Alleviating oxidative damage-induced telomere attrition: a potential mechanism for inhibition by folic acid of apoptosis in neural stem cells

2021 ◽  
Author(s):  
Zhenshu Li ◽  
Wen Li ◽  
Dezheng Zhou ◽  
Jing Zhao ◽  
Yue Ma ◽  
...  
Keyword(s):  
Folic Acid ◽  
Oxidative Damage ◽  
Telomere Length ◽  
Telomerase Activity ◽  
Telomeric Dna ◽  
Concentration Cell ◽  
Folate Concentration ◽  
Telomere Attrition ◽  
Dna Oxidative Damage ◽  
Intracellular Ros

Abstract DNA oxidative damage can cause telomere attrition or dysfunction that triggers cell senescence and apoptosis. The hypothesis of this study is that folic acid decreases apoptosis in neural stem cells (NSCs) by preventing oxidative stress-induced telomere attrition. Primary cultures of NSCs were incubated for 9 days with various concentrations of folic acid (0 - 40 µM ) and then incubated for 24 h with a combination of folic acid and an oxidant (100 µM hydrogen peroxide, H 2 O 2 ), antioxidant (10 mM N-acetyl-L-cysteine, NAC) or vehicle. Intracellular folate concentration, apoptosis rate, cell proliferative capacity, telomere length, telomeric DNA oxidative damage, telomerase activity, intracellular reactive oxygen species (ROS) levels, cellular oxidative damage, and intracellular antioxidant enzyme activities were determined. The results showed that folic acid deficiency in NSCs decreased intracellular folate concentration, cell proliferation, telomere length and telomerase activity, but increased apoptosis, telomeric DNA oxidative damage and intracellular ROS levels. In contrast, folic acid supplementation dose-dependently increased intracellular folate concentration, cell proliferative capacity, telomere length and telomerase activity but decreased apoptosis, telomeric DNA oxidative damage and intracellular ROS levels. Exposure to H 2 O 2 aggravated telomere attrition and oxidative damage whereas NAC alleviated the latter. High doses of folic acid prevented telomere attrition and telomeric DNA oxidative damage by H 2 O 2 . In conclusion, inhibition of telomeric DNA oxidative damage and telomere attrition in NSCs maybe potential mechanisms of inhibiting NSCs apoptosis by folic acid.

scholarly journals Folic Acid Decreases Astrocyte Apoptosis by Preventing Oxidative Stress-Induced Telomere Attrition

2019 ◽  
Vol 21 (1) ◽  
pp. 62 ◽  
Author(s):  
Wen Li ◽  
Yue Ma ◽  
Zhenshu Li ◽  
Xin Lv ◽  
Xinyan Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Folic Acid ◽  
Oxidative Damage ◽  
Telomere Length ◽  
Primary Cultures ◽  
Folic Acid Deficiency ◽  
Telomeric Dna ◽  
Telomere Attrition ◽  
Dna Oxidative Damage

Astrocytes are the most widely distributed cells in the brain, and astrocyte apoptosis may play an important role in the pathogenesis of neurodegenerative diseases. Folate is required for the normal development of the nervous system, but its effect on astrocyte apoptosis is unclear. In this study, we hypothesized that folic acid (the therapeutic form of folate) decreases astrocyte apoptosis by preventing oxidative stress-induced telomere attrition. Primary cultures of astrocytes were incubated for 12 days with various concentrations of folic acid (0–40 μmol/L), then cell proliferation, apoptosis, intracellular folate concentration, intracellular homocysteine (Hcy) concentration, intracellular reactive oxygen species (ROS) levels, telomeric DNA oxidative damage, and telomere length were determined. The results showed that folic acid deficiency decreased intracellular folate, cell proliferation, and telomere length, whereas it increased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In contrast, folic acid dose-dependently increased intracellular folate, cell proliferation, and telomere length but it decreased Hcy concentration, ROS levels, telomeric DNA oxidative damage, and apoptosis. In conclusion, folic acid inhibited apoptosis in astrocytes. The underlying mechanism for this protective effect may be that folic acid decreased oxidative stress and thereby prevented telomeric DNA oxidative damage and telomere attrition.

scholarly journals Telomere length: how the length makes a difference

2020 ◽  
Vol 47 (9) ◽  
pp. 7181-7188 ◽  
Author(s):  
M. Lulkiewicz ◽  
J. Bajsert ◽  
P. Kopczynski ◽  
W. Barczak ◽  
B. Rubis
Keyword(s):  
Telomere Length ◽  
Meta Analysis ◽  
Telomerase Activity ◽  
Human Cells ◽  
Attrition Rate ◽  
Severe Damage ◽  
Telomere Attrition ◽  
Adult Men ◽  
Cell Life ◽  
Real Value

Abstract Telomerase is perceived as an immortality enzyme that might provide longevity to cells and whole organisms. Importantly, it is generally inactive in most somatic cells of healthy, adult men. Consequently, its substrates, i.e. telomeres, get shorter in most human cells with time. Noteworthy, cell life limitation due to telomere attrition during cell divisions, may not be as bad as it looks since longer cell life means longer exposition to harmful factors. Consequently, telomere length (attrition rate) becomes a factor that is responsible for inducing the signaling that leads to the elimination of cells that lived long enough to acquire severe damage. It seems that telomere length that depends on many different factors (including telomerase activity but also genetic factors, a hormonal profile that reflects sex, etc.) might become a useful marker of aging and exposition to stress. Thus in the current paper, we review the factors that affect telomere length in human cells focusing on sex that all together with different environmental and hormonal regulations as well as parental aspect affect telomere attrition rate. We also raise some limitations in the assessment of telomere length that hinders a trustworthy meta-analysis that might lead to acknowledgment of the real value of this parameter.

scholarly journals Yeast Est2p Affects Telomere Length by Influencing Association of Rap1p with Telomeric Chromatin

2008 ◽  
Vol 28 (7) ◽  
pp. 2380-2390 ◽  
Author(s):  
Hong Ji ◽  
Christopher J. Adkins ◽  
Bethany R. Cartwright ◽  
Katherine L. Friedman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Telomere Length ◽  
Specific Binding ◽  
Telomerase Activity ◽  
Negative Regulator ◽  
Wild Type ◽  
Telomeric Dna ◽  
Telomere Length Homeostasis

ABSTRACT In Saccharomyces cerevisiae, the sequence-specific binding of the negative regulator Rap1p provides a mechanism to measure telomere length: as the telomere length increases, the binding of additional Rap1p inhibits telomerase activity in cis. We provide evidence that the association of Rap1p with telomeric DNA in vivo occurs in part by sequence-independent mechanisms. Specific mutations in EST2 (est2-LT) reduce the association of Rap1p with telomeric DNA in vivo. As a result, telomeres are abnormally long yet bind an amount of Rap1p equivalent to that observed at wild-type telomeres. This behavior contrasts with that of a second mutation in EST2 (est2-up34) that increases bound Rap1p as expected for a strain with long telomeres. Telomere sequences are subtly altered in est2-LT strains, but similar changes in est2-up34 telomeres suggest that sequence abnormalities are a consequence, not a cause, of overelongation. Indeed, est2-LT telomeres bind Rap1p indistinguishably from the wild type in vitro. Taken together, these results suggest that Est2p can directly or indirectly influence the binding of Rap1p to telomeric DNA, implicating telomerase in roles both upstream and downstream of Rap1p in telomere length homeostasis.

scholarly journals Functional Diversification of Replication Protein A Paralogs and Telomere Length Maintenance in Arabidopsis

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 989-1002
Author(s):  
Behailu B. Aklilu ◽  
François Peurois ◽  
Carole Saintomé ◽  
Kevin M. Culligan ◽  
Daniela Kobbe ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Telomere Length ◽  
Protein A ◽  
Replication Protein A ◽  
Telomerase Activity ◽  
Replication Protein ◽  
Telomeric Dna ◽  
Telomere Shortening ◽  
Replication Group

Replication protein A (RPA) is essential for many facets of DNA metabolism. The RPA gene family expanded in Arabidopsis thaliana with five phylogenetically distinct RPA1 subunits (RPA1A-E), two RPA2 (RPA2A and B), and two RPA3 (RPA3A and B). RPA1 paralogs exhibit partial redundancy and functional specialization in DNA replication (RPA1B and RPA1D), repair (RPA1C and RPA1E), and meiotic recombination (RPA1A and RPA1C). Here, we show that RPA subunits also differentially impact telomere length set point. Loss of RPA1 resets bulk telomeres at a shorter length, with a functional hierarchy for replication group over repair and meiosis group RPA1 subunits. Plants lacking RPA2A, but not RPA2B, harbor short telomeres similar to the replication group. Telomere shortening does not correlate with decreased telomerase activity or deprotection of chromosome ends in rpa mutants. However, in vitro assays show that RPA1B2A3B unfolds telomeric G-quadruplexes known to inhibit replications fork progression. We also found that ATR deficiency can partially rescue short telomeres in rpa2a mutants, although plants exhibit defects in growth and development. Unexpectedly, the telomere shortening phenotype of rpa2a mutants is completely abolished in plants lacking the RTEL1 helicase. RTEL1 has been implicated in a variety of nucleic acid transactions, including suppression of homologous recombination. Thus, the lack of telomere shortening in rpa2a mutants upon RTEL1 deletion suggests that telomere replication defects incurred by loss of RPA may be bypassed by homologous recombination. Taken together, these findings provide new insight into how RPA cooperates with replication and recombination machinery to sustain telomeric DNA.

scholarly journals The Hsp90 Molecular Chaperone Modulates Multiple Telomerase Activities

2007 ◽  
Vol 28 (1) ◽  
pp. 457-467 ◽  
Author(s):  
Oyetunji A. Toogun ◽  
Diane C. DeZwaan ◽  
Brian C. Freeman
Keyword(s):  
Dna Binding ◽  
Telomere Length ◽  
Reverse Transcription ◽  
Molecular Chaperone ◽  
Telomerase Activity ◽  
Client Protein ◽  
Telomeric Dna ◽  
Nucleotide Addition

ABSTRACT The Hsp90 molecular chaperone is a highly abundant eukaryotic molecular chaperone. While it is understood that Hsp90 modulates a significant number of proteins, the mechanistic contributions made by Hsp90 to a client protein typically are not well understood. Here we investigate the yeast Hsp90 regulatory roles with telomerase. Telomerase lengthens chromosome termini by specifically associating with single-stranded telomeric DNA and appending nucleotides by reverse transcription. We have found that the yeast Hsp90 homolog Hsp82p promotes both telomerase DNA binding and nucleotide addition properties. By isolating telomerase from different allelic backgrounds we observed distinct defects. For example, in an hsp82 T101I strain telomerase displayed decreased nucleotide processivity, whereas both DNA binding and extension activities were lowered in a G170D background. The decline in telomerase DNA binding correlated with a loss of Hsp82p association. No matter the defect, telomerase activity was recovered upon Hsp82p addition. Importantly, telomere length and telomerase telomere occupancy was yeast Hsp90 dependent. Taken together, our results indicate that Hsp82p promotes telomerase DNA association and facilitates DNA extension once telomerase is engaged with the DNA.

scholarly journals Telomerase activity can mediate the effects of growth on telomeres during post-natal development in a wild bird

2021 ◽  
Author(s):  
Jose C. Noguera ◽  
Alberto Velando
Keyword(s):  
Telomere Length ◽  
Bird Species ◽  
Growth Period ◽  
Postnatal Growth ◽  
Telomerase Activity ◽  
Activity Levels ◽  
Telomere Attrition ◽  
Somatic Tissues ◽  
Negative Effect ◽  
Larus Michahellis

In wild animals, telomere attrition during early development has been linked with several fitness penalties throughout life. Telomerase enzyme can elongate telomeres, but it is generally assumed that its activity is suppressed in most somatic tissues upon birth. However, recent evidence suggests that this may not be the rule for long-lived bird species. We have therefore investigated whether telomerase activity is maintained during the postnatal growth period in a wild yellow-legged gull (Larus michahellis) population. Our results indicate that telomerase activity is not negligible in the blood cells, but activity levels sharply decline from hatching to fledging following a similar pattern to that observed in telomere length. Our results further suggest that the observed variation in telomere length may be the result of a negative effect of fast growth on telomerase activity, thus providing a new mechanism through which growth rates may affect telomere dynamics and potentially life-history trajectories.

scholarly journals Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency

2016 ◽  
Vol 48 (2) ◽  
pp. 350-358 ◽  
Author(s):  
Amparo Escribano ◽  
Sara Pastor ◽  
Ana Reula ◽  
Silvia Castillo ◽  
Silvia Vicente ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
High Risk ◽  
Telomere Length ◽  
Telomerase Activity ◽  
Multiple Hypothesis Testing ◽  
Intermediate Risk ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Antitrypsin Deficiency ◽  
Risk Patients

Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2–18 years) diagnosed with AATD and 18 controls (aged 3–16 years).Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity, hTERT expression and AATD phenotypes; high-risk patients showed shorter telomeres, lower hTERT expression and decreased telomerase activity than intermediate-risk and low-risk patients.AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression.

scholarly journals Spontaneous replication fork collapse regulates telomere length homeostasis in wild type cells

2020 ◽  
Author(s):  
Margherita Paschini ◽  
Cynthia M. Reyes ◽  
Abigail E. Gillespie ◽  
Karen A. Lewis ◽  
Leslie W. Glustrom ◽  
...  
Keyword(s):  
Dna Replication ◽  
Telomere Length ◽  
Replication Fork ◽  
Telomerase Activity ◽  
Wild Type ◽  
Telomeric Dna ◽  
Telomeric Repeats ◽  
Subsequent Response ◽  
Linear Chromosomes ◽  
Telomere Length Homeostasis

AbstractTelomeres present unique challenges for genomes with linear chromosomes, including the inability of the semi-conservative DNA replication machinery to fully duplicate the ends of linear molecules. This is solved in virtually all eukaryotes by the enzyme telomerase, through the addition of telomeric repeats onto chromosome ends. It is widely assumed that the primary site of action for telomerase is the single-stranded G-rich overhang at the ends of chromosomes, formed after DNA replication is complete. We show here that the preferred substrate for telomerase in wild type yeast is instead a collapsed fork generated during replication of duplex telomeric DNA. Furthermore, newly collapsed forks are extensively elongated by telomerase by as much as ∼200 nucleotides in a single cell division, indicating that a major source of newly synthesized telomeric repeats in wild type cells occurs at collapsed forks. Fork collapse and the subsequent response by telomerase are coordinated by the dual activities of a telomere-dedicated RPA-like complex, which facilitates replication of duplex telomeric DNA and also recruits telomerase to the fork, thereby ensuring a high probability of re-elongation if DNA replication fails. We further show that the ability of telomerase to elongate newly collapsed forks is dependent on the Rad51 protein, indicating that telomerase activity in response to fork collapse proceeds through a regulatory pathway distinct from how telomerase engages fully replicated chromosome termini. We propose a new model in which spontaneous replication fork collapse and the subsequent response by telomerase is a major determinant of telomere length homeostasis.

Sign in / Sign up

Export Citation Format

Share Document