scholarly journals Revisiting Telomere Shortening in Cancer

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 107 ◽  
Author(s):  
Keiji Okamoto ◽  
Hiroyuki Seimiya
Keyword(s):  
Cancer Cells ◽  
Telomere Length ◽  
Prognostic Biomarker ◽  
Telomere Maintenance ◽  
Epigenetic Alterations ◽  
Telomere Shortening ◽  
Normal Tissues ◽  
Genome Wide ◽  
Unlimited Growth ◽  
Protective Structures

Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker.

Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance

2020 ◽  
Vol 20 (6) ◽  
pp. 498-507 ◽  
Author(s):  
Connor A.H. Thompson ◽  
Judy M.Y. Wong
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Reverse Transcriptase ◽  
Cancer Cells ◽  
Telomere Length ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Alternative Mechanism ◽  
Dependent Manner ◽  
Mitochondrial Integrity

Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expressed at higher levels than necessary for maintaining functional telomere length, suggesting other possible adaptive functions. Emerging non-canonical roles of TERT include regulation of non-telomeric DNA damage responses, promotion of cell growth and proliferation, acceleration of cell cycle kinetics, and control of mitochondrial integrity following oxidative stress. Non-canonical activities of TERT primarily show cellular protective effects, and nuclear TERT has been shown to protect against cell death following double-stranded DNA damage, independent of its role in telomere length maintenance. TERT has been suggested to act as a chromatin modulator and participate in the transcriptional regulation of gene expression. TERT has also been reported to regulate transcript levels through an RNA-dependent RNA Polymerase (RdRP) activity and produce siRNAs in a Dicer-dependent manner. At the mitochondria, TERT is suggested to protect against oxidative stress-induced mtDNA damage and promote mitochondrial integrity. These extra-telomeric functions of TERT may be advantageous in the context of increased proliferation and metabolic stress often found in rapidly-dividing cancer cells. Understanding the spectrum of non-canonical functions of telomerase may have important implications for the rational design of anti-cancer chemotherapeutic drugs.

Regulation And Effect Of Telomerase And Telomeric Length In Stem Cells

2020 ◽  
Vol 15 ◽  
Author(s):  
Basak Celtikci ◽  
Gulnihal Kulaksiz Erkmen ◽  
Zeliha Gunnur Dikmen
Keyword(s):  
Telomere Length ◽  
Somatic Cells ◽  
Telomere Maintenance ◽  
The Other ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Telomere Shortening ◽  
Maintenance Mechanism ◽  
Associated Diseases ◽  
Human Telomerase

: Telomeres are the protective end caps of eukaryotic chromosomes and they decide the proliferative lifespan of somatic cells, as the guardians of the cell replication. Telomere length in leucocytes reflects telomere length in other somatic cells. Leucocyte telomere length can be a biomarker of human ageing. The risk of diseases, which are associated with reduced cell proliferation and tissue degeneration, including aging or aging-associated diseases, such as dyskeratosis congenita, cardiovascular diseases, pulmonary fibrosis and aplastic anemia, are correlated with an increase in short telomeres. On the other hand, the risk of diseases, which are associated with increased proliferative growth, including major cancers, is correlated with long telomeres. In most of the cancers, a telomere maintenance mechanism during DNA replication is essential. The reactivation of the functional ribonucleoprotein holoenzyme complex [telomerase] starts the cascade from normal and premalignant somatic cells to advanced malignant cells. Telomerase is overexpressed during the development of cancer and embryonic stem cells, through controlling genome integrity, cancer formation and stemness. Cancer cells have mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis, and halting cell division by critically short telomeres. Modulation of the human telomerase reverse transcriptase is the ratelimiting step for the production of functional telomerase and the telomere maintenance. Human telomerase reverse transcriptase promoter promotes its gene expression only in tumor cells, but not in normal cells. Some cancers activate an alternative lengthening of telomeres maintenance mechanism via DNA recombination to unshorten their telomeres. Not only heritability but also oxidative stress, inflammation, environmental factors, and therapeutic interventions have an effect on telomere shortening, explaining the variability in telomere length across individuals. There have been a large number of publications, which correlate human diseases with progressive telomere shortening. Telomere length of an individual at birth is also important to follow up telomere shortening, and it can be used as biomarkers for healthy aging. On the other hand, understanding of cellular stress factors, which affect stem cell behavior, will be useful in regeneration or treatment in cancer and age-associated diseases. In this review, we will understand the connection between stem cell and telomere biology, cancer, and aging-associated diseases. This connection may be useful for discovering novel drug targets and improve outcomes for patients having cancer and aging-associated diseases.

scholarly journals Telomere length and human hippocampal neurogenesis

2020 ◽  
Vol 45 (13) ◽  
pp. 2239-2247 ◽  
Author(s):  
Alish B. Palmos ◽  
Rodrigo R. R. Duarte ◽  
Demelza M. Smeeth ◽  
Erin C. Hedges ◽  
Douglas F. Nixon ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Psychiatric Disorder ◽  
Telomere Length ◽  
Gene Networks ◽  
Hippocampal Neurogenesis ◽  
Telomere Maintenance ◽  
Adult Hippocampal Neurogenesis ◽  
Telomere Shortening ◽  
Age Related

Abstract Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10−5), and risk for schizophrenia (P ≤ 1 × 10−10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.

scholarly journals Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Yangyang Yu ◽  
Wenwen Jia ◽  
Yao Lyu ◽  
Dingwen Su ◽  
Mingliang Bai ◽  
...  
Keyword(s):  
Telomere Length ◽  
Knockout Mice ◽  
Embryonic Stem ◽  
Telomere Maintenance ◽  
Reproductive Capacity ◽  
Mouse Development ◽  
Telomere Shortening ◽  
Shelterin Complex ◽  
Telomere Homeostasis ◽  
Novel Protein

Abstract Telomere maintenance is critical for chromosome stability. Here we report that periodic tryptophan protein 1 (PWP1) is involved in regulating telomere length homeostasis. Pwp1 appears to be essential for mouse development and embryonic stem cell (ESC) survival, as homozygous Pwp1-knockout mice and ESCs have never been obtained. Heterozygous Pwp1-knockout mice had shorter telomeres and decreased reproductive capacity. Pwp1 depletion induced rapid telomere shortening accompanied by reduced shelterin complex and increased DNA damage in telomeric regions. Mechanistically, PWP1 bound and stabilized the shelterin complex via its WD40 domains and regulated the overall level of H4K20me3. The rescue of telomere length in Pwp1-deficient cells by PWP1 overexpression depended on SUV4-20H2 co-expression and increased H4K20me3. Therefore, our study revealed a novel protein involved in telomere homeostasis in both mouse and human cells. This knowledge will improve our understanding of how chromatin structure and histone modifications are involved in maintaining telomere integrity.

Telomerase Activity and Telomere Length of CD4+CD25+ Regulatory T-Cells under Conditions of In Vitro and In Vivo Expansion.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3857-3857
Author(s):  
Dominik G.F. Wolf ◽  
Anna M. Wolf ◽  
Christian Koppelstaetter ◽  
Holger F. Rumpold ◽  
Gert Mayer ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Telomere Length ◽  
Cancer Patients ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Healthy Human ◽  
Telomere Shortening

Abstract The expandability of CD4+CD25+ regulatory T-cells (Treg) has been shown in vitro and in vivo. Activation of telomerase activity is a prerequisite for clonal expansion and telomere maintenance in T-cells. There is currently no data available on the expression and function of telomerase in proliferating Treg. Analyses of telomere length by flow-FISH, real-time PCR and Southern blotting revealed that Treg isolated from healthy human volunteers have significantly shortened telomeres when compared to CD4+CD25− T-cells. However, telomere length is not further shortened in Treg isolated from the peripheral blood of cancer patients, despite the observation that the regulatory T-cell pool of these patients was significantly enlarged. To gain further insight into maintenance of telomere length of Treg, we induced in vitro proliferation of Treg by stimulation with anti-CD3 and IL-2. This led to a rapid increase of telomerase activity, as determined by PCR-ELISA. However, when we focused on the proliferating fraction of Treg using a sorting strategy based on the dilution of CFSE, we could show a significant telomere shortening in Treg with high proliferative and immmuno-suppressive capacity. Of note, proliferating CFSElow Treg are characterized by high telomerase activity, which however seems to be insufficient to avoid further telomere shortening under conditions of strong in vitro stimulation. In contrast, under conditions of in vivo expansion of Treg in cancer patients, the induction of telomerase activity is likely to compensate for further telomere erosion. These data might be of importance when considering the application of in vitro expanded Treg for the treatment of GvHD or autoimmune diseases, as telomere shortening might be associated with genomic instability.

Implication of Telomerase in Functions Besides Telomere Elongation in Human Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-40-SCI-40
Author(s):  
Francesca Gazzaniga ◽  
Jue Lin ◽  
Elizabeth Blackburn
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Core Protein ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Independent Functions ◽  
Equity Ownership

Abstract Abstract SCI-40 The ribonucleoprotein enzyme telomerase, which counteracts telomere shortening by adding telomeric DNA repeats to the 3’ ends of chromosomes, contains a core protein reverse transcriptase (called hTERT in humans), the essential template-containing RNA (hTER) and associated factors. Thus, telomerase is capable of circumventing the limit on cell division imposed by telomere attrition. Telomerase enzymatic activity is readily detectable in stem and progenitor cell populations, but is largely downregulated in most adult somatic human cells. In contrast, telomerase is highly active in the large majority (∼80%–90%) of cancer cells. While telomerase is essential for telomere maintenance in cells in vitro and in vivo, several studies now also indicate that telomerase may have telomere-independent functions. We previously showed that lowering the level of the telomerase ribonucleoprotein (RNP) enzyme complex causes rapid changes in cell cycle program in human and mouse cancer cells: partial reduction of telomerase induced by directly lowering telomerase RNP component levels causes altered transcriptional profiles and reduced glucose metabolism in human cancer cells, yet bulk telomere shortening or detectable telomere uncapping are not required for these effects. Work by others has shown that reduction of telomerase core protein component level reduced Wnt signaling and caused Wnt-mutant like developmental defects in Xenopus and mouse and aberrant hematopoiesis in zebrafish embryos. We acutely depleted telomerase RNA components in cultured T cells from healthy human adults using shRNAs targeting both the telomerase protein and the RNA component of telomerase (hTR), delivered immediately after in vitro stimulation. Cell proliferation and telomerase activity levels were quantified through the first and second stimulation cycles. Effects of such telomerase RNP reduction on cell proliferation were observed in time frames too short to be accounted for by bulk telomere attrition. Models to account for these findings will be discussed. Disclosures: Lin: Telome Health, Inc.: Consultancy, Equity Ownership. Blackburn:Telome Health, Inc: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Transcriptional activity of TRF2 is telomere length dependent

2016 ◽  
Author(s):  
Ananda Kishore Mukherjee ◽  
Shalu Sharma ◽  
Parashar Dhapola ◽  
Dhurjhoti Saha ◽  
Tabish Hussain ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genome Stability ◽  
Telomere Maintenance ◽  
Regulatory Control ◽  
Gene Promoters ◽  
Multiple Gene ◽  
Telomere Repeat ◽  
Genome Wide ◽  
Binding Factor

AbstractTRF2 is a telomere repeat binding factor crucial for telomere maintenance and genome stability. An emerging non-conventional role of TRF2 is as a transcriptional regulator through extra-telomeric bindings. Herein we report that increase in telomere length leads to sequestration of TRF2 at the telomeres leading to reduced extra-telomeric TRF2 occupancy genome wide. Decrease in TRF2 occupancy was found on multiple gene promoters in cells with elongated telomeres, including the cell cycle regulator kinase-p21. We found that TRF2 is a transcriptional repressor of p21, and, interestingly, TRF2-mediated regulatory control of p21 is telomere length dependent.

scholarly journals The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans

2018 ◽  
Author(s):  
Dayana A. Delgado ◽  
Chenan Zhang ◽  
Kathryn Demanelis ◽  
Lin S. Chen ◽  
Jianjun Gao ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genetic Relatedness ◽  
Meta Analysis ◽  
Telomere Maintenance ◽  
Leukocyte Telomere Length ◽  
Relative Pair ◽  
Identity By Descent ◽  
Novel Approach ◽  
Genome Wide ◽  
Heritable Trait

ABSTRACTLeukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h2): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., “direct” inheritance). Prior studies of LTL h2have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5,069 Bangladeshi adults with substantial relatedness. For each of the 7,254 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (Tshared). We then estimated the association between Tsharedand the squared pairwise difference in LTL ((ΔLTL)2) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ). The association between Tsharedand (ΔLTL)2was inverse among all relative pair types. In a meta-analysis including all relative pairs (ϕ >0.05), the association between Tsharedand (ΔLTL)2(P=0.002) was stronger than the association between ϕ and (ΔLTL)2(P=0.45). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h2despite telomere “reprogramming” during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h2attributable to direction transmission.

Topographical analysis of telomere length and correlation with genomic instability in whole mount prostatectomies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11107-11107
Author(s):  
A. M. Joshua ◽  
P. Marrano ◽  
A. Evans ◽  
T. Van der Kwast ◽  
M. Zielenska ◽  
...  
Keyword(s):  
Telomere Length ◽  
Chromosomal Instability ◽  
Chromosomal Abnormalities ◽  
Chromosome 8 ◽  
Telomere Maintenance ◽  
Current Evidence ◽  
Telomere Shortening ◽  
Whole Mount ◽  
Trisomy 7

11107 Background: Many critical events in prostatic carcinogenesis appear to relate to the emergence of chromosomal instability and acquisition of genomic rearrangements. Characteristic abnormalities such as 8p loss, 8q gain, trisomy 7, PTEN microdeletions and TMPRSS2-ERG gene fusions appear to mediate mechanisms to increase neoplastic transformation in prostate cancer. Current evidence suggests that telomere dysfunction is a likely causative factor for some of these abnormalities on the basis of its relationship to mechanisms such as the break-fusion-bridge cycle that can lead to the onset of chromosomal instability. Methods: In this study, we correlated telomere length in various prostatic histologies by quantitative FISH with genomic markers of chromosomal instability by standard FISH and immunohistochemical measures of proliferation in 3 whole mount prostatectomies. Results: After analysing approximately 25,000 cells, we found that telomere shortening was correlated with an increase in the number of cells with abnormalities on chromosome 8, such as an increase in the average number of c-myc signals (r∼0.35, p∼0.02). However, there were no significant correlations with abnormalities such as trisomy 7 or abnormalities of the PTEN locus in any sample. Additional findings included; associations found with the probability of C-MYC aberrations in stroma with greater proximity to cancer (<1,000 um), a correlation between telomere length in a number of prostatic histologies (normal, atrophy, HPIN and cancer) with the adjacent stroma, and a lack of correlation between the Ki67 index of various histologies and their telomere length - all suggesting the importance of microenvironmental effects on telomere maintenance in the prostate. Finally, we also report significant telomere shortening in BPH in 2 cases, a phenomenon that has not been noted previously. Conclusions: This is the first study to directly link a mechanism of chromosomal instability with specific chromosomal abnormalities in prostatic carcinogenesis and also suggests that the microenvironmental milieu is of critical importance in the evolution of in vivo telomere homeostasis. No significant financial relationships to disclose.

Accelerated Shortening of Long Telomeres and Accumulation of Short Telomeres in Dyskeratosis Congenita.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1053-1053
Author(s):  
Monica Bessler ◽  
Rachida Bouharich ◽  
Shashikant Kulkarni ◽  
Sara Freeman ◽  
Hong-Yan Du ◽  
...  
Keyword(s):  
Telomere Length ◽  
Gene Mutation ◽  
Gene Deletion ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Parental Origin ◽  
Telomere Shortening ◽  
Genetic Components ◽  
Affected Parent ◽  
Normal Controls

Abstract Dyskeratosis congenita (DC) is the first human disease whose pathogenesis has been directly linked to an impairment of telomere maintenance. Telomeres protect chromosome ends from end to end fusion and degradation. Loss of telomere function causes cell cycle arrest or cell death. Telomeres are maintained by the telomerase ribonucloprotein complex whose integral RNA component, the telomerase RNA or TERC RNA, contains the sequences that act as a template for the synthesis of telomeric repeats. Autosomal dominant DC (AD DC), a rare inherited bone marrow failure syndrome, is caused by mutations in TERC, the RNA component of telomerase. Patients with AD DC have very short telomeres. Haploinsufficiency has been proposed to be the mechanism for telomere shortening in TERC gene mutation carriers. Individuals with AD DC not only inherited the TERC gene mutation but also the shortened telomeres from the affected parent. Here we studied the telomere dynamics over 3 generations in a 32-member extended family with AD DC due to a TERC gene deletion. The investigation of telomere length within a single family has the advantage that the molecular lesion responsible for telomere shortening is uniform and that the contribution of other genetic components influencing telomere length is similar. Our analysis shows that peripheral blood cells from family members haploinsufficient for TERC have very short telomeres (6.68 kb, range 5.53–8.45, SD 1.13, normal controls: 9.15 kb rage 8.56–10.77, SD 1.22). In contrast to normal controls, whose telomere lengths shorten with age, the telomere lengths in all individuals carrying the TERC gene deletion are equally short irrespective of their age. To study the inheritance of short telomeres and the effect of TERC haploinsufficiency on specific telomere lengths in affected individuals and their relatives we carried out Q-FISH analysis using polymorphic subtelomeric probes on chromosomes 11p, 7p, and 1p, which are able to distinguish the parental origin of telomeres in this family. Our analysis showed that in children of affected parents who have inherited the gene deletion, paternal and maternal telomeres are similarly short, and similar in length to those of the affected parent. In children of affected parents who have normal TERC genes paternal and maternal telomeres are again similar in length, and similar to those of the unaffected parent. These results are consistent with a model in which telomerase preferentially acts on the shortest telomeres. When TERC is limiting this leads to the accelerated shortening of longer telomeres and the accumulation of short telomeres. The limited amount of active telomerase in TERC RNA haploinsufficiency may not be able to maintain the minimal length of the increasing number of short telomeres. Thus, the number of critically short telomeres and the degree of residual telomerase activity may determine the onset of disease in patients with DC.

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