lower RTL z-scores after adjustment for childhood and demographic covariates (95% CI: -20.5%, -2.0%; p-trend = 0.03; p-heterogeneity = 0.62). There was no evidence of effect modification by R/S. Physical abuse was not associated with telomere length. CONCLUSIONS: Sexual abuse in childhood or adolescence was associated with a marker of accelerated biological aging, decreased telomere length. The lack of moderation by R/S may be due to inability to capture the appropriate time period for those beliefs and practices.


Assuntos
Leucócitos/metabolismo , Telômero/genética , Adolescente , Criança , Humanos , Abuso Físico
10.
Nat Commun ; 11(1): 5297, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082350

RESUMO

Extrachromosomal telomeric circles are commonly invoked as important players in telomere maintenance, but their origin has remained elusive. Using electron microscopy analysis on purified telomeres we show that, apart from known structures, telomeric repeats accumulate internal loops (i-loops) that occur in the proximity of nicks and single-stranded DNA gaps. I-loops are induced by single-stranded damage at normal telomeres and represent the majority of telomeric structures detected in ALT (Alternative Lengthening of Telomeres) tumor cells. Our data indicate that i-loops form as a consequence of the exposure of single-stranded DNA at telomeric repeats. Finally, we show that these damage-induced i-loops can be excised to generate extrachromosomal telomeric circles resulting in loss of telomeric repeats. Our results identify damage-induced i-loops as a new intermediate in telomere metabolism and reveal a simple mechanism that links telomere damage to the accumulation of extrachromosomal telomeric circles and to telomere erosion.


Assuntos
Telômero/química , Telômero/metabolismo , Animais , DNA de Cadeia Simples/química , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/metabolismo , Humanos , Camundongos , Telômero/genética , Homeostase do Telômero
11.
Biochim Biophys Acta Mol Cell Res ; 1867(12): 118845, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32910990

RESUMO

Mutations in DKC1, NOP10, and TINF2 genes, coding for proteins in telomerase and shelterin complexes, are responsible for diverse diseases known as telomeropathies and ribosomopathies, including dyskeratosis congenita (DC, ORPHA 1775). These genes contribute to the DC phenotype through mechanisms that are not completely understood. We previously demonstrated in models of DC that oxidative stress is an early and independent event that occurs prior to telomere shortening. To clarify the mechanisms that induce oxidative stress, we silenced genes DKC1, NOP10, and TINF2 with siRNA technology. With RNA array hybridisation, we found several altered pathways for each siRNA model. Afterwards, we identified common related genes. The silenced cell line with the most deregulated genes and pathways was siNOP10, followed by siDKC1, and then by siTINF2 to a lesser extent. The siDKC1 and siNOP10 models shared altered expression of genes in the p53 pathway, while siNOP10 and siTINF2 had the adherens junction pathway in common. We also observed that depletion of DKC1 and NOP10 H/ACA ribonucleoprotein produced ribosomal biogenesis impairment which, in turn, promoted p53 pathway activation. Finally, we found that those enzymes responsible for GSH synthesis were down-regulated in models of siDKC1 and siNOP10. In contrast, the silenced cells for TINF2 showed no disruption of ribosomal biogenesis or oxidative stress and did not produce p53 pathway activation. These results indicate that depletion of DKC1 and NOP10 promotes oxidative stress and disrupts ribosomal biogenesis which, in turn, activates the p53 pathway.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Nucleares/genética , Estresse Oxidativo/genética , Ribonucleoproteínas Nucleolares Pequenas/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular , Mutação/genética , RNA Interferente Pequeno , Ribossomos/genética , Telomerase/genética , Telômero/genética , Encurtamento do Telômero/genética , Proteínas de Ligação a Telômeros/genética
12.
Nucleic Acids Res ; 48(17): 9660-9680, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32890403

RESUMO

Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of one putative translesion Pol in African trypanosomes, which we now name TbPolIE. Previously, we demonstrated that TbPolIE is associated with telomeric sequences and here we show that RNAi-mediated depletion of TbPolIE transcripts results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. We also show that TbPolIE displays pronounced localization at the nuclear periphery, and that its depletion leads to chromosome segregation defects and increased levels of endogenous DNA damage. Finally, we demonstrate that TbPolIE depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this putative translesion DNA polymerase to host immune evasion by antigenic variation.


Assuntos
Variação Antigênica , DNA Polimerase Dirigida por DNA/metabolismo , Telômero/genética , Trypanosoma brucei brucei/genética , Linhagem Celular , Núcleo Celular/enzimologia , Núcleo Celular/genética , Segregação de Cromossomos , Replicação do DNA , DNA Polimerase Dirigida por DNA/genética , Regulação da Expressão Gênica , Genoma de Protozoário , Humanos , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Interferência de RNA , Telômero/metabolismo , Trypanosoma brucei brucei/metabolismo , Trypanosoma brucei brucei/patogenicidade , Glicoproteínas Variantes de Superfície de Trypanosoma/genética
13.
Sci Rep ; 10(1): 15786, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978426

RESUMO

Exposure to the endocrine disruptor bisphenol A (BPA) has been linked with immune disorders and increased tumour risk. Our previous work in activated human peripheral blood mononuclear cells demonstrated that exposure to "low-dose" BPA diminished telomerase activity via an ER/GPR30-ERK signalling pathway. Leukocyte telomerase activity and telomere maintenance are crucial for normal immune function and homeostasis. We thus here further studied the effects of BPA on human T cell subpopulations. Exposure to 0.3-3 nM BPA, i. e. at doses in the realm of human exposure, notably reduced telomerase activity in activated CD8 + T but not CD4 + T cells in a non-monotonic response pattern as determined by the TRAP-ELISA assay. Under long-term BPA exposure, significant telomere length shortening, reduction in mitochondrial DNA copy number, cell proliferation and IFN-γ as well as hTERT protein suppression could be observed in CD8 + lymphocytes, as analysed by qRT-PCR, flow cytometry and western blot analysis. This study extends our previous in vitro findings that "low-dose" BPA has potential negative effects on healthy human cytotoxic T cell response. These results might merit some special attention to further investigate chronic BPA exposure in the context of adaptive immune response dysfunction and early onset of cancer in man.


Assuntos
Compostos Benzidrílicos/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Leucócitos Mononucleares/metabolismo , Fenóis/farmacologia , Encurtamento do Telômero/efeitos dos fármacos , Telômero/genética , Adulto , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Relação Dose-Resposta a Droga , Depuradores de Radicais Livres/farmacologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Transdução de Sinais , Fatores de Tempo , Adulto Jovem
14.
Environ Res ; 191: 110113, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32841635

RESUMO

BACKGROUND: Environmental exposures including air pollutants, toxic metals, and psychosocial stress have been associated with shorter telomere length (TL) in newborns. These exposures have in turn been linked to an enhanced inflammatory immune response. Increased inflammation during pregnancy may be a central biological pathway linking environmental factors with reduced TL at birth. Approaches that more comprehensively characterize the prenatal inflammatory milieu rather than targeting specific individual cytokines in relation to newborn TL may better elucidate inflammatory mechanisms. METHODS: Analyses included 129 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured 92 inflammation related proteins during pregnancy in maternal serum using the Olink protein array and quantified cord blood relative leukocyte TL (rLTL) via qPCR. We leveraged a tree-based machine learning algorithm to select the most important inflammatory related proteins jointly associated with rLTL. We then evaluated the combined association between the selected proteins with rLTL using Bayesian Weighted Quantile Sum (BWQS) Regression. Analyses were adjusted for gestational week of serum collection, maternal race/ethnicity, age, and education, and fetal sex. We evaluated major biological function of the identified proteins by using the UniProtKB, a centralized repository of curated functional information. RESULTS: Three proteins were negatively and linearly associated with rLTL (CASP8 ß: -0.22 p = 0.008, BNGF ß: -0.43 p = 0.033, TRANCE ß: 0.38 p = 0.004). Results from BWQS regression showed a significant overall decrease in rLTL (ß: -0.26 95%CrI: -0.43, -0.07) per quartile increase of the mixture, with CASP8 contributing the greatest weight (CASP8 50%; BNGF 27%, and TRANCE 23%). The identified proteins were involved in the regulation of apoptotic processes and cell proliferation. CONCLUSIONS: This proteomics approach identifies novel maternal prenatal inflammatory protein biomarkers associated with shortened rLTL in newborns.


Assuntos
Poluentes Atmosféricos , Sangue Fetal , Teorema de Bayes , Criança , Feminino , Humanos , Recém-Nascido , Leucócitos , Gravidez , Telômero/genética
15.
Exp Hematol ; 90: 12-17, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32858091

RESUMO

Mammalian Rap1 is a part of the telomere binding complex named shelterin and is one of the most conserved telomeric proteins. With its essential requirement in lower species to its becoming necessary in higher species, it appears to have gained and lost several functions simultaneously evolving with telomeres. Mammalian Rap1 has been reported to play a role in inflammation, metabolism, and oxidative stress. Mammalian Rap1 has also been found to regulate DNA damage response from telomeres in senescent cells. Recently our group uncovered its novel role in stem cell maintenance, and modulation of the chemotherapeutic response. Mechanistically it was found to function as an adaptor via protein-protein interactions and to modulate the response to DNA damage. In the current review we highlight newly identified functions of Rap1 in regulating telomeric and general DNA damage response with its impact at the cellular and organismal levels.


Assuntos
Dano ao DNA , Homeostase , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Células-Tronco Neoplásicas , Proteínas de Ligação a Telômeros/metabolismo , Animais , Senescência Celular , Humanos , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais , Telômero/genética , Telômero/metabolismo , Telômero/patologia , Proteínas de Ligação a Telômeros/genética
16.
Oncogene ; 39(36): 5811-5824, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32733068

RESUMO

Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. In contrast, telomerase activity is silenced in most adult somatic cells. Thus, telomerase represents an attractive target for highly selective cancer therapeutics. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. The discovery of prevalent mutations in the TERT promoter region in many cancers and recent advances in telomerase biology has led to a renewed interest in targeting this enzyme. Here we discuss recent efforts targeting telomerase, including immunotherapies and direct telomerase inhibitors, as well as emerging approaches such as targeting TERT gene expression driven by TERT promoter mutations. We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. Although much work remains to be done, effective strategies targeting telomerase will have a transformative impact for cancer therapy and the prospect of clinically effective drugs is boosted by recent advances in structural models of human telomerase.


Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Telomerase/antagonistas & inibidores , Animais , Biomarcadores Tumorais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/diagnóstico , Neoplasias/etiologia , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero , Resultado do Tratamento
17.
Mol Ecol ; 29(16): 2951-2953, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745307

RESUMO

The relationship of telomere shortening and cellular ageing in cultured cells such as fibroblasts is straightforward: telomeres shorten with an increasing number of cell divisions until they trigger replicative senescence which prevents further mitotic cycles. But studies investigating the relationship between telomere shortening and ageing in whole organisms show contrasting results: while there is a clear decline in telomere length (TL) with chronological age in some species such as humans, no such decline is observed in others. In this issue of Molecular Ecology, Foley et al. (2020) show that experiencing harsh weather conditions correlates with longitudinal telomere shortening in the bat species Myotis myotis, whereas chronological age does not (Foley et al., 2020). Further, the authors investigated whether genetics influence TL and find a low heritability (h2  = 0.01-0.06) again suggesting that environmental effects are the dominant drivers of variation in TL in this species. These are important findings as there is disagreement in the literature about the relative magnitude of genetic and environmental effects contributing to TL variation in different species. This paper investigating the impact of environmental effects makes a novel and important contribution to the literature on TL in free-living mammals.


Assuntos
Quirópteros , Encurtamento do Telômero , Animais , Senescência Celular , Quirópteros/genética , Humanos , Telômero/genética , Tempo (Meteorologia)
18.
Sci Rep ; 10(1): 13174, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764541

RESUMO

The African baobab (Adansonia digitata L.), also referred to as the "Tree of Life", is a majestic, long-lived and multipurpose tree of sub-Saharan Africa. Internationally, a growing demand for baobab products in the food, pharmaceutical and cosmetics industries has been observed. Considering this, there is a need for scientific information on the genetics and breeding of A. digitata, including cytogenetics, genetic diversity and reproductive biology. The objectives of our cytogenetic research were to determine the genome size, chromosome number, and organization of ribosomal DNA (45S and 5SrDNA) of A. digitata. Flow cytometry analysis revealed a 2C-DNA value of 3.8 ± 0.6 pg (1Cx monoploid genome size 919.1 ± 62.9 Mbp). Using our improved chromosome preparation technique, we were able to unequivocally count the chromosomes resulting in 2n = 4x = 168, a revised chromosome number for A. digitata. Fluorescent in situ hybridization (FISH) analysis revealed two massively large variants of 45S rDNA and their corresponding nucleolus organizer regions (NOR). The NOR variants were about two to four times larger than the main body of their respective chromosomes. To our knowledge, this is the first report of this phenomenon in a plant species. Furthermore, we found that FISH analysis using the Arabidopsis-type telomere repeat sequence probe clarified and confirmed the new chromosome number and characterized the 45S rDNA structural organization.


Assuntos
Adansonia/citologia , Adansonia/genética , Cromossomos de Plantas/genética , DNA Ribossômico/genética , Hibridização in Situ Fluorescente , Sequências Repetitivas de Ácido Nucleico , Telômero/genética
19.
Sci Rep ; 10(1): 13986, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814800

RESUMO

Telomeres play an important role in maintaining chromosomal integrity. With each cell division, telomeres are shortened and leukocyte telomere length (LTL) has therefore been considered a marker for biological age. LTL is associated with various lifetime stressors and health-related outcomes. Transgenerational effects have been implicated in newborns, with maternal stress, depression, and anxiety predicting shorter telomere length at birth, possibly reflecting the intrauterine growth environment. Previous studies, with relatively small sample sizes, have reported an effect of maternal stress, BMI, and depression during pregnancy on the LTL of newborns. Here, we attempted to replicate previous findings on prenatal stress and newborn LTL in a sample of 1405 infants using a qPCR-based method. In addition, previous research has been expanded by studying the relationship between maternal sleep quality and LTL. Maternal prenatal stress, anxiety, depression, BMI, and self-reported sleep quality were evaluated with self-reported questionnaires. Despite sufficient power to detect similar or even considerably smaller effects than those previously reported in the literature, we were unable to replicate the previous correlation between maternal stress, anxiety, depression, or sleep with LTL. We discuss several possible reasons for the discrepancies between our findings and those previously described.


Assuntos
Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Transtornos do Sono-Vigília/fisiopatologia , Estresse Psicológico/fisiopatologia , Homeostase do Telômero/genética , Feminino , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Autorrelato , Inquéritos e Questionários , Telômero/genética , Telômero/metabolismo
20.
PLoS Pathog ; 16(8): e1008326, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804988

RESUMO

CRISPR/Cas has become the state-of-the-art technology for genetic manipulation in diverse organisms, enabling targeted genetic changes to be performed with unprecedented efficiency. Here we report on the first establishment of robust CRISPR/Cas editing in the important necrotrophic plant pathogen Botrytis cinerea based on the introduction of optimized Cas9-sgRNA ribonucleoprotein complexes (RNPs) into protoplasts. Editing yields were further improved by development of a novel strategy that combines RNP delivery with cotransformation of transiently stable vectors containing telomeres, which allowed temporary selection and convenient screening for marker-free editing events. We demonstrate that this approach provides superior editing rates compared to existing CRISPR/Cas-based methods in filamentous fungi, including the model plant pathogen Magnaporthe oryzae. Genome sequencing of edited strains revealed very few additional mutations and no evidence for RNP-mediated off-targeting. The high performance of telomere vector-mediated editing was demonstrated by random mutagenesis of codon 272 of the sdhB gene, a major determinant of resistance to succinate dehydrogenase inhibitor (SDHI) fungicides by in bulk replacement of the codon 272 with codons encoding all 20 amino acids. All exchanges were found at similar frequencies in the absence of selection but SDHI selection allowed the identification of novel amino acid substitutions which conferred differential resistance levels towards different SDHI fungicides. The increased efficiency and easy handling of RNP-based cotransformation is expected to accelerate molecular research in B. cinerea and other fungi.


Assuntos
Botrytis/fisiologia , Sistemas CRISPR-Cas , Edição de Genes , Oryza/microbiologia , Doenças das Plantas/microbiologia , Ribonucleoproteínas/antagonistas & inibidores , Telômero/genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Oryza/genética , Doenças das Plantas/genética , Ribonucleoproteínas/genética
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