Chronic stress elevates telomerase activity in rats

The enzyme telomerase lengthens telomeres—protective structures containing repetitive DNA sequences at chromosome ends. Telomere shortening is associated with diseases of ageing in mammals. Chronic stress has been related to shorter immune-cell telomeres, but telomerase activity under stress may be low, permitting telomere loss, or high, partially attenuating it. We developed an experimental model to examine the impacts of extended unpredictable stress on telomerase activity in male rats. Telomerase activity was 54 per cent higher in stressed rats than in controls, and associated with stress-related physiological and behavioural outcomes. This significant increase suggests a potential mechanism for resilience to stress-related replicative senescence.

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Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

Nature Communications ◽

10.1038/s41467-021-21878-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ryan M. Baxley ◽

Wendy Leung ◽

Megan M. Schmit ◽

Jacob Peter Matson ◽

Lulu Yin ◽

...

Keyword(s):

Immune Cell ◽

Nk Cell ◽

Restrictive Cardiomyopathy ◽

Telomerase Activity ◽

Compound Heterozygous ◽

Minichromosome Maintenance ◽

Telomere Shortening ◽

Clinical Phenotypes ◽

Eukaryotic Dna ◽

Minichromosome Maintenance Protein

AbstractMinichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

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Rapid Telomere Shortening in Children

Blood ◽

10.1182/blood.v93.9.2824.409k18_2824_2830 ◽

1999 ◽

Vol 93 (9) ◽

pp. 2824-2830 ◽

Cited By ~ 23

Author(s):

Steven L. Zeichner ◽

Paul Palumbo ◽

YanRu Feng ◽

Xiaodong Xiao ◽

Dennis Gee ◽

...

Keyword(s):

Cell Division ◽

Mononuclear Cells ◽

Replicative Senescence ◽

Average Rate ◽

Telomerase Activity ◽

Rapid Progression ◽

Peripheral Blood Mononuclear ◽

Telomere Shortening ◽

Dividing Cells ◽

Immunodeficiency Syndrome

Telomere shortening may reflect the total number of divisions experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in peripheral blood mononuclear cells (PBMCs) obtained longitudinally from nine different infants during the first 3 years of life (270 bp per year) is more than fourfold higher than in adults and does not correlate with telomerase activity. These results show that the rate of telomere loss changes during ontogeny, suggesting the existence of periods of accelerated cell division. Because human immunodeficiency virus (HIV) preferentially infects actively dividing cells, our observation suggesting accelerated cell division in children may provide an explanation for some of the distinctive pathogenic features of the HIV disease in infants, including higher viral loads and more rapid progression to acquired immunodeficiency syndrome (AIDS).

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Feline chronic kidney disease is associated with shortened telomeres and increased cellular senescence

AJP Renal Physiology ◽

10.1152/ajprenal.00527.2012 ◽

2013 ◽

Vol 305 (3) ◽

pp. F295-F303 ◽

Cited By ~ 17

Author(s):

Jessica M. Quimby ◽

David G. Maranon ◽

Christine L. R. Battaglia ◽

Shannon M. McLeland ◽

William T. Brock ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Statistical Significance ◽

Interventional Therapy ◽

Telomerase Activity ◽

Telomere Shortening ◽

Amplification Protocol ◽

Protective Structures ◽

Kidney Liver

Telomeres are protective structures at the ends of chromosomes that have important implications for aging. To address the question of whether telomeres contribute to feline chronic kidney disease (CKD), we evaluated kidney, liver, and skin samples from 12 cats with naturally occurring CKD, 12 young normal cats, and 6 old normal cats. Telomere length was assessed using standard telomere fluorescent in situ hybridization (TEL-FISH) combined with immunohistochemistry (TELI-FISH) to identify proximal (PTEC) and distal tubular epithelial cells (DTEC), whereas senescence-associated β-galactosidase (SABG) staining was used to evaluate senescence. Results revealed statistically significant decreases in the average telomere fluorescence intensity (TFI) of PTEC in CKD cats compared with young and geriatric normal cats, and in the DTEC of CKD cats compared with young normal cats. When histograms of individual TFI were compared, statistically significant decreases in the PTEC and DTEC of CKD cats were observed compared with young and geriatric normal cats. Concomitantly, a statistically significant increase in SABG staining was seen in CKD kidney samples compared with young normal cats. CKD cats tended to have increased SABG staining in the kidney compared with normal geriatric cats, but this did not reach statistical significance. No significant telomere shortening in liver or skin from any group was observed. Real-time quantitative telomeric repeat amplification protocol assessment of renal telomerase activity revealed comparable low levels of telomerase activity in all groups. Our results suggest that shortened telomeres and increased senescence in the kidneys of CKD cats may represent novel targets for interventional therapy.

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TERT promoter alterations could provide a solution for Peto’s paradox in rodents

Scientific Reports ◽

10.1038/s41598-020-77648-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Balázs Vedelek ◽

Asha Kiran Maddali ◽

Nurgul Davenova ◽

Viktor Vedelek ◽

Imre M. Boros

Keyword(s):

Transcription Factor ◽

Tumor Suppressor ◽

Binding Sites ◽

Promoter Activity ◽

Replicative Senescence ◽

Somatic Cells ◽

Telomerase Activity ◽

Cell Number ◽

Telomere Shortening ◽

Tert Promoter

AbstractCancer is a genetic disease caused by changes in gene expression resulting from somatic mutations and epigenetic changes. Although the probability of mutations is proportional with cell number and replication cycles, large bodied species do not develop cancer more frequently than smaller ones. This notion is known as Peto’s paradox, and assumes stronger tumor suppression in larger animals. One of the possible tumor suppressor mechanisms involved could be replicative senescence caused by telomere shortening in the absence of telomerase activity. We analysed telomerase promoter activity and transcription factor binding in mammals to identify the key element of telomerase gene inactivation. We found that the GABPA transcription factor plays a key role in TERT regulation in somatic cells of small rodents, but its binding site is absent in larger beavers. Protein binding and reporter gene assays verify different use of this site in different species. The presence or absence of the GABPA TF site in TERT promoters of rodents correlates with TERT promoter activity; thus it could determine whether replicative senescence plays a tumor suppressor role in these species, which could be in direct relation with body mass. The GABPA TF binding sites that contribute to TERT activity in somatic cells of rodents are analogous to those mutated in human tumors, which activate telomerase by a non-ALT mechanism.

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Rapid Telomere Shortening in Children

Blood ◽

10.1182/blood.v93.9.2824 ◽

1999 ◽

Vol 93 (9) ◽

pp. 2824-2830 ◽

Cited By ~ 107

Author(s):

Steven L. Zeichner ◽

Paul Palumbo ◽

YanRu Feng ◽

Xiaodong Xiao ◽

Dennis Gee ◽

...

Keyword(s):

Cell Division ◽

Mononuclear Cells ◽

Replicative Senescence ◽

Average Rate ◽

Telomerase Activity ◽

Rapid Progression ◽

Peripheral Blood Mononuclear ◽

Telomere Shortening ◽

Dividing Cells ◽

Immunodeficiency Syndrome

Abstract Telomere shortening may reflect the total number of divisions experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in peripheral blood mononuclear cells (PBMCs) obtained longitudinally from nine different infants during the first 3 years of life (270 bp per year) is more than fourfold higher than in adults and does not correlate with telomerase activity. These results show that the rate of telomere loss changes during ontogeny, suggesting the existence of periods of accelerated cell division. Because human immunodeficiency virus (HIV) preferentially infects actively dividing cells, our observation suggesting accelerated cell division in children may provide an explanation for some of the distinctive pathogenic features of the HIV disease in infants, including higher viral loads and more rapid progression to acquired immunodeficiency syndrome (AIDS).

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Closed chromatin loops at the ends of chromosomes

The Journal of Cell Biology ◽

10.1083/jcb.200403118 ◽

2004 ◽

Vol 166 (2) ◽

pp. 161-165 ◽

Cited By ~ 95

Author(s):

Tatiana Nikitina ◽

Christopher L. Woodcock

Keyword(s):

Electron Microscopy ◽

Telomere Length ◽

Telomerase Activity ◽

Chromatin Conformation ◽

Chicken Erythrocyte ◽

Telomere Shortening ◽

Mouse Lymphocyte ◽

Associated Proteins ◽

Protective Structures ◽

Telomere Chromatin

The termini of eukaryotic chromosomes contain specialized protective structures, the telomeres, composed of TTAGGG repeats and associated proteins which, together with telomerase, control telomere length. Telomere shortening is associated with senescence and inappropriate telomerase activity may lead to cancer. Little is known about the chromatin context of telomeres, because, in most cells, telomere chromatin is tightly anchored within the nucleus. We now report the successful release of telomere chromatin from chicken erythrocyte and mouse lymphocyte nuclei, both of which have a reduced karyoskeleton. Electron microscopy reveals telomere chromatin fibers in the form of closed terminal loops, which correspond to the “t-loop” structures adopted by telomere DNA. The ability to recognize isolated telomeres in their native chromatin conformation opens the way for detailed structural and compositional studies.

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On the comparative biology of mammalian telomeres: Telomere length co-evolves with body mass and lifespan

10.31219/osf.io/9yuc3 ◽

2020 ◽

Author(s):

Michael Le Pepke ◽

Dan Eisenberg

Keyword(s):

Telomere Length ◽

Body Mass ◽

Dna Sequences ◽

Replicative Senescence ◽

Telomerase Activity ◽

Sensitivity Analyses ◽

Inverse Association ◽

Mammal Species ◽

Data Set ◽

Telomere Biology

Telomeres, the short repetitive DNA sequences that cap the ends of linear chromosomes, shorten during cell division and are implicated in senescence in most species. The enzyme telomerase can rebuild telomeres but is repressed in many mammals that exhibit replicative senescence, presumably as a tumor suppression mechanism. It is therefore important that we have an accurate understanding of the (co-)evolution of telomere biology and life-history traits that has shaped the diversity of senescence patterns across species. Gomes et al. (2011) produced a large data set on telomere length (TL), telomerase activity, body mass and lifespan among 57 mammal species. We re-analyzed their data set using the same phylogenetic multiple regressions presented in the original publication and several sensitivity analyses. We found substantial inconsistencies in our results compared to Gomes et al.'s. Consistent with Gomes et al. we found an inverse association between TL and lifespan. Contrary to the analyses reported in Gomes et al., we found that there was a generally robust inverse association between TL and mass, and only weak non-robust evidence for an association between telomerase activity and mass. These results suggest that shorter TL may have been selected for in larger and longer-lived species – likely as a mechanism to suppress cancer. However, our results call into question past results suggesting that high telomerase activity has been selected against in larger species and stress the need for careful attention to model construction and sensitivity analyses.

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Bi-allelic MCM10 mutations cause telomere shortening with immune dysfunction and cardiomyopathy

10.1101/844498 ◽

2019 ◽

Author(s):

Ryan M. Baxley ◽

Wendy Leung ◽

Megan M. Schmit ◽

Jacob Peter Matson ◽

Marissa K. Oram ◽

...

Keyword(s):

Immune Cell ◽

Nk Cell ◽

Restrictive Cardiomyopathy ◽

Telomerase Activity ◽

Compound Heterozygous ◽

Minichromosome Maintenance ◽

Telomere Shortening ◽

Clinical Phenotypes ◽

Eukaryotic Dna ◽

Minichromosome Maintenance Protein

ABSTRACTMinichromosome maintenance protein 10 (Mcm10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 mutations in patients with distinctive but overlapping clinical phenotypes – natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of Mcm10-associated disease, we modeled these mutations in human cell lines. Mcm10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of Mcm10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in Mcm10-deficient cells require endonucleolytic processing by Mus81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic mutations in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes in both NKD and CM patients.

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Repetitive DNA sequences near three humanβ-type globin genes

Nucleic Acids Research ◽

10.1093/nar/8.15.3319 ◽

1980 ◽

Vol 8 (15) ◽

pp. 3319-3333 ◽

Cited By ~ 24

Author(s):

Lesley W. Coggins ◽

G.Joan Grindlay ◽

J.Keith Vass ◽

Alison A. Slater ◽

Paul Montague ◽

...

Keyword(s):

Repetitive Dna ◽

Dna Sequences ◽

Repetitive Dna Sequences ◽

Globin Genes

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Reclassification of Kidney Clear Cell Carcinoma Based on Immune Cell Gene-Related DNA CpG Pairs

Biomedicines ◽

10.3390/biomedicines9020215 ◽

2021 ◽

Vol 9 (2) ◽

pp. 215

Author(s):

Qizhan Luo ◽

Thomas-Alexander Vögeli

Keyword(s):

Cell Carcinoma ◽

Immune Cell ◽

Clear Cell ◽

Clear Cell Carcinoma ◽

Pairwise Comparison ◽

Clinicopathological Features ◽

Immune Checkpoints ◽

Potential Mechanism ◽

Tissue Samples

Background: A new method was developed based on the relative ranking of gene expression level, overcoming the flaw of the batch effect, and having reliable results in various studies. In the current study, we defined the two methylation sites as a pair. The methylation level in a specific sample was subject to pairwise comparison to calculate a score for each CpGs-pair. The score was defined as a CpGs-pair score. If the first immune-related CpG value was higher than the second one in a specific CpGs-pair, the output score of this immune-related CpGs-pair was 1; otherwise, the output score was 0. This study aimed to construct a new classification of Kidney Clear Cell Carcinoma (KIRC) based on DNA CpGs (methylation sites) pairs. Methods: In this study, the biomarkers of 28 kinds of immune infiltration cells and corresponding methylation sites were acquired. The methylation data were compared between KIRC and normal tissue samples, and differentially methylated sites (DMSs) were obtained. Then, DNA CpGs-pairs were obtained according to the pairs of DMSs. In total, 441 DNA CpGs-pairs were utilized to construct a classification using unsupervised clustering analysis. We also analyzed the potential mechanism and therapy of different subtypes, and validated them in a testing set. Results: The classification of KIRC contained three subgroups. The clinicopathological features were different across three subgroups. The distribution of immune cells, immune checkpoints and immune-related mechanisms were significantly different across the three clusters. The mutation and copy number variation (CNV) were also different. The clinicopathological features and potential mechanism in the testing dataset were consistent with those in the training set. Conclusions: Our findings provide a new accurate and stable classification for developing personalized treatments for the new specific subtypes.

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