International Journal of Molecular Sciences

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7 pages, 479 KiB

Open AccessEditorial

Role of Telomeres and Telomerase in Cancer and Aging

by Gabriele Saretzki

Int. J. Mol. Sci. 2023, 24(12), 9932; https://doi.org/10.3390/ijms24129932 - 9 Jun 2023

Cited by 5 | Viewed by 3800

Abstract

Seventeen papers published in 2019 and early 2020 demonstrate the ongoing interest and research concerning telomeres and telomerase in aging and cancer [...] Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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Research

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12 pages, 1923 KiB

Open AccessArticle

CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells

by Luan Wen, Changzhi Zhao, Jun Song, Linyuan Ma, Jinxue Ruan, Xiaofeng Xia, Y. Eugene Chen, Jifeng Zhang, Peter X. Ma and Jie Xu

Int. J. Mol. Sci. 2020, 21(2), 653; https://doi.org/10.3390/ijms21020653 - 19 Jan 2020

Cited by 22 | Viewed by 5819

Abstract

Mammalian telomere lengths are primarily regulated by telomerase, a ribonucleoprotein consisting of a reverse transcriptase (TERT) and an RNA subunit (TERC). TERC is constitutively expressed in all cells, whereas TERT expression is temporally and spatially regulated, such that in most adult somatic cells, [...] Read more.

Mammalian telomere lengths are primarily regulated by telomerase, a ribonucleoprotein consisting of a reverse transcriptase (TERT) and an RNA subunit (TERC). TERC is constitutively expressed in all cells, whereas TERT expression is temporally and spatially regulated, such that in most adult somatic cells, TERT is inactivated and telomerase activity is undetectable. Most tumor cells activate TERT as a mechanism for preventing progressive telomere attrition to achieve proliferative immortality. Therefore, inactivating TERT has been considered to be a promising means of cancer therapy. Here we applied the CRISPR/Cas9 gene editing system to target the TERT gene in cancer cells. We report that disruption of TERT severely compromises cancer cell survival in vitro and in vivo. Haploinsufficiency of TERT in tumor cells is sufficient to result in telomere attrition and growth retardation in vitro. In vivo, TERT haploinsufficient tumor cells failed to form xenograft after transplantation to nude mice. Our work demonstrates that gene editing-mediated TERT knockout is a potential therapeutic option for treating cancer. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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23 pages, 6624 KiB

Open AccessArticle

A Novel Tissue and Stem Cell Specific TERF1 Splice Variant Is Downregulated in Tumour Cells

by Yousef Ashraf Tawfik Morcos, Gregoire Najjar, Sabine Meessen, Britta Witt, Anca Azoitei, Mukesh Kumar, Gamal Wakileh, Klaus Schwarz, Hubert Schrezenmeier, Friedemann Zengerling, Christian Bolenz and Cagatay Günes

Int. J. Mol. Sci. 2020, 21(1), 85; https://doi.org/10.3390/ijms21010085 - 20 Dec 2019

Cited by 2 | Viewed by 3997

Abstract

In this study, we describe the identification of a novel splice variant of TERF1/PIN2, one of the main components of the telomeric shelterin complex. This new splice variant is identical to TERF1, apart from a 30 amino acid internal insertion near to the [...] Read more.

In this study, we describe the identification of a novel splice variant of TERF1/PIN2, one of the main components of the telomeric shelterin complex. This new splice variant is identical to TERF1, apart from a 30 amino acid internal insertion near to the C-terminus of TERF1. Based on genome comparison analyses and RNA expression data, we show that this splice variant is conserved among hominidae but absent from all other species. RNA expression and histological analyses show specific expression in human spermatogonial and hematopoietic stem cells (HSCs), while all other analyzed tissues lack the expression of this TERF1-isoform, hence the name TERF1-tsi (TERF1-tissue-specific-isoform). In addition, we could not detect any expression in primary human cells and established cancer cell lines. Immunohistochemistry results involving two new rabbit polyclonal antibodies, generated against TERF1-tsi specific peptides, indicate nuclear localization of TERF1-tsi in a subset of spermatogonial stem cells. In line with this observation, immunofluorescence analyzes in various cell lines consistently revealed that ectopic TERF1-tsi localizes to the cell nucleus, mainly but not exclusively at telomeres. In a first attempt to evaluate the impact of TERF1-tsi in the testis, we have tested its expression in normal testis samples versus matched tumor samples from the same patients. Both RT-PCR and IHC show a specific downregulation of TERF1-tsi in tumor samples while the expression of TERF1 and PIN2 remains unchanged. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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13 pages, 2164 KiB

Open AccessArticle

Telomerase Does Not Improve DNA Repair in Mitochondria upon Stress but Increases MnSOD Protein under Serum-Free Conditions

by Alexander Martens, Bianca Schmid, Olasubomi Akintola and Gabriele Saretzki

Int. J. Mol. Sci. 2020, 21(1), 27; https://doi.org/10.3390/ijms21010027 - 19 Dec 2019

Cited by 24 | Viewed by 4396

Abstract

Telomerase is best known for its function in maintaining telomeres but has also multiple additional, non-canonical functions. One of these functions is the decrease of oxidative stress and DNA damage due to localisation of the telomerase protein TERT into mitochondria under oxidative stress. [...] Read more.

Telomerase is best known for its function in maintaining telomeres but has also multiple additional, non-canonical functions. One of these functions is the decrease of oxidative stress and DNA damage due to localisation of the telomerase protein TERT into mitochondria under oxidative stress. However, the exact molecular mechanisms behind these protective effects are still not well understood. We had shown previously that overexpression of human telomerase reverse transcriptase (hTERT) in human fibroblasts results in a decrease of mitochondrial DNA (mtDNA) damage after oxidative stress. MtDNA damage caused by oxidative stress is removed via the base excision repair (BER) pathway. Therefore we aimed to analyse whether telomerase is able to improve this pathway. We applied different types of DNA damaging agents such as irradiation, arsenite treatment (NaAsO₂) and treatment with hydrogen peroxide (H₂O₂). Using a PCR-based assay to evaluate mtDNA damage, we demonstrate that overexpression of hTERT in MRC-5 fibroblasts protects mtDNA from H₂O₂ and NaAsO₂ induced damage, compared with their isogenic telomerase-negative counterparts. However, overexpression of hTERT did not seem to increase repair of mtDNA after oxidative stress, but promoted increased levels of manganese superoxide dismutase (MnSOD) and forkhead-box-protein O3 (FoxO3a) proteins during incubation in serum free medium as well as under oxidative stress, while no differences were found in protein levels of catalase. Together, our results suggest that rather than interfering with mitochondrial DNA repair mechanisms, such as BER, telomerase seems to increase antioxidant defence mechanisms to prevent mtDNA damage and to increase cellular resistance to oxidative stress. However, the result has to be reproduced in additional cellular systems in order to generalise our findings. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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12 pages, 1649 KiB

Open AccessArticle

Telomeres and Longevity: A Cause or an Effect?

by Huda Adwan Shekhidem, Lital Sharvit, Eva Leman, Irena Manov, Asael Roichman, Susanne Holtze, Derek M. Huffman, Haim Y. Cohen, Thomas Bernd Hildebrandt, Imad Shams and Gil Atzmon

Int. J. Mol. Sci. 2019, 20(13), 3233; https://doi.org/10.3390/ijms20133233 - 1 Jul 2019

Cited by 32 | Viewed by 8441

Abstract

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition [...] Read more.

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a “biological thermometer” that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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14 pages, 627 KiB

Open AccessArticle

Exploring the Relationship of Relative Telomere Length and the Epigenetic Clock in the LipidCardio Cohort

by Verena L. Banszerus, Valentin M. Vetter, Bastian Salewsky, Maximilian König and Ilja Demuth

Int. J. Mol. Sci. 2019, 20(12), 3032; https://doi.org/10.3390/ijms20123032 - 21 Jun 2019

Cited by 27 | Viewed by 4995

Abstract

Telomere length has been accepted widely as a biomarker of aging. Recently, a novel candidate biomarker has been suggested to predict an individual’s chronological age with high accuracy: The epigenetic clock is based on the weighted DNA methylation (DNAm) fraction of a number [...] Read more.

Telomere length has been accepted widely as a biomarker of aging. Recently, a novel candidate biomarker has been suggested to predict an individual’s chronological age with high accuracy: The epigenetic clock is based on the weighted DNA methylation (DNAm) fraction of a number of cytosine-phosphate-guanine sites (CpGs) selected by penalized regression analysis. Here, an established methylation-sensitive single nucleotide primer extension method was adapted, to estimate the epigenetic age of the 1005 participants of the LipidCardio Study, a patient cohort characterised by high prevalence of cardiovascular disease, based on a seven CpGs epigenetic clock. Furthermore, we measured relative leukocyte telomere length (rLTL) to assess the relationship between the established and the promising new measure of biological age. Both rLTL (0.79 ± 0.14) and DNAm age (69.67 ± 7.27 years) were available for 773 subjects (31.6% female; mean chronological age= 69.68 ± 11.01 years; mean DNAm age acceleration = −0.01 ± 7.83 years). While we detected a significant correlation between chronological age and DNAm age (n = 779, R = 0.69), we found neither evidence of an association between rLTL and the DNAm age (β = 3.00, p = 0.18) nor rLTL and the DNAm age acceleration (β = 2.76, p = 0.22) in the studied cohort, suggesting that DNAm age and rLTL measure different aspects of biological age. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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22 pages, 1339 KiB

Open AccessArticle

Repression of TERRA Expression by Subtelomeric DNA Methylation Is Dependent on NRF1 Binding

by Gabriel Le Berre, Virginie Hossard, Jean-Francois Riou and Anne-Laure Guieysse-Peugeot

Int. J. Mol. Sci. 2019, 20(11), 2791; https://doi.org/10.3390/ijms20112791 - 7 Jun 2019

Cited by 13 | Viewed by 4074

Abstract

Chromosome ends are transcribed into long noncoding telomeric repeat-containing RNA (TERRA) from subtelomeric promoters. A class of TERRA promoters are associated with CpG islands embedded in repetitive DNA tracts. Cytosines in these subtelomeric CpG islands are frequently methylated in telomerase-positive cancer cells, and [...] Read more.

Chromosome ends are transcribed into long noncoding telomeric repeat-containing RNA (TERRA) from subtelomeric promoters. A class of TERRA promoters are associated with CpG islands embedded in repetitive DNA tracts. Cytosines in these subtelomeric CpG islands are frequently methylated in telomerase-positive cancer cells, and demethylation induced by depletion of DNA methyltransferases is associated with increased TERRA levels. However, the direct evidence and the underlying mechanism regulating TERRA expression through subtelomeric CpG islands methylation are still to establish. To analyze TERRA regulation by subtelomeric DNA methylation in human cell line (HeLa), we used an epigenetic engineering tool based on CRISPR-dCas9 (clustered regularly interspaced short palindromic repeats – dead CRISPR associated protein 9) associated with TET1 (ten-eleven 1 hydroxylase) to specifically demethylate subtelomeric CpG islands. This targeted demethylation caused an up-regulation of TERRA, and the enhanced TERRA production depended on the methyl-sensitive transcription factor NRF1 (nuclear respiratory factor 1). Since AMPK (AMP-activated protein kinase) is a well-known activator of NRF1, we treated cells with an AMPK inhibitor (compound C). Surprisingly, compound C treatment increased TERRA levels but did not inhibit AMPK activity in these experimental conditions. Altogether, our results provide new insight in the fine-tuning of TERRA at specific subtelomeric promoters and could allow identifying new regulators of TERRA. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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20 pages, 5193 KiB

Open AccessArticle

Telomerase Inhibitor TMPyP4 Alters Adhesion and Migration of Breast-Cancer Cells MCF7 and MDA-MB-231

by Natalia Konieczna, Aleksandra Romaniuk-Drapała, Natalia Lisiak, Ewa Totoń, Anna Paszel-Jaworska, Mariusz Kaczmarek and Błażej Rubiś

Int. J. Mol. Sci. 2019, 20(11), 2670; https://doi.org/10.3390/ijms20112670 - 30 May 2019

Cited by 31 | Viewed by 5047

Abstract

Human telomeres were one of the first discovered and characterized sequences forming quadruplex structures. Association of these structures with oncogenic and tumor suppressor proteins suggests their important role in cancer development and therapy efficacy. Since cationic porphyrin TMPyP4 is known as G-quadruplex stabilizer [...] Read more.

Human telomeres were one of the first discovered and characterized sequences forming quadruplex structures. Association of these structures with oncogenic and tumor suppressor proteins suggests their important role in cancer development and therapy efficacy. Since cationic porphyrin TMPyP4 is known as G-quadruplex stabilizer and telomerase inhibitor, the aim of the study was to analyze the anticancer properties of this compound in two different human breast-cancer MCF7 and MDA-MB-231 cell lines. The cytotoxicity of TMPyP4 alone or in combination with doxorubicin was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromid) and clonogenic assays, and the cell-cycle alterations were analyzed by flow cytometry. Telomerase expression and activity were evaluated using qPCR and telomeric repeat amplification protocol (TRAP) assays, respectively. The contribution of G-quadruplex inhibitor to protein pathways engaged in cell survival, DNA repair, adhesion, and migration was performed using immunodetection. Scratch assay and functional assessment of migration and cell adhesion were also performed. Consequently, it was revealed that in the short term, TMPyP4 neither revealed cytotoxic effect nor sensitized MCF7 and MDA-MB-231 to doxorubicin, but altered breast-cancer cell adhesion and migration. It suggests that TMPyP4 might substantially contribute to a significant decrease in cancer cell dissemination and, consequently, cancer cell survival reduction. Importantly, this effect might not be associated with telomeres or telomerase. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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12 pages, 3067 KiB

Open AccessArticle

The Effects of Proteasome Inhibitors on Telomerase Activity and Regulation in Multiple Myeloma Cells

by Naama Shalem-Cohavi, Einat Beery, Jardena Nordenberg, Uri Rozovski, Pia Raanani, Meir Lahav and Orit Uziel

Int. J. Mol. Sci. 2019, 20(10), 2509; https://doi.org/10.3390/ijms20102509 - 21 May 2019

Cited by 9 | Viewed by 3541

Abstract

The importance of telomerase, the enzyme that maintains telomere length, has been reported in many malignancies in general and in multiple myeloma (MM) in particular. Proteasome inhibitors are clinically used to combat effectively MM. Since the mechanism of action of proteasome inhibitors has [...] Read more.

The importance of telomerase, the enzyme that maintains telomere length, has been reported in many malignancies in general and in multiple myeloma (MM) in particular. Proteasome inhibitors are clinically used to combat effectively MM. Since the mechanism of action of proteasome inhibitors has not been fully described we sought to clarify its potential effect on telomerase activity (TA) in MM cells. Previously we showed that the first generation proteasome inhibitor bortezomib (Brt) inhibits TA in MM cells by both transcriptional and post-translational mechanisms and has a potential clinical significance. In the current study we focused around the anti- telomerase activity of the new generation of proteasome inhibitors, epoxomicin (EP) and MG-132 in order to clarify whether telomerase inhibition represents a class effect. We have exposed MM cell lines, ARP-1, CAG, RPMI 8226 and U266 to EP or MG and the following parameters were assessed: viability; TA, hTERT expression, the binding of hTERT (human telomerase reverse transcriptase) transcription factors and post-translational modifications. Epoxomicin and MG-132 differentially downregulated the proliferation and TA in all MM cell lines. The downregulation of TA and the expression of hTERT were faster in CAG than in ARP-1 cells. Epoxomicin was more potent than MG-132 and therefore further mechanistic studies were performed using this compound. The inhibition of TA was mainly transcriptionally regulated. The binding of three positive regulator transcription factors: SP1, c-Myc and NF-κB to the hTERT promoter was decreased by EP in CAG cells as well as their total cellular expression. In ARP-1 cells the SP1 and c-MYC binding and protein levels were similarly affected by EP while NF-κB was not affected. Interestingly, the transcription factor WT-1 (Wilms’ tumor-1) exhibited an increased binding to the hTERT promoter while its total cellular amount remained unchanged. Our results combined with our previous study of bortezomib define telomerase as a general target for proteasome inhibitors. The inhibitory effect of TA is exerted by several regulatory levels, transcriptional and post translational. SP1, C-Myc and NF-κB were involved in mediating these effects. A novel finding of this study is the role of WT-1 in the regulation of telomerase which appears as a negative regulator of hTERT expression. The results of this study may contribute to future development of telomerase inhibition as a therapeutic modality in MM. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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12 pages, 2198 KiB

Open AccessArticle

Compromised Chondrocyte Differentiation Capacity in TERC Knockout Mouse Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer

by Wei-Fang Chang, Yun-Hsin Wu, Jie Xu and Li-Ying Sung

Int. J. Mol. Sci. 2019, 20(5), 1236; https://doi.org/10.3390/ijms20051236 - 12 Mar 2019

Cited by 6 | Viewed by 4252

Abstract

Mammalian telomere lengths are primarily regulated by telomerase, consisting of a reverse transcriptase protein (TERT) and an RNA subunit (TERC). We previously reported the generation of mouse Terc^+/− and Terc^−/− embryonic stem cells (ntESCs) by somatic cell nuclear transfer. [...] Read more.

Mammalian telomere lengths are primarily regulated by telomerase, consisting of a reverse transcriptase protein (TERT) and an RNA subunit (TERC). We previously reported the generation of mouse Terc^+/− and Terc^−/− embryonic stem cells (ntESCs) by somatic cell nuclear transfer. In the present work, we investigated the germ layer development competence of Terc^−/−, Terc^+/− and wild-type (Terc^+/+) ntESCs. The telomere lengths are longest in wild-type but shortest in Terc^−/− ntESCs, and correlate reversely with the population doubling time. Interestingly, while in vitro embryoid body (EB) differentiation assay reveals EB size difference among ntESCs of different genotypes, the more stringent in vivo teratoma assay demonstrates that Terc^−/− ntESCs are severely defective in differentiating into the mesodermal lineage cartilage. Consistently, in a directed in vitro chondrocyte differentiation assay, the Terc^−/− cells failed in forming Collagen II expressing cells. These findings underscore the significance in maintaining proper telomere lengths in stem cells and their derivatives for regenerative medicine. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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Review

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24 pages, 437 KiB

Open AccessReview

Telomere Maintenance in Pediatric Cancer

by Sandra Ackermann and Matthias Fischer

Int. J. Mol. Sci. 2019, 20(23), 5836; https://doi.org/10.3390/ijms20235836 - 20 Nov 2019

Cited by 11 | Viewed by 3761

Abstract

Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases and cancer. Substantial progress has been made in recent decades in understanding the complex molecular relationships in this research field. However, the majority of telomere [...] Read more.

Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related diseases and cancer. Substantial progress has been made in recent decades in understanding the complex molecular relationships in this research field. However, the majority of telomere studies have been conducted in adults. The data on telomere dynamics in pediatric cancers is limited, and interpretation can be challenging, especially in cases where results are contrasting to those in adult entities. This review describes recent advances in the molecular characterization of structure and function of telomeres, regulation of telomerase activity in cancer pathogenesis in general, and highlights the key advances that have expanded our views on telomere biology in pediatric cancer, with special emphasis on the central role of telomere maintenance in neuroblastoma. Furthermore, open questions in the field of telomere maintenance research are discussed in the context of recently published literature. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

21 pages, 1083 KiB

Open AccessReview

Replication Stress at Telomeric and Mitochondrial DNA: Common Origins and Consequences on Ageing

by Pauline Billard and Delphine A Poncet

Int. J. Mol. Sci. 2019, 20(19), 4959; https://doi.org/10.3390/ijms20194959 - 8 Oct 2019

Cited by 39 | Viewed by 9385

Abstract

Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication [...] Read more.

Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication stress-induced DNA damage of telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) can be considered a common origin of senescence in vitro, with consequences on ageing in vivo. Unexpectedly, mtDNA and telDNA share common features indicative of a high degree of replicative stress, such as G-quadruplexes, D-loops, RNA:DNA heteroduplexes, epigenetic marks, or supercoiling. To avoid these stresses, both compartments use similar enzymatic strategies involving, for instance, endonucleases, topoisomerases, helicases, or primases. Surprisingly, many of these replication helpers are active at both telDNA and mtDNA (e.g., RNAse H1, FEN1, DNA2, RecQ helicases, Top2α, Top2β, TOP3A, DNMT1/3a/3b, SIRT1). In addition, specialized telomeric proteins, such as TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component), or TIN2 (shelterin complex), shuttle from telomeres to mitochondria, and, by doing so, modulate mitochondrial metabolism and the production of ROS, in a feedback manner. Hence, mitochondria and telomeres use common weapons and cooperate to resist/prevent replication stresses, otherwise producing common consequences, namely senescence and ageing. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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15 pages, 896 KiB

Open AccessReview

Telomerase Reverse Transcriptase (TERT) in Action: Cross-Talking with Epigenetics

by Xiaotian Yuan and Dawei Xu

Int. J. Mol. Sci. 2019, 20(13), 3338; https://doi.org/10.3390/ijms20133338 - 7 Jul 2019

Cited by 44 | Viewed by 7864

Abstract

Telomerase, an RNA-dependent DNA polymerase with telomerase reverse transcriptase (TERT) as the catalytic component, is silent due to the tight repression of the TERT gene in most normal human somatic cells, whereas activated only in small subsets of cells, including stem cells, activated [...] Read more.

Telomerase, an RNA-dependent DNA polymerase with telomerase reverse transcriptase (TERT) as the catalytic component, is silent due to the tight repression of the TERT gene in most normal human somatic cells, whereas activated only in small subsets of cells, including stem cells, activated lymphocytes, and other highly proliferative cells. In contrast, telomerase activation via TERT induction is widespread in human malignant cells, which is a prerequisite for malignant transformation. It is well established that TERT/telomerase extends telomere length, thereby conferring sustained proliferation capacity to both normal and cancerous cells. The recent evidence has also accumulated that TERT/telomerase may participate in the physiological process and oncogenesis independently of its telomere-lengthening function. For instance, TERT is shown to interact with chromatin remodeling factors and to regulate DNA methylation, through which multiple cellular functions are attained. In the present review article, we summarize the non-canonical functions of TERT with a special emphasis on its cross-talk with epigenetics: How TERT contributes to epigenetic alterations in physiological processes and cancer, and how the aberrant epigenetics in turn facilitate TERT expression and function, eventually promoting cancer either initiation or progression or both. Finally, we briefly discuss clinical implications of the TERT-related methylation. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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13 pages, 1252 KiB

Open AccessReview

Quantitative Biology of Human Shelterin and Telomerase: Searching for the Weakest Point

by Pavel Veverka, Tomáš Janovič and Ctirad Hofr

Int. J. Mol. Sci. 2019, 20(13), 3186; https://doi.org/10.3390/ijms20133186 - 28 Jun 2019

Cited by 19 | Viewed by 8257

Abstract

The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent works have provided new insights into the mechanisms of how human shelterin assembles and recruits telomerase to telomeres. Inhibition of [...] Read more.

The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent works have provided new insights into the mechanisms of how human shelterin assembles and recruits telomerase to telomeres. Inhibition of telomerase activity and telomerase recruitment to chromosome ends is a promising target for anticancer therapy. Here, we summarize results of quantitative assessments and newly emerged structural information along with the status of the most promising approaches to telomerase inhibition in cancer cells. We focus on the mechanism of shelterin assembly and the mechanisms of how shelterin affects telomerase recruitment to telomeres, addressing the conceptual dilemma of how shelterin allows telomerase action and regulates other essential processes. We evaluate how the identified critical interactions of telomerase and shelterin might be elucidated in future research of new anticancer strategies. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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13 pages, 471 KiB

Open AccessReview

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

by Nissim Arish, Dmytro Petukhov and Shulamit B. Wallach-Dayan

Int. J. Mol. Sci. 2019, 20(12), 2996; https://doi.org/10.3390/ijms20122996 - 19 Jun 2019

Cited by 29 | Viewed by 5346

Abstract

Telomeres are distal chromosome regions associated with specific protein complexes that protect the chromosome against degradation and aberrations. Telomere maintenance capacity is an essential indication of healthy cell populations, and telomere damage is observed in processes such as malignant transformation, apoptosis, or cell [...] Read more.

Telomeres are distal chromosome regions associated with specific protein complexes that protect the chromosome against degradation and aberrations. Telomere maintenance capacity is an essential indication of healthy cell populations, and telomere damage is observed in processes such as malignant transformation, apoptosis, or cell senescence. At a cellular level, telomere damage may result from genotoxic stress, decreased activity of telomerase enzyme complex, dysfunction of shelterin proteins, or changes in expression of telomere-associated RNA such as TERRA. Clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.). Thus, telomere length and maintenance can serve as an important prognostic factor as well as a potential target for new strategies of treatment for interstitial lung diseases (ILDs) and associated pulmonary pathologies. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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17 pages, 556 KiB

Open AccessReview

Telomerase and Telomeres Biology in Thyroid Cancer

by Benedetta Donati and Alessia Ciarrocchi

Int. J. Mol. Sci. 2019, 20(12), 2887; https://doi.org/10.3390/ijms20122887 - 13 Jun 2019

Cited by 19 | Viewed by 5130

Abstract

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops [...] Read more.

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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22 pages, 833 KiB

Open AccessReview

Stilbene Compounds Inhibit Tumor Growth by the Induction of Cellular Senescence and the Inhibition of Telomerase Activity

by Yu-Hsuan Lee, Yu-Ying Chen, Ya-Ling Yeh, Ying-Jan Wang and Rong-Jane Chen

Int. J. Mol. Sci. 2019, 20(11), 2716; https://doi.org/10.3390/ijms20112716 - 2 Jun 2019

Cited by 27 | Viewed by 5227

Abstract

Cellular senescence is a state of cell cycle arrest characterized by a distinct morphology, gene expression pattern, and secretory phenotype. It can be triggered by multiple mechanisms, including those involved in telomere shortening, the accumulation of DNA damage, epigenetic pathways, and the senescence-associated [...] Read more.

Cellular senescence is a state of cell cycle arrest characterized by a distinct morphology, gene expression pattern, and secretory phenotype. It can be triggered by multiple mechanisms, including those involved in telomere shortening, the accumulation of DNA damage, epigenetic pathways, and the senescence-associated secretory phenotype (SASP), and so on. In current cancer therapy, cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation in cells at risk for malignant transformation. Therefore, compounds that stimulate the growth inhibition effects of senescence while limiting its detrimental effects are believed to have great clinical potential. In this review article, we first review the current knowledge of the pro- and antitumorigeneic functions of senescence and summarize the key roles of telomerase in the regulation of senescence in tumors. Second, we review the current literature regarding the anticancer effects of stilbene compounds that are mediated by the targeting of telomerase and cell senescence. Finally, we provide future perspectives on the clinical utilization of stilbene compounds, especially resveratrol and pterostilbene, as novel cancer therapeutic remedies. We conclude and propose that stilbene compounds may induce senescence and may potentially be used as the therapeutic or adjuvant agents for cancers with high telomerase activity. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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16 pages, 1022 KiB

Open AccessReview

Telomerase-Targeted Cancer Immunotherapy

by Eishiro Mizukoshi and Shuichi Kaneko

Int. J. Mol. Sci. 2019, 20(8), 1823; https://doi.org/10.3390/ijms20081823 - 12 Apr 2019

Cited by 85 | Viewed by 11426

Abstract

Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to [...] Read more.

Telomerase, an enzyme responsible for the synthesis of telomeres, is activated in many cancer cells and is involved in the maintenance of telomeres. The activity of telomerase allows cancer cells to replicate and proliferate in an uncontrolled manner, to infiltrate tissue, and to metastasize to distant organs. Studies to date have examined the mechanisms involved in the survival of cancer cells as targets for cancer therapeutics. These efforts led to the development of telomerase inhibitors as anticancer drugs, drugs targeting telomere DNA, viral vectors carrying a promoter for human telomerase reverse transcriptase (hTERT) genome, and immunotherapy targeting hTERT. Among these novel therapeutics, this review focuses on immunotherapy targeting hTERT and discusses the current evidence and future perspectives. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2019)

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