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1.
High Blood Press Cardiovasc Prev ; 26(4): 321-329, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31325087

RESUMO

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


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Telômero/metabolismo , Fatores Etários , Envelhecimento/genética , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Senescência Celular , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Medição de Risco , Fatores de Risco , Transdução de Sinais , Telômero/genética , Telômero/patologia , Homeostase do Telômero , Encurtamento do Telômero , Fatores de Tempo
2.
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
3.
Chemistry ; 25(47): 11085-11097, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31219221

RESUMO

Naphthalene diimide (NDI) dyads exhibiting a different substitution pattern and linker length have been synthesised and evaluated as G-quadruplex (G4) ligands, by investigating their cytotoxicity in selected cell lines. The dyads with the long C7 linker exhibit extremely low IC50 values, below 10 nm, on different cancer cell lines. Contrary, the dyads with the shorter C4 linker were much less effective, with IC values increasing up to 1 µm. Among the three dyads with the longest linker, small differences in the IC50 values emerge, suggesting that the linker length plays a more important role than the substitution pattern. We have further shown that the dyads are able to induce cellular DNA damage response, which is not limited to the telomeric regions and is likely the origin of their cytotoxicity. Both absorption titration and dynamic light scattering of the most cytotoxic dyads in the presence of hTel22 highlight their ability to induce effective G4 aggregation, acting as non-covalent cross-linking agents.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Quadruplex G , Imidas/farmacologia , Naftalenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidas/síntese química , Imidas/química , Ligantes , Metáfase/efeitos dos fármacos , Microscopia de Fluorescência , Naftalenos/síntese química , Naftalenos/química , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Telômero/efeitos dos fármacos , Telômero/metabolismo
4.
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
5.
Mol Biol (Mosk) ; 53(2): 268-273, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31099776

RESUMO

Many human genes that control human embryonic development and differentiation of human cells form chromosomal contact with rRNA gene clusters, which are involved in the epigenetic regulation of many genes. The sites of rRNA gene contact often fall on extended (up to 50 kb) regions containing a chromatin mark, H3K27ac histone, typical for superenhancers, as well as on pericentromeric and subtelomeric regions of chromosomes. We found that the DUX4 genes located in the subtelomeric region of human chromosome 4 are surrounded by regions that are often in contact with the rRNA genes. The 25 kb region of this chromosome, presented in version hg19 of the sequenced human genome, contains several copies of the DUX4 gene. The sites of rRNA gene contacts located around this region contain methylation sites as well as CTCF binding sites. It is assumed that the rRNA gene contacts are important in silencing these DUX4 gene copies.


Assuntos
DNA Ribossômico/genética , Desenvolvimento Embrionário/genética , Proteínas de Homeodomínio/genética , Família Multigênica/genética , Fator de Ligação a CCCTC/metabolismo , Cromatina/genética , Cromatina/metabolismo , Cromossomos Humanos Par 4/genética , Epigênese Genética , Histonas/química , Histonas/metabolismo , Humanos , Telômero/genética , Telômero/metabolismo
6.
Nat Commun ; 10(1): 2253, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138795

RESUMO

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


Assuntos
DNA Helicases/genética , Replicação do DNA/genética , RecQ Helicases/genética , Homeostase do Telômero/genética , Telômero/metabolismo , Morte Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , DNA Helicases/metabolismo , Células HEK293 , Células HeLa , Humanos , RecQ Helicases/metabolismo , Ribonuclease H/genética , Ribonuclease H/metabolismo
7.
Nat Commun ; 10(1): 2252, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138797

RESUMO

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


Assuntos
Proteínas de Transporte/metabolismo , DNA Helicases/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , RecQ Helicases/metabolismo , Homeostase do Telômero , Telômero/metabolismo , Linhagem Celular Tumoral , Replicação do DNA , Células HCT116 , Células HEK293 , Células HeLa , Humanos
8.
Adv Clin Chem ; 90: 81-132, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31122612

RESUMO

Ever since their discovery, the telomeres and the telomerase have been topics of intensive research, first as a mechanism of cellular aging and later as an indicator of health and diseases in humans. By protecting the chromosome ends, the telomeres play a vital role in preserving the information in our genome. Telomeres shorten with age and the rate of telomere erosion provides insight into the proliferation history of cells. The pace of telomere attrition is known to increase at the onset of several pathological conditions. Telomere shortening has been emerging as a potential contributor in the pathogenesis of several neurological disorders including autism spectrum disorders (ASD), schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD) and depression. The rate of telomere attrition in the brain is slower than that of other tissues owing to the low rate of cell proliferation in brain. Telomere maintenance is crucial for the functioning of stem cells in brain. Taking together the studies on telomere attrition in various neurological disorders, an association between telomere shortening and disease status has been demonstrated in schizophrenia, AD and depression, in spite of a few negative reports. But, studies in ASD and PD have failed to produce conclusive results. The cause-effect relationship between TL and neurological disorders is yet to be elucidated. The factors responsible for telomere erosion, which have also been implicated in the pathogenesis of neurological disorders, need to be explored in detail. Telomerase activation is now being considered as a potential therapeutic strategy for neurological disorders.


Assuntos
Doenças do Sistema Nervoso/genética , Telômero/genética , Telômero/metabolismo , Animais , Southern Blotting , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase
9.
J Cancer Res Clin Oncol ; 145(6): 1509-1519, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016380

RESUMO

PURPOSE: Maintaining telomeres by recruiting telomerase-to-chromosome ends is essential for cancer cell survival. Inhibiting telomerase recruitment to telomeres represents a novel strategy for telomere-based lung cancer therapy. However, approaches for interrupting telomerase recruitment for cancer therapy still need to be explored. METHODS: The telomere-binding protein TPP1 is responsible for recruiting telomerase to telomeres and synthesizing telomeres through the association between the oligosaccharide/oligonucleotide-binding (OB)-fold domain of TPP1 and telomerase reverse transcriptase. We overexpressed the TPP1 OB domain (TPP1-OB) by lentivirus infection in lung cancer cells. Telomere length was examined by Southern blot analysis of terminal restriction fragments. The effects of TPP1-OB on cell proliferation, the cell cycle, apoptosis, chemosensitivity, and tumor growth were evaluated in vitro and in vivo. RESULT: TPP1-OB inhibited the recruitment of telomerase to telomeres and shortened telomere length by acting as a dominant-negative mutant of TPP1. TPP1-OB resulted in reduced cell proliferation, G1 cell cycle arrest, and increased cell apoptosis in lung cancer cells. Cell apoptosis occurred mainly through the caspase-3-dependent signaling pathway. TPP1-OB also suppressed anchorage-independent growth and tumor growth in vivo. Moreover, we demonstrated that TPP1-OB enhances the sensitivity of lung cancer cells to the chemotherapeutic drug paclitaxel. CONCLUSION: Our results suggest that inhibiting TPP1-mediated telomerase recruitment by expressing the TPP1-OB domain is a potential novel strategy for telomere-targeted lung cancer therapy.


Assuntos
Oligonucleotídeos/metabolismo , Oligossacarídeos/metabolismo , Telomerase/antagonistas & inibidores , Proteínas de Ligação a Telômeros/metabolismo , Telômero/metabolismo , Células A549 , Animais , Apoptose/fisiologia , Proliferação de Células/fisiologia , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Domínios Proteicos , Telomerase/metabolismo
10.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013622

RESUMO

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


Assuntos
Quadruplex G , Proteínas de Neoplasias/química , Telomerase/química , Homeostase do Telômero , Telômero/química , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Ressonância Magnética Nuclear Biomolecular , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Telômero/metabolismo
11.
Proc Natl Acad Sci U S A ; 116(12): 5659-5664, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30842278

RESUMO

Cohesin is a key determinant of chromosome architecture due to its DNA binding and tethering ability. Cohesin binds near centromeres and chromosome arms and also close to telomeres, but its role near telomeres remains elusive. In budding yeast, transcription within 20 kb of telomeres is repressed, in part by the histone-modifying silent information regulator (SIR) complex. However, extensive subtelomeric repressed domains lie outside the SIR-binding region, but the mechanism of silencing in these regions remains poorly understood. Here, we report a role for cohesin in subtelomeric silencing that extends even beyond the zone of SIR binding. Clusters of subtelomeric genes were preferentially derepressed in a cohesin mutant, whereas SIR binding was unaltered. Genetic interactions with known telomere silencing factors indicate that cohesin operates independent of the SIR-mediated pathway for telomeric silencing. Mutant cells exhibited Mpk1-dependent Sir3 hyperphosphorylation that contributes to subtelomeric derepression to a limited extent. Compaction of subtelomeric domains and tethering to the nuclear envelope were impaired in mutant cells. Our findings provide evidence for a unique SIR-independent mechanism of subtelomeric repression mediated by cohesin.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiologia , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/fisiologia , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/fisiologia , Telômero/fisiologia , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Fúngica da Expressão Gênica/genética , Regulação Fúngica da Expressão Gênica/fisiologia , Inativação Gênica/fisiologia , Histonas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/metabolismo , Telômero/genética , Telômero/metabolismo
12.
Mol Pain ; 15: 1744806919842962, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900507

RESUMO

Telomere length, a measure of cellular aging, is inversely associated with chronic pain severity. While psychological resilience factors (e.g., optimism, acceptance, positive affect, and active coping) are associated with lower levels of clinical pain and greater physical functioning, it is unknown whether resilience may buffer against telomere shortening in individuals with chronic pain. Additionally, a broader conceptualization of resilience that includes social and biobehavioral factors may improve our understanding of the relationship between resilience, chronic pain, and health outcomes. In individuals with and without chronic knee pain, we investigated whether (1) psychological resilience would be positively associated with telomere length and if (2) a broader conceptualization of resilience including social and biobehavioral factors would strengthen the association. Seventy-nine adults, 45 to 85 years of age, with and without knee pain completed demographic, health, clinical pain, psychological, social, and biobehavioral questionnaires. Resilience levels were determined by summing the total number of measures indicating resilience based on published clinical ranges and norms. Blood samples were collected, and telomere length was determined. In regression analyses controlling for sex, race, age, and characteristic pain intensity, greater psychological resilience and psychosocial/biobehavioral resilience were associated with longer telomeres ( p = .0295 and p = .0116, respectively). When compared, psychosocial/biobehavioral resilience was significantly more predictive of telomere length than psychological resilience ( p < .0001). Findings are promising and encourage further investigations to enhance understanding of the biological interface of psychosocial and biobehavioral resilience factors in individuals with musculoskeletal chronic pain conditions.


Assuntos
Senescência Celular/fisiologia , Dor Crônica/metabolismo , Articulação do Joelho/patologia , Resiliência Psicológica , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Psicológico/metabolismo , Inquéritos e Questionários , Telômero/metabolismo
13.
Nat Commun ; 10(1): 1001, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824709

RESUMO

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


Assuntos
DNA/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Hibridização de Ácido Nucleico , Fatores de Transcrição de Octâmero/metabolismo , Fator de Processamento Associado a PTB/metabolismo , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Telômero/metabolismo , Animais , Linhagem Celular Tumoral , Replicação do DNA , Recombinação Homóloga , Humanos , Camundongos , RNA não Traduzido , Homeostase do Telômero , Proteínas de Ligação a Telômeros/metabolismo
14.
BMC Cancer ; 19(1): 232, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871494

RESUMO

BACKGROUND: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic. METHODS: We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference. RESULTS: Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p < 0.01). Furthermore, we demonstrate a strong impact of ALT on survival. In fact, ALT+ patients showed a statistically significant higher risk of death than ALT- patients, when also considering data from multivariate analyses (RR = 1.50; 95% CI: 1.15-1.96; p = 0.003; HR = 2.02; 95% CI: 1.22-3.38; p = 0.007). CONCLUSIONS: Our results indicate that ALT is associated with an increased risk of death in patients with sarcoma. In these neoplasms, ALT should be taken into account for a precise prognostic stratification and design of potential therapeutic strategies.


Assuntos
Sarcoma/patologia , Homeostase do Telômero , Telômero/metabolismo , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Sarcoma/metabolismo , Sarcoma/mortalidade , Análise de Sobrevida
15.
Nat Commun ; 10(1): 970, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30814509

RESUMO

Faithful meiotic chromosome inheritance and fertility rely on the stimulation of meiotic crossover recombination by potentially genotoxic DNA double-strand breaks (DSBs). To avoid excessive damage, feedback mechanisms down-regulate DSBs, likely in response to initiation of crossover repair. In Saccharomyces cerevisiae, this regulation requires the removal of the conserved DSB-promoting protein Hop1/HORMAD during chromosome synapsis. Here, we identify privileged end-adjacent regions (EARs) spanning roughly 100 kb near all telomeres that escape DSB down-regulation. These regions retain Hop1 and continue to break in pachynema despite normal synaptonemal complex deposition. Differential retention of Hop1 requires the disassemblase Pch2/TRIP13, which preferentially removes Hop1 from telomere-distant sequences, and is modulated by the histone deacetylase Sir2 and the nucleoporin Nup2. Importantly, the uniform size of EARs among chromosomes contributes to disproportionately high DSB and repair signals on short chromosomes in pachynema, suggesting that EARs partially underlie the curiously high recombination rate of short chromosomes.


Assuntos
Cromossomos Fúngicos/genética , Quebras de DNA de Cadeia Dupla , Meiose/genética , Saccharomyces cerevisiae/genética , Telômero/genética , Pareamento Cromossômico/genética , Cromossomos Fúngicos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Nucleares/metabolismo , Recombinação Genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/metabolismo , Sirtuína 2/metabolismo , Telômero/metabolismo
16.
Transl Res ; 209: 1-13, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30768925

RESUMO

Pulmonary fibrosis refers to the development of diffuse parenchymal abnormalities in the lung that cause dyspnea, cough, hypoxemia, and impair gas exchange, ultimately leading to respiratory failure. Though pulmonary fibrosis can be caused by a variety of underlying etiologies, ranging from genetic defects to autoimmune diseases to environmental exposures, once fibrosis develops it is irreversible and most often progressive, such that fibrosis of the lung is one of the leading indications for lung transplantation. This review aims to provide a concise summary of the recent advances in our understanding of the genetics and genomics of pulmonary fibrosis, idiopathic pulmonary fibrosis in particular, and how these recent discoveries may be changing the clinical approach to diagnosing and treating patients with fibrotic interstitial lung disease.


Assuntos
Fibrose Pulmonar Idiopática/terapia , Pesquisa Médica Translacional , Diagnóstico Precoce , Predisposição Genética para Doença , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/genética , Fenótipo , Telômero/metabolismo
17.
Med Hypotheses ; 124: 95-97, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30798927

RESUMO

In this article, we hypothesize that eating a low acid (and particularly a low phosphate) diet and/or supplementing the diet with base precursors such as bicarbonate would have a number of helpful effects on aging, by:Although the present data is mainly from studies in invertebrate and small animal models, extrapolation of these results, as well as some associated results in human studies, suggests that low acid diets, or neutralization of the low grade metabolic acidosis seen in aging human subjects would possibly allow us to live longer and remain healthier.


Assuntos
Acidose/fisiopatologia , Envelhecimento , Bicarbonatos/metabolismo , Dieta , Rim/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Coortes , Creatinina , Regulação para Baixo , Glucuronidase/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Pessoa de Meia-Idade , Fosfatos/metabolismo , Ratos , Insuficiência Renal/metabolismo , Telomerase/metabolismo , Telômero/metabolismo , Adulto Jovem
18.
Spectrochim Acta A Mol Biomol Spectrosc ; 212: 388-395, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30703662

RESUMO

G-quadruplexes are well-known DNA secondary structures which can be formed both within the DNA and the RNA sequences of the human genome. While many functions of G-quadruplex during cell regulatory events are still unknown, a number of reports have established their role in finding new cancer therapies. In this report, we provide a detailed account of Thioflavin T (ThT) interacting with a promoter gene (c-Myc) which has relevance in several types of human cancers. Using a variety of spectroscopic techniques, we have shown that the binding of ThT is selective to c-Myc G-quadruplex only, having poor interactions with the duplex DNA sequences. UV-Visible titration experiments show that binding involves stacking interactions which were further corroborated by CD experiments. Fluorescence studies showed that the binding of ThT to c-Myc G-quadruplex results in a large increase in the fluorescence emission spectrum of c-Myc G-quadruplex while the same to duplex DNAs was much poor. Binding of ThT to c-Myc G-quadruplex results in thermal stabilization of the quadruplex DNA by up to 7.4 °C and Job plot experiments demonstrated the presence of 1:1 and 2:1 ligand to quadruplex complexes. Finally, the docking study suggested that ThT stacks with the guanine bases in one of the grooves which is in agreement with the CD studies. These results are expected to provide leads into the design of new ThT analogs and derivatives for enhancing the stability and selectivity of new G-quadruplex targeting ligands.


Assuntos
Benzotiazóis/metabolismo , DNA/química , Quadruplex G , Proteínas Proto-Oncogênicas c-myc/genética , Análise Espectral/métodos , Dicroísmo Circular , Humanos , Simulação de Acoplamento Molecular , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Telômero/metabolismo , Temperatura Ambiente
19.
Nat Rev Genet ; 20(5): 299-309, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30760854

RESUMO

Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.


Assuntos
Envelhecimento/genética , Genômica/história , Neoplasias/genética , Telomerase/genética , Telômero/química , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Envelhecimento/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica , Genômica/métodos , História do Século XX , História do Século XXI , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Progéria/genética , Progéria/metabolismo , Progéria/patologia , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Ribonucleoproteínas Nucleolares Pequenas/genética , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Telomerase/metabolismo , Telômero/metabolismo , Homeostase do Telômero , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
20.
Gen Comp Endocrinol ; 276: 14-21, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30796896

RESUMO

Anthropogenic impacts, such as noise pollution from transportation networks, can serve as stressors to some wildlife species. For example, increased exposure to traffic noise has been found to alter baseline and stress-induced corticosterone levels, reduce body condition and reproductive success, and increase telomere attrition in free-living birds. However, it remains unknown if alterations in nestling phenotype are due to direct or indirect effects of noise exposure. For example, indirect (maternal) effects of noise may occur if altered baseline and stress-induced corticosterone in mothers results in differential deposition of yolk steroids or other components in eggs. Noise exposure may also alter nestling corticosterone levels directly, given that nestlings cannot escape the nest during development. Here, we examined maternal versus direct effects of traffic noise exposure on baseline and stress-induced corticosterone levels, and body condition (as measured by size-corrected mass) in nestling tree swallows (Tachycineta bicolor). We used a two-way factorial design and partially cross-fostered eggs between nests exposed to differing levels (i.e. amplitudes) of traffic noise. For nestlings that were not cross-fostered, we also investigated the effects of traffic noise on telomere dynamics. Our results show a positive relationship between nestling baseline and stress-induced corticosterone and nestling noise exposure, but not maternal noise exposure. While we did not find a relationship between noise and body condition in nestlings, nestling baseline corticosterone was negatively associated with body condition. We also found greater telomere attrition for nestlings from nests with greater traffic noise amplitudes. These results suggest that direct, rather than maternal, effects result in potentially long-lasting consequences of noise exposure. Reduced nestling body condition and increased telomere attrition have been shown to reduce post-fledging survival in this species. Given that human transportation networks continue to expand, strategies to mitigate noise exposure on wildlife during critical periods (i.e. breeding) may be needed to maintain local population health in free-living passerines, such as tree swallows.


Assuntos
Exposição Ambiental , Comportamento de Nidação/fisiologia , Ruído , Andorinhas/fisiologia , Telômero/metabolismo , Poluição Relacionada com o Tráfego , Animais , Corticosterona/sangue , Feminino , Modelos Teóricos , Estresse Fisiológico , Andorinhas/sangue , Homeostase do Telômero
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