Editorial

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Open AccessEditorial

Special Issue: “Telomerase: Role in Health and Aging”

by Yegor E. Yegorov

Biomedicines 2022, 10(11), 2957; https://doi.org/10.3390/biomedicines10112957 - 17 Nov 2022

Cited by 2 | Viewed by 1096

Abstract

We would like to introduce the new volume: “Telomerase and Telomeres: Its Role in Health and Aging 2 [...] Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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Research

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15 pages, 2241 KiB

Open AccessArticle

hTERT DNA Methylation Analysis Identifies a Biomarker for Retinoic Acid-Induced hTERT Repression in Breast Cancer Cell Lines

by Eric Nguyen, Andréa Richerolle, Júlia Sánchez-Bellver, Jacqueline Varennes and Evelyne Ségal-Bendirdjian

Biomedicines 2022, 10(3), 695; https://doi.org/10.3390/biomedicines10030695 - 17 Mar 2022

Cited by 2 | Viewed by 1879

Abstract

Telomerase reactivation is responsible for telomere preservation in about 90% of cancers, providing cancer cells an indefinite proliferating potential. Telomerase consists of at least two main subunits: a catalytic reverse transcriptase protein (hTERT) and an RNA template subunit. Strategies to inhibit [...] Read more.

Telomerase reactivation is responsible for telomere preservation in about 90% of cancers, providing cancer cells an indefinite proliferating potential. Telomerase consists of at least two main subunits: a catalytic reverse transcriptase protein (hTERT) and an RNA template subunit. Strategies to inhibit hTERT expression seem promising for cancer treatment. Previous works showed that all-trans retinoic acid (ATRA) induces hTERT repression in acute promyelocytic leukemia cells, resulting in their death. Here, we investigated the effects of ATRA in a subset of breast cancer cell lines. The mutational status of hTERT promoter and the methylation patterns at a single CpG resolution were assessed. We observed an inverse relationship between hTERT expression after ATRA treatment and the methylation level of a specific CpG at chr5: 1,300,438 in a region of hTERT gene at −5 kb of the transcription initiation site. This observation highlighted the significance of this region, whose methylation profile could represent a promising biomarker to predict the sensitivity to ATRA-induced hTERT repression in specific breast cancer subtypes. As hTERT repression promotes drug-induced cell death, checking the methylation status of this unique region and the specific CpG included can help in decision-making to include ATRA in combination therapy and contributes to a better clinical outcome. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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13 pages, 1907 KiB

Open AccessArticle

Lung Fibroblasts from Idiopathic Pulmonary Fibrosis Patients Harbor Short and Unstable Telomeres Leading to Chromosomal Instability

by Radhia M’Kacher, Madeleine Jaillet, Bruno Colicchio, Eirini Vasarmidi, Arnaud Mailleux, Alain Dieterlen, Caroline Kannengiesser, Claire Borie, Noufissa Oudrhiri, Steffen Junker, Philippe Voisin, Eric Jeandidier, Patrice Carde, Michael Fenech, Annelise Bennaceur-Griscelli, Bruno Crestani and Raphael Borie

Biomedicines 2022, 10(2), 310; https://doi.org/10.3390/biomedicines10020310 - 28 Jan 2022

Cited by 5 | Viewed by 2586

Abstract

Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary lung fibroblasts from 13 IPF patients (including seven patients with pathogenic variants in TRGs) and seven controls. Automatized high-throughput detection of telomeric FISH signals highlighted lower signal intensity in lung fibroblasts from IPF patients, suggesting a telomere length defect in these cells. The increased detection of telomere loss and terminal deletion in IPF cells, particularly in TRG-mutated cells (IPF-TRG), supports the notion that these cells have unstable telomeres. Furthermore, fibroblasts from IPF patients with TRGs mutations exhibited dicentric chromosomes and anaphase bridges. Collectively, our study indicates that fibroblasts from IPF patients exhibit telomere and chromosome instability that likely contribute to the physiopathology. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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13 pages, 1958 KiB

Open AccessArticle

The Relationship between Telomere Length and Gestational Weight Gain: Findings from the Mamma & Bambino Cohort

by Andrea Maugeri, Roberta Magnano San Lio, Maria Clara La Rosa, Giuliana Giunta, Marco Panella, Antonio Cianci, Maria Anna Teresa Caruso, Antonella Agodi and Martina Barchitta

Biomedicines 2022, 10(1), 67; https://doi.org/10.3390/biomedicines10010067 - 30 Dec 2021

Cited by 10 | Viewed by 1798

Abstract

Inadequate gestational weight gain (GWG) affects a growing number of pregnancies, influencing intrauterine environment and long-term health. Uncovering molecular mechanisms associated with GWG could be helpful to develop public health strategies for tackling this issue. Here, our study aimed to understand the relationship [...] Read more.

Inadequate gestational weight gain (GWG) affects a growing number of pregnancies, influencing intrauterine environment and long-term health. Uncovering molecular mechanisms associated with GWG could be helpful to develop public health strategies for tackling this issue. Here, our study aimed to understand the relationship of DNA telomere length with weigh gain during pregnancy, using data and samples from the ongoing prospective “Mamma & Bambino” study (Catania, Italy). GWG was calculated according to the Institute of Medicine (IOM) guidelines. Relative telomere length was assessed by real-time quantitative polymerase chain reaction in 252 samples of maternal leucocyte DNA (mlDNA) and 150 samples of cell-free DNA (cfDNA) from amniotic fluid. We observed that relative telomere length of mlDNA seemed to weakly increase with GWG. In contrast, telomere length of cfDNA exhibited a U-shaped relationship with GWG. Women with adequate GWG showed longer telomere length than those who gained weight inadequately. Accordingly, the logistic regression model confirmed the association between telomere length of cfDNA and adequate GWG, after adjusting for potential confounders. Our findings suggest an early effect of GWG on telomere length of cfDNA, which could represent a molecular mechanism underpinning the effects of maternal behaviours on foetal well-being. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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17 pages, 1656 KiB

Open AccessArticle

TERT Promoter Mutations Increase Sense and Antisense Transcription from the TERT Promoter

by François Hafezi, Lisa Jaxel, Morgane Lemaire, Jonathan D. Turner and Danielle Perez-Bercoff

Biomedicines 2021, 9(12), 1773; https://doi.org/10.3390/biomedicines9121773 - 26 Nov 2021

Cited by 6 | Viewed by 2418

Abstract

Background: Chief among mechanisms of telomerase reverse transcriptase (TERT) reactivation is the appearance of mutations in the TERT promoter. The two main TERT promoter mutations are C>T transitions located −146C>T and −124C>T upstream from the translational start site. They generate a novel Ets/TCF [...] Read more.

Background: Chief among mechanisms of telomerase reverse transcriptase (TERT) reactivation is the appearance of mutations in the TERT promoter. The two main TERT promoter mutations are C>T transitions located −146C>T and −124C>T upstream from the translational start site. They generate a novel Ets/TCF binding site. Both mutations are mutually exclusive and −124C>T is strikingly overrepresented in most cancers. We investigated whether this mutational bias and mutual exclusion could be due to transcriptional constraints. Methods: We compared sense and antisense transcription of a panel of TERT promoter-luciferase vectors harboring the −124C>T and -146C>T mutations alone or together. lncRNA TAPAS levels were measured by RT-PCR. Results: Both mutations generally increased TERT transcription by 2–4-fold regardless of upstream and downstream regulatory elements. The double mutant increased transcription in an additive fashion, arguing against a direct transcriptional constraint. The −146C>T mutation, alone or in combination with −124C>T, also unleashed antisense transcription. In line with this finding, lncRNA TAPAS was higher in cells with mutated TERT promoter (T98G and U87) than in cells with wild-type promoter, suggesting that lncRNA TAPAS may balance the effect of TERT promoter mutations. Conclusions: −146C>T and −124C>T TERT promoter mutations increase TERT sense and antisense transcription, and the double mutant features higher transcription levels. Increased antisense transcription may contain TERT expression within sustainable levels. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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14 pages, 3476 KiB

Open AccessArticle

Telomerase Reverse Transcriptase Increases Proliferation and Lifespan of Human NK Cells without Immortalization

by Maria A. Streltsova, Maria O. Ustiuzhanina, Eugene V. Barsov, Sofya A. Kust, Rodion A. Velichinskii and Elena I. Kovalenko

Biomedicines 2021, 9(6), 662; https://doi.org/10.3390/biomedicines9060662 - 09 Jun 2021

Cited by 10 | Viewed by 2756

Abstract

NK cells are the first line of defense against viruses and malignant cells, and their natural functionality makes these cells a promising candidate for cancer cell therapy. The genetic modifications of NK cells, allowing them to overcome some of their inherent limitations, such [...] Read more.

NK cells are the first line of defense against viruses and malignant cells, and their natural functionality makes these cells a promising candidate for cancer cell therapy. The genetic modifications of NK cells, allowing them to overcome some of their inherent limitations, such as low proliferative potential, can enable their use as a therapeutic product. We demonstrate that hTERT-engineered NK cell cultures maintain a high percentage of cells in the S/G2 phase for an extended time after transduction, while the life span of NK cells is measurably extended. Bulk and clonal NK cell cultures pre-activated in vitro with IL-2 and K562-mbIL21 feeder cells can be transduced with hTERT more efficiently compared with the cells activated with IL-2 alone. Overexpressed hTERT was functionally active in transduced NK cells, which displayed upregulated expression of the activation marker HLA-DR, and decreased expression of the maturation marker CD57 and activating receptor NKp46. Larger numbers of KIR2DL2/3+ cells in hTERT-engineered populations may indicate that NK cells with this phenotype are more susceptible to transduction. The hTERT-modified NK cells demonstrated a high natural cytotoxic response towards K562 cells and stably expressed Ki67, a proliferation marker. Overall, our data show that ectopic hTERT expression in NK cells enhances their activation and proliferation, extends in vitro life span, and can be a useful tool in developing NK-based cancer cell therapies. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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Review

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23 pages, 1775 KiB

Open AccessReview

Telomeres and Telomerase in the Control of Stem Cells

by Alexey Yu. Lupatov and Konstantin N. Yarygin

Biomedicines 2022, 10(10), 2335; https://doi.org/10.3390/biomedicines10102335 - 20 Sep 2022

Cited by 9 | Viewed by 6029

Abstract

Stem cells serve as a source of cellular material in embryogenesis and postnatal growth and regeneration. This requires significant proliferative potential ensured by sufficient telomere length. Telomere attrition in the stem cells and their niche cells can result in the exhaustion of the [...] Read more.

Stem cells serve as a source of cellular material in embryogenesis and postnatal growth and regeneration. This requires significant proliferative potential ensured by sufficient telomere length. Telomere attrition in the stem cells and their niche cells can result in the exhaustion of the regenerative potential of high-turnover organs, causing or contributing to the onset of age-related diseases. In this review, stem cells are examined in the context of the current telomere-centric theory of cell aging, which assumes that telomere shortening depends not just on the number of cell doublings (mitotic clock) but also on the influence of various internal and external factors. The influence of the telomerase and telomere length on the functional activity of different stem cell types, as well as on their aging and prospects of use in cell therapy applications, is discussed. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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10 pages, 1466 KiB

Open AccessReview

How Structural Features Define Biogenesis and Function of Human Telomerase RNA Primary Transcript

by Maria Rubtsova and Olga Dontsova

Biomedicines 2022, 10(7), 1650; https://doi.org/10.3390/biomedicines10071650 - 08 Jul 2022

Cited by 3 | Viewed by 1699

Abstract

Telomerase RNA has been uncovered as a component of the telomerase enzyme, which acts as a reverse transcriptase and maintains the length of telomeres in proliferated eukaryotic cells. Telomerase RNA is considered to have major functions as a template for telomeric repeat synthesis [...] Read more.

Telomerase RNA has been uncovered as a component of the telomerase enzyme, which acts as a reverse transcriptase and maintains the length of telomeres in proliferated eukaryotic cells. Telomerase RNA is considered to have major functions as a template for telomeric repeat synthesis and as a structural scaffold for telomerase. However, investigations of its biogenesis and turnover, as well as structural data, have provided evidence of functions of telomerase RNA that are not associated with telomerase activity. The primary transcript produced from the human telomerase RNA gene encodes for the hTERP protein, which presents regulatory functions related to autophagy, cellular proliferation, and metabolism. This review focuses on the specific features relating to the biogenesis and structure of human telomerase RNA that support the existence of an isoform suitable for functioning as an mRNA. We believe that further investigation into human telomerase RNA biogenesis mechanisms will provide more levels for manipulating cellular homeostasis, survival, and transformation mechanisms, and may contribute to a deeper understanding of the mechanisms of aging. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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16 pages, 1004 KiB

Open AccessReview

Somatic Mutations of Hematopoietic Cells Are an Additional Mechanism of Body Aging, Conducive to Comorbidity and Increasing Chronification of Inflammation

by Yegor E. Yegorov, Anastasia V. Poznyak, Evgeny E. Bezsonov, Alexander D. Zhuravlev, Nikita G. Nikiforov, Khava S. Vishnyakova and Alexander N. Orekhov

Biomedicines 2022, 10(4), 782; https://doi.org/10.3390/biomedicines10040782 - 27 Mar 2022

Cited by 4 | Viewed by 2597

Abstract

It is known that the development of foci of chronic inflammation usually accompanies body aging. In these foci, senescent cells appear with a pro-inflammatory phenotype that helps maintain inflammation. Their removal with the help of senolytics significantly improves the general condition of the [...] Read more.

It is known that the development of foci of chronic inflammation usually accompanies body aging. In these foci, senescent cells appear with a pro-inflammatory phenotype that helps maintain inflammation. Their removal with the help of senolytics significantly improves the general condition of the body and, according to many indicators, contributes to rejuvenation. The cells of the immune system participate in the initiation, development, and resolution of inflammation. With age, the human body accumulates mutations, including the cells of the bone marrow, giving rise to the cells of the immune system. We assume that a number of such mutations formed with age can lead to the appearance of “naive” cells with an initially pro-inflammatory phenotype, the migration of which to preexisting foci of inflammation contributes not to the resolution of inflammation but its chronicity. One of such cell variants are monocytes carrying mitochondrial mutations, which may be responsible for comorbidity and deterioration in the prognosis of the course of pathologies associated with aging, such as atherosclerosis, arthritis, osteoporosis, and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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26 pages, 659 KiB

Open AccessReview

Detection of TERT Promoter Mutations as a Prognostic Biomarker in Gliomas: Methodology, Prospects, and Advances

by Tsimur Hasanau, Eduard Pisarev, Olga Kisil, Naosuke Nonoguchi, Florence Le Calvez-Kelm and Maria Zvereva

Biomedicines 2022, 10(3), 728; https://doi.org/10.3390/biomedicines10030728 - 21 Mar 2022

Cited by 15 | Viewed by 6844

Abstract

This article reviews the existing approaches to determining the TERT promoter mutational status in patients with various tumoral diseases of the central nervous system. The operational characteristics of the most common methods and their transferability in medical practice for the selection or monitoring [...] Read more.

This article reviews the existing approaches to determining the TERT promoter mutational status in patients with various tumoral diseases of the central nervous system. The operational characteristics of the most common methods and their transferability in medical practice for the selection or monitoring of personalized treatments based on the TERT status and other related molecular biomarkers in patients with the most common tumors, such as glioblastoma, oligodendroglioma, and astrocytoma, are compared. The inclusion of new molecular markers in the course of CNS clinical management requires their rapid and reliable assessment. Availability of molecular evaluation of gliomas facilitates timely decisions regarding patient follow-up with the selection of the most appropriate treatment protocols. Significant progress in the inclusion of molecular biomarkers for their subsequent clinical application has been made since 2016 when the WHO CNS classification first used molecular markers to classify gliomas. In this review, we consider the methodological approaches used to determine mutations in the promoter region of the TERT gene in tumors of the central nervous system. In addition to classical molecular genetical methods, other methods for determining TERT mutations based on mass spectrometry, magnetic resonance imaging, next-generation sequencing, and nanopore sequencing are reviewed with an assessment of advantages and disadvantages. Beyond that, noninvasive diagnostic methods based on the determination of the mutational status of the TERT promoter are discussed. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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19 pages, 883 KiB

Open AccessReview

Telomeres and Age-Related Diseases

by Hans-Jürgen Gruber, Maria Donatella Semeraro, Wilfried Renner and Markus Herrmann

Biomedicines 2021, 9(10), 1335; https://doi.org/10.3390/biomedicines9101335 - 27 Sep 2021

Cited by 39 | Viewed by 4762

Abstract

Telomeres are at the non-coding ends of linear chromosomes. Through a complex 3-dimensional structure, they protect the coding DNA and ensure appropriate separation of chromosomes. Aging is characterized by a progressive shortening of telomeres, which compromises their structure and function. Because of their [...] Read more.

Telomeres are at the non-coding ends of linear chromosomes. Through a complex 3-dimensional structure, they protect the coding DNA and ensure appropriate separation of chromosomes. Aging is characterized by a progressive shortening of telomeres, which compromises their structure and function. Because of their protective function for genomic DNA, telomeres appear to play an important role in the development and progression of many age-related diseases, such as cardiovascular disease (CVD), malignancies, dementia, and osteoporosis. Despite substantial evidence that links telomere length with these conditions, the nature of these observations remains insufficiently understood. Therefore, future studies should address the question of causality. Furthermore, analytical methods should be further improved with the aim to provide informative and comparable results. This review summarize the actual knowledge of telomere biology and the possible implications of telomere dysfunction for the development and progression of age-related diseases. Furthermore, we provide an overview of analytical techniques for the measurement of telomere length and telomerase activity. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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17 pages, 1742 KiB

Open AccessReview

Ovarian Telomerase and Female Fertility

by Simon Toupance, Anne-Julie Fattet, Simon N. Thornton, Athanase Benetos, Jean-Louis Guéant and Isabelle Koscinski

Biomedicines 2021, 9(7), 842; https://doi.org/10.3390/biomedicines9070842 - 20 Jul 2021

Cited by 8 | Viewed by 5375

Abstract

Women’s fertility is characterized both quantitatively and qualitatively mainly by the pool of ovarian follicles. Monthly, gonadotropins cause an intense multiplication of granulosa cells surrounding the oocyte. This step of follicular development requires a high proliferation ability for these cells. Telomere length plays [...] Read more.

Women’s fertility is characterized both quantitatively and qualitatively mainly by the pool of ovarian follicles. Monthly, gonadotropins cause an intense multiplication of granulosa cells surrounding the oocyte. This step of follicular development requires a high proliferation ability for these cells. Telomere length plays a crucial role in the mitotic index of human cells. Hence, disrupting telomere homeostasis could directly affect women’s fertility. Strongly expressed in ovaries, telomerase is the most effective factor to limit telomeric attrition and preserve ovarian reserve. Considering these facts, two situations of infertility could be correlated with the length of telomeres and ovarian telomerase activity: PolyCystic Ovary Syndrome (PCOS), which is associated with a high density of small antral follicles, and Premature Ovarian Failure (POF), which is associated with a premature decrease in ovarian reserve. Several authors have studied this topic, expecting to find long telomeres and strong telomerase activity in PCOS and short telomeres and low telomerase activity in POF patients. Although the results of these studies are contradictory, telomere length and the ovarian telomerase impact in women’s fertility disorders appear obvious. In this context, our research perspectives aimed to explore the stimulation of ovarian telomerase to limit the decrease in the follicular pool while avoiding an increase in cancer risk. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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26 pages, 1836 KiB

Open AccessReview

Alternative Splicing of Human Telomerase Reverse Transcriptase (hTERT) and Its Implications in Physiological and Pathological Processes

by Anna A. Plyasova and Dmitry D. Zhdanov

Biomedicines 2021, 9(5), 526; https://doi.org/10.3390/biomedicines9050526 - 09 May 2021

Cited by 11 | Viewed by 3920

Abstract

Alternative splicing (AS) of human telomerase catalytic subunit (hTERT, human telomerase reverse transcriptase) pre-mRNA strongly regulates telomerase activity. Several proteins can regulate AS in a cell type-specific manner and determine the functions of cells. In addition to being involved in telomerase activity regulation, [...] Read more.

Alternative splicing (AS) of human telomerase catalytic subunit (hTERT, human telomerase reverse transcriptase) pre-mRNA strongly regulates telomerase activity. Several proteins can regulate AS in a cell type-specific manner and determine the functions of cells. In addition to being involved in telomerase activity regulation, AS provides cells with different splice variants that may have alternative biological activities. The modulation of telomerase activity through the induction of hTERT AS is involved in the development of different cancer types and embryos, and the differentiation of stem cells. Regulatory T cells may suppress the proliferation of target human and murine T and B lymphocytes and NK cells in a contact-independent manner involving activation of TERT AS. This review focuses on the mechanism of regulation of hTERT pre-mRNA AS and the involvement of splice variants in physiological and pathological processes. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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14 pages, 1240 KiB

Open AccessReview

Telomerase in Brain: The New Kid on the Block and Its Role in Neurodegenerative Diseases

by Gabriele Saretzki and Tengfei Wan

Biomedicines 2021, 9(5), 490; https://doi.org/10.3390/biomedicines9050490 - 29 Apr 2021

Cited by 19 | Viewed by 4958

Abstract

Telomerase is an enzyme that in its canonical function extends and maintains telomeres, the ends of chromosomes. This reverse transcriptase function is mainly important for dividing cells that shorten their telomeres continuously. However, there are a number of telomere-independent functions known for the [...] Read more.

Telomerase is an enzyme that in its canonical function extends and maintains telomeres, the ends of chromosomes. This reverse transcriptase function is mainly important for dividing cells that shorten their telomeres continuously. However, there are a number of telomere-independent functions known for the telomerase protein TERT (Telomerase Reverse Transcriptase). This includes the shuttling of the TERT protein from the nucleus to mitochondria where it decreases oxidative stress, apoptosis sensitivity and DNA damage. Recently, evidence has accumulated on a protective role of TERT in brain and postmitotic neurons. This function might be able to ameliorate the effects of toxic proteins such as amyloid-β, pathological tau and α-synuclein involved in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the protective mechanisms of TERT are not clear yet. Recently, an activation of autophagy as an important protein degradation process for toxic neuronal proteins by TERT has been described. This review summarises the current knowledge about the non-canonical role of the telomerase protein TERT in brain and shows its potential benefit for the amelioration of brain ageing and neurodegenerative diseases such as AD and PD. This might form the basis for the development of novel strategies and therapies against those diseases. Full article

(This article belongs to the Special Issue Telomerase: Role in Health and Aging)

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