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1.
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
2.
Hum Genet ; 139(12): 1531-1539, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32533363

RESUMO

The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5' UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are "biologically older", as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are "biologically older" than men carrying the normal size allele in the same age group.


Assuntos
Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Telômero/genética , Tremor/genética , Regiões 5' não Traduzidas/genética , Adulto , Idoso , Alelos , Ataxia/patologia , Síndrome do Cromossomo X Frágil/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Telômero/patologia , Telômero/ultraestrutura , Homeostase do Telômero/genética , Tremor/patologia , Expansão das Repetições de Trinucleotídeos/genética , Adulto Jovem
3.
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
4.
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
5.
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
6.
Lipids Health Dis ; 19(1): 11, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952540

RESUMO

BACKGROUND: Previous evidence suggests that plasma phospholipid fatty acids (PPFAs) and HOMA insulin resistance (HOMA-IR) are independently related to leukocyte telomere length (LTL). However, there is limited evidence of regarding the effect of their interaction on relative LTL (RLTL). Therefore, here, we aimed to determine the effect of the interaction between PPFAs and HOMA-IR on RLTL. METHODS: We conducted a cross-sectional study, involving a total of 1246 subjects aged 25-74 years. PPFAs and RLTL were measured, and HOMA-IR was calculated. The effect of the interaction between PPFAs and HOMA-IR on RLTL was assessed by univariate analysis, adjusting for potential confounders. RESULTS: In age-adjusted analyses, multivariate linear regression revealed a significant association of the levels of elaidic acid, HOMA-IR, monounsaturated fatty acids (MUFA) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) with RLTL. After adjustment of age and gender, race, smoking, drinking, tea, and exercise, elaidic acid, and omega-3 (n-3) PUFA were negatively associated with RLTL, and HOMA-IR and n-6 PUFA were positively associated with RLTL. These associations were not significantly altered upon further adjustment for anthropometric and biochemical indicators. Meanwhile, the effect of the interaction of elaidic acid and HOMA-IR on RLTL was significant, and remained unchanged even after adjusting for the aforementioned potential confounders. Interestingly, individuals who had the lowest HOMA-IR and the highest elaidic acid levels presented the shortest RLTL. CONCLUSIONS: Our findings indicated that shorter RLTL was associated with lower HOMA-IR and higher elaidic acid level. These findings might open a new avenue for exploring the potential role of the interaction between elaidic acid and HOMA-IR in maintaining RLTL.


Assuntos
Resistência à Insulina/fisiologia , Leucócitos/metabolismo , Fosfolipídeos/sangue , Telômero/metabolismo , Adulto , Idoso , Estudos Transversais , Ácidos Graxos Monoinsaturados/sangue , Ácidos Graxos Ômega-6/sangue , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Telômero/genética , Homeostase do Telômero/genética , Homeostase do Telômero/fisiologia
7.
J Neurooncol ; 147(1): 1-14, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31960234

RESUMO

PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance. METHODS: We analyzed cell-specific telomere length (CS-TL) on a single cell level in 46 astrocytoma samples (WHO II-IV) by modified immune-quantitative fluorescence in situ hybridization, using endothelial cells as internal reference. In the same samples, we determined IDH1/TERT promoter mutation status and ATRX expression. The interaction of IDH1R132H mutation and CS-TL was studied in vitro using an IDH1R132H doxycycline-inducible glioma cell line system. RESULTS: Virtually all ALTpositive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALTpositive samples had IDH1R132H mutations, resulting in a significantly longer CS-TL of IDH1R132H gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDHwildtype, ATRX expression, lack of ALT and short CS-TL. ALT, TERT promoter mutations, and CS-TL remained without prognostic significance, when correcting for IDH1 status. In vitro, overexpression of IDHR132H in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT. CONCLUSION: ALT is the major telomere maintenance mechanism in IDHR132H mutated astrocytomas, while TERT promoter mutations were associated with IDHwildtype glioma. IDH1R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1R132H mutations, ATRX loss, and ALT.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Isocitrato Desidrogenase/genética , Telomerase/genética , Homeostase do Telômero/genética , Proteína Nuclear Ligada ao X/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Célula Única , Células Tumorais Cultivadas , Adulto Jovem
8.
Toxicol Lett ; 322: 20-31, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31923465

RESUMO

Particulate matter (PM) from combustion processes has been associated with oxidative stress to DNA, whereas effects related to telomere dysfunction are less investigated. We collected air-borne PM from a passenger cabin of a diesel-propelled train and at a training facility for smoke diving exercises. Effects on oxidative stress biomarkers, genotoxicity measured by the comet assay and telomere length in PM-exposed A549 cells were compared with the genotoxicity and telomere length in peripheral blood mononuclear cells (PBMCs) from human volunteers exposed to the same aerosol source. Although elevated levels of DNA strand breaks and oxidatively damaged DNA in terms of Fpg-sensitive sites were observed in PBMCs from exposed humans, the PM collected at same locations did not cause genotoxicity in the comet assay in A549 cells. Nevertheless, A549 cells displayed telomere length shortening after four weeks exposure to PM. This is in line with slightly shorter telomere length in PBMCs from exposed humans, although it was not statistically significant. In conclusion, the results indicate that genotoxic potency measured by the comet assay of PM in A549 cells may not predict genotoxicity in exposed humans, whereas telomere length measurements may be a novel indicator of genotoxic stress in cell cultures and humans.


Assuntos
Dano ao DNA , Exposição por Inalação/efeitos adversos , Material Particulado/toxicidade , Fumaça/efeitos adversos , Homeostase do Telômero/efeitos dos fármacos , Emissões de Veículos/toxicidade , Células A549 , Poluentes Ocupacionais do Ar/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Bombeiros , Humanos , Exposição por Inalação/análise , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Tamanho da Partícula , Homeostase do Telômero/genética
9.
Sci Rep ; 10(1): 1197, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988393

RESUMO

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Coortes , Feminino , Genótipo , Humanos , Japão , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Homeostase do Telômero/genética
10.
PLoS One ; 15(1): e0227616, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923255

RESUMO

BACKGROUND: Non-ST elevation acute coronary syndrome (NSTEACS) occurs more frequently in older patients with an increased occurrence of recurrent cardiac events following the index presentation. Telomeres are structures consisting of repeated DNA sequences as associated shelterin proteins at the ends of chromosomes. We aim to determine whether telomere length (TL) and telomerase activity (TA) predicted poor outcomes in older patients presenting with NSTEACS undergoing invasive care. METHOD: Older patients undergoing invasive management for NSTEACS were recruited to the ICON-1 biomarker study (NCT01933581). Peripheral blood mononuclear cells (PBMC) were recovered on 153 patients. DNA was isolated and mean TL was measured by quantitative PCR expressed as relative T (telomere repeat copy number) to S (single copy gene number) ratio (T/S ratio), and a telomere repeat amplification assay was used to assess TA during index presentation with NSTEACS. Primary clinical outcomes consisted of death, myocardial infarction (MI), unplanned revascularisation, stroke and significant bleeding recorded at 1 year. TL and TA were divided into tertile groups for analysis. Cox proportional hazards regression was performed. Ordinal regression was performed to evaluate the relationship between TL and TA and traditional cardiovascular risk factors at baseline. RESULTS: 298 patients were recruited in the ICON-1 study of which 153 had PBMC recovered. The mean age was 81.0 ± 4.0 years (64% male). Mean telomere length T/S ratio was 0.47 ± 0.25 and mean TA was 1.52 ± 0.61 units. The primary composite outcome occurred in 44 (28.8%) patients. There was no association between short TL or low TA and incidence of the primary composite outcome (Hazard Ratio [HR] 1.50, 95% Confidence Interval [CI] 0.68-3.34, p = 0.32 and HR 1.33, 95% CI 0.52-3.36, p = 0.51 respectively). CONCLUSION: TL and TA are not found to be associated with the incidence of adverse outcomes in older patients presenting with NSTEACS undergoing invasive care. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT01933581.


Assuntos
Infarto do Miocárdio sem Supradesnível do Segmento ST/genética , Homeostase do Telômero/genética , Telômero/genética , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/metabolismo , Idoso , Idoso de 80 Anos ou mais , Angiografia Coronária , Feminino , Hemorragia/complicações , Humanos , Incidência , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/complicações , Telomerase/genética , Telômero/metabolismo , Homeostase do Telômero/fisiologia , Resultado do Tratamento
11.
PLoS Biol ; 18(1): e3000594, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31895940

RESUMO

Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway.


Assuntos
Proteínas Correpressoras/fisiologia , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Chaperonas Moleculares/fisiologia , Troca de Cromátide Irmã/genética , Telômero/genética , Proteína Nuclear Ligada ao X/fisiologia , Animais , Células Cultivadas , Embrião de Mamíferos , Feminino , Células HeLa , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/patologia , Camundongos , Camundongos Knockout , Transdução de Sinais/genética , Telômero/metabolismo , Homeostase do Telômero/genética , Talassemia alfa/genética , Talassemia alfa/patologia
12.
Am J Phys Anthropol ; 171(3): 520-528, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31845317

RESUMO

OBJECTIVES: Telomeres, emerging biomarkers of aging, are comprised of DNA repeats located at chromosomal ends that shorten with cellular replication and age in most human tissues. In contrast, spermatocyte telomeres lengthen with age. These changes in telomere length (TL) appear to be heritable, as older paternal ages of conception (PAC) predict longer offspring TL. Mouse-model studies raise questions about the potential for effects of paternal experiences on human offspring TL, as they suggest that smoking, inflammation, DNA damage, and stressors all shorten sperm TL. Here, we examined whether factors from the paternal environment predict offspring TL as well as interact with PAC to predict offspring TL. MATERIALS AND METHODS: Using data from the Philippines, we tested if smoking, psychosocial stressors, or shorter knee height (a measure of early life adversity) predict shorter offspring TL. We also tested if these interacted with PAC in predicting offspring TL. RESULTS: While we did not find the predicted associations, we observed a trend toward fathers with shorter knee height having offspring with longer TL. In addition, we found that knee height interacted with PAC to predict offspring TL. Specifically, fathers with shorter knee heights showed a stronger positive effect of PAC on offspring TL. DISCUSSION: While the reasons for these associations remain uncertain, shorter knee height is characteristic of earlier puberty. Since spermatocyte TL increases with the production of sperm, we speculate that individuals with earlier puberty, and its concomitant commencement of production of sperm, had more time to accumulate longer sperm telomeres.


Assuntos
Estatura , Herança Paterna , Fumar/efeitos adversos , Estresse Psicológico/psicologia , Homeostase do Telômero/genética , Encurtamento do Telômero/genética , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Filipinas , Adulto Jovem
13.
Nat Commun ; 10(1): 4723, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624261

RESUMO

Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.


Assuntos
Envelhecimento/genética , Células-Tronco Embrionárias/metabolismo , Longevidade/genética , Homeostase do Telômero/genética , Telômero/genética , Envelhecimento/metabolismo , Animais , Dano ao DNA , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/genética
14.
Bioessays ; 41(11): e1900095, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31577044

RESUMO

Reproduction, a basic property of biological life, entails costs for an organism, ultimately detectable as reduction in survival prospects. Telomeres are an excellent candidate biomarker for explaining these reproductive costs, because their shortening correlates with increased mortality risk. For similar reasons, telomeres are perceived as biomarkers of individual "quality." The relationship between reproduction and telomere dynamics is reviewed, emphasizing that cost and quality perspectives, commonly presented in isolation, should be integrated. While a majority of correlative studies have confirmed the relationship between telomere dynamics and various reproductive outputs, only limited experimental support exists showing that reproduction causes telomeres to shorten. A shift of focus to experimental manipulations of reproductive effort/telomere dynamics is crucial. However, the observation of survival reduction in response to these manipulations is essential for establishing telomeres as genuine biomarkers, allowing to unravel trade-offs related to reproduction.


Assuntos
Reprodução/genética , Homeostase do Telômero/genética , Telômero/genética , Animais , Biomarcadores/metabolismo , Humanos
15.
J Biol Chem ; 294(40): 14574-14590, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31375564

RESUMO

Human tankyrase-1 (TNKS) is a member of the poly(ADP-ribose) polymerase (PARP) superfamily of proteins that posttranslationally modify themselves and target proteins with ADP-ribose (termed PARylation). The TNKS ankyrin repeat domain mediates interactions with a growing number of structurally and functionally diverse binding partners, linking TNKS activity to multiple critical cell processes, including Wnt signaling, Golgi trafficking, and telomere maintenance. However, some binding partners can engage TNKS without being modified, suggesting that separate parameters influence TNKS interaction and PARylation. Here, we present an analysis of the sequence and structural features governing TNKS interactions with two model binding partners: the PARylated partner telomeric repeat-binding factor 1 (TRF1) and the non-PARylated partner GDP-mannose 4,6-dehydratase (GMD). Using a combination of TNKS-binding assays, PARP activity assays, and analytical ultracentrifugation sedimentation analysis, we found that both the specific sequence of a given TNKS-binding peptide motif and the quaternary structure of individual binding partners play important roles in TNKS interactions. We demonstrate that GMD forms stable 1:1 complexes with the TNKS ankyrin repeat domain; yet, consistent with results from previous studies, we were unable to detect GMD modification. We also report in vitro evidence that TNKS primarily directs PAR modification to glutamate/aspartate residues. Our results suggest that TNKS-binding partners possess unique sequence and structural features that control binding and PARylation. Ultimately, our findings highlight the binding partner:ankyrin repeat domain interface as a viable target for inhibition of TNKS activity.


Assuntos
Hidroliases/química , Complexos Multiproteicos/química , Estrutura Quaternária de Proteína/genética , Tanquirases/química , Proteínas de Ligação a Telômeros/química , Adenosina Difosfato Ribose/química , Motivos de Aminoácidos/genética , Sequência de Aminoácidos , Repetição de Anquirina/genética , Ácido Aspártico/genética , Sítios de Ligação/genética , Ácido Glutâmico/genética , Humanos , Hidroliases/genética , Hidroliases/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Poli(ADP-Ribose) Polimerases/química , Ligação Proteica/genética , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade , Tanquirases/genética , Tanquirases/metabolismo , Homeostase do Telômero/genética , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Via de Sinalização Wnt/genética
16.
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
17.
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
18.
Mol Cell ; 75(3): 469-482.e6, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31278054

RESUMO

A significant fraction (∼10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). There are no known molecular, ALT-specific, therapeutic targets. We have identified TSPYL5 (testis-specific Y-encoded-like protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT+ cell viability. TSPYL5 was described as an inhibitor of the USP7 deubiquitinase. We report that TSPYL5 prevents the poly-ubiquitination of POT1-a shelterin component-and protects POT1 from proteasomal degradation exclusively in ALT+ cells. USP7 depletion rescued POT1 poly-ubiquitination and loss, suggesting that the deubiquitinase activates POT1 E3 ubiquitin ligase(s). Similarly, PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT+ cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies and identify TSPYL5 as an ALT+ cancer-specific therapeutic target.


Assuntos
Neoplasias/genética , Proteínas Nucleares/genética , Homeostase do Telômero/genética , Proteínas de Ligação a Telômeros/genética , Peptidase 7 Específica de Ubiquitina/genética , Linhagem Celular , Sobrevivência Celular/genética , Humanos , Neoplasias/patologia , Proteína da Leucemia Promielocítica/genética , Ligação Proteica/genética , Proteólise , Telômero/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética
19.
Genes Dev ; 33(13-14): 814-827, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171703

RESUMO

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


Assuntos
Núcleo Celular/metabolismo , DNA/biossíntese , Leucemia Promielocítica Aguda/fisiopatologia , Mitose , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , RecQ Helicases/metabolismo , Homeostase do Telômero/genética , Motivos de Aminoácidos , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Leucemia Promielocítica Aguda/genética , Fenótipo , Transporte Proteico , Proteína SUMO-1/metabolismo , Telômero/genética , Telômero/metabolismo
20.
Nat Commun ; 10(1): 2491, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171785

RESUMO

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


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Reparo do DNA/genética , Leucócitos/metabolismo , Homeostase do Telômero/genética , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Respiratórias/genética , Singapura , Adulto Jovem
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