ijms-logo

Journal Browser

Journal Browser

Role of Telomeres and Telomerase in Cancer and Aging 2020

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 20050

Special Issue Editor

Ageing Biology Centre and Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
Interests: telomerase in ageing and cancer; TERT in mitochondria and brain; oxidative stress; mitochondria; senescence and ageing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Telomeres and telomerase have been receiving ever-increasing interest from the scientific community. This includes biologists deciphering the complex mechanisms and interactions between the different components of telomeres and telomerase, as well as clinicians aiming to use telomere lengths as a biomarker for aging and diseases. Ever more details emerge about the tightly-regulated interaction of telomerase activity in the regulation of telomere lengths, and many mechanisms still remain a mystery, ready to be solved.

Telomerase activity is under tight physiological regulation in human tissues, where the enzyme is active in only a few adult tissues, such as endothelial cells and lymphocytes, but can be upregulated in many types of adult stem cells. Telomere shortening has been associated with cellular senescence and the aging process, as well as major diseases, such as atherosclerosis, obesity, and cardiovascular disease. It is thus of high clinical relevance and is often measured in easily-accessible blood monocytes. By contrast, telomerase activity is highly upregulated and associated with tumorigenesis by maintaining telomeres and thereby constituting an important prerequisite for the ongoing proliferation of cancer cells. Our growing understanding of the mechanisms of telomerase upregulation during cancer development might help in tumor prognosis and in the development of new anticancer treatments and therapies.

In addition, many telomere-independent functions for the telomerase reverse transcriptase protein TERT have been discovered, which add to the complexity of telomerase and the multitude of its functions. It also extends the function of telomerase in its noncanonical role to cell types such as neurons, and organs such as the brain.

The aim of this Special Issue is to demonstrate and share new results and growing knowledge about the roles of telomeres and telomerase during processes such as aging and cancer development.

Dr. Gabriele Saretzki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Telomere length
  • Telomerase activity
  • TERT
  • TERC
  • Shelterin
  • Stem cells
  • Dyskerin
  • Cellular senescence
  • Aging
  • Cancer

Published Papers (6 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

11 pages, 797 KiB  
Article
Targeting Telomere Biology in Acute Lymphoblastic Leukemia
by Axel Karow, Monika Haubitz, Elisabeth Oppliger Leibundgut, Ingrid Helsen, Nicole Preising, Daniela Steiner, Tobias M. Dantonello, Roland A. Ammann, Jochen Roessler, Mutlu Kartal-Kaess, Alexander Röth and Gabriela M. Baerlocher
Int. J. Mol. Sci. 2021, 22(13), 6653; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136653 - 22 Jun 2021
Cited by 8 | Viewed by 2350
Abstract
Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and [...] Read more.
Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment. Full article
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2020)
Show Figures

Figure 1

15 pages, 1541 KiB  
Article
The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins
by Aleksandra O. Travina, Nadya V. Ilicheva, Alexey G. Mittenberg, Sergey V. Shabelnikov, Anastasia V. Kotova and Olga I. Podgornaya
Int. J. Mol. Sci. 2021, 22(7), 3293; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073293 - 24 Mar 2021
Cited by 10 | Viewed by 2266
Abstract
Telomere-binding factor 2 (TRF2) is part of the shelterin protein complex found at chromosome ends. Lamin A/C interacts with TRF2 and influences telomere position. TRF2 has an intrinsically disordered region between the ordered dimerization and DNA-binding domains. This domain is referred to as [...] Read more.
Telomere-binding factor 2 (TRF2) is part of the shelterin protein complex found at chromosome ends. Lamin A/C interacts with TRF2 and influences telomere position. TRF2 has an intrinsically disordered region between the ordered dimerization and DNA-binding domains. This domain is referred to as the long linker region of TRF2, or udTRF2. We suggest that udTRF2 might be involved in the interaction between TRF2 and lamins. The recombinant protein corresponding to the udTRF2 region along with polyclonal antibodies against this region were used in co-immunoprecipitation with purified lamina and nuclear extracts. Co-immunoprecipitation followed by Western blots and mass spectrometry indicated that udTRF2 interacts with lamins, preferably lamins A/C. The interaction did not involve any lamin-associated proteins, was not dependent on the post-translation modification of lamins, nor did it require their higher-order assembly. Besides lamins, a number of other udTRF2-interacting proteins were identified by mass spectrometry, including several heterogeneous nuclear ribonucleoproteins (hnRNP A2/B1, hnRNPA1, hnRNP A3, hnRNP K, hnRNP L, hnRNP M), splicing factors (SFPQ, NONO, SRSF1, and others), helicases (DDX5, DHX9, and Eif4a3l1), topoisomerase I, and heat shock protein 71, amongst others. Some of the identified interactors are known to be involved in telomere biology; the roles of the others remain to be investigated. Thus, the long linker region of TRF2 (udTRF2) is a regulatory domain responsible for the association between TRF2 and lamins and is involved in interactions with other proteins. Full article
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2020)
Show Figures

Figure 1

21 pages, 2500 KiB  
Article
Three-Dimensional Nuclear Telomere Profiling as a Biomarker for Recurrence in Oligodendrogliomas: A Pilot Study
by Macoura Gadji, Shubha Mathur, Brigitte Bélanger, Jaganmohan Reddy Jangamreddy, Josée Lamoureux, Ana Maria Crous Tsanaclis, David Fortin, Régen Drouin and Sabine Mai
Int. J. Mol. Sci. 2020, 21(22), 8539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228539 - 12 Nov 2020
Cited by 2 | Viewed by 1729
Abstract
Mechanisms of recurrence in oligodendrogliomas are poorly understood. Recurrence might be driven by telomere dysfunction-mediated genomic instability. In a pilot study, we investigated ten patients with oligodendrogliomas at the time of diagnosis (first surgery) and after recurrence (second surgery) using three-dimensional nuclear telomere [...] Read more.
Mechanisms of recurrence in oligodendrogliomas are poorly understood. Recurrence might be driven by telomere dysfunction-mediated genomic instability. In a pilot study, we investigated ten patients with oligodendrogliomas at the time of diagnosis (first surgery) and after recurrence (second surgery) using three-dimensional nuclear telomere analysis performed with quantitative software TeloView® (Telo Genomics Corp, Toronto, Ontario, Canada). 1p/19q deletion status of each patient was determined by fluorescent in situ hybridization on touch preparation slides. We found that a very specific 3D telomeric profile was associated with two pathways of recurrence in oligodendrogliomas independent of their 1p/19q status: a first group of 8 patients displayed significantly different 3D telomere profiles between both surgeries (p < 0.0001). Their recurrence happened at a mean of 231.375 ± 117.42 days and a median time to progression (TTP) of 239 days, a period defined as short-term recurrence; and a second group of three patients displayed identical 3D telomere profiles between both surgery samples (p > 0.05). Their recurrence happened at a mean of 960.666 ± 86.19 days and a median TTP of 930 days, a period defined as long-term recurrence. Our results suggest a potential link between nuclear telomere architecture and telomere dysfunction with time to recurrence in oligodendrogliomas, independently of the 1p/19q status. Full article
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2020)
Show Figures

Figure 1

13 pages, 1113 KiB  
Article
Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita
by Margherita Vieri, Martin Kirschner, Mareike Tometten, Anne Abels, Benjamin Rolles, Susanne Isfort, Jens Panse, Tim H. Brümmendorf and Fabian Beier
Int. J. Mol. Sci. 2020, 21(19), 7196; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197196 - 29 Sep 2020
Cited by 18 | Viewed by 2679
Abstract
Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and [...] Read more.
Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (TERT, n = 1),in the telomerase RNA component (TERC, n = 2) and in dyskerin pseudouridine synthase 1 (DKC1, n = 1) and found no substantial differences in the activity of these three agents in patients with TERC/TERT mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased TERT expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated TERT expression, thereby underscoring the involvement of TERT in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients’ individual co-morbidities, e.g., pre-existing liver disease and expected side-effects. Full article
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2020)
Show Figures

Figure 1

8 pages, 582 KiB  
Communication
Myelosuppression in Patients Treated with the Telomerase Inhibitor Imetelstat Is Not Mediated through Activation of Toll-Like Receptors
by Gabriela M. Baerlocher, Joshua Rusbuldt, Jacqueline Bussolari and Fei Huang
Int. J. Mol. Sci. 2020, 21(18), 6550; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186550 - 08 Sep 2020
Cited by 3 | Viewed by 2496
Abstract
Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were manageable and reversible. Toll-like receptors (TLRs) are proteins [...] Read more.
Imetelstat sodium (GRN163L; hereafter, imetelstat) is a first-in-class telomerase inhibitor that has demonstrated activity in patients with myeloproliferative neoplasms (MPNs). Treatment with imetelstat has been associated with thrombocytopenia and other hematologic adverse effects that were manageable and reversible. Toll-like receptors (TLRs) are proteins that recognize pathogen-associated molecular patterns and stimulate innate immune and pro-apoptotic responses. Because imetelstat is an oligonucleotide, and some oligonucleotides can activate TLRs, we conducted an in vitro study to rule out the possibility of imetelstat-associated thrombocytopenia by off-target effects through activation of TLRs. We used HEK293 cell lines stably co-expressing a human TLR gene and an NFκB-inducible reporter to investigate whether imetelstat can activate TLR signaling. We treated the cells with imetelstat or control oligonucleotides for 20 h, and used absorbance of the culture media to calculate the reporter activity. Treatment with imetelstat within or beyond the clinically relevant concentrations had no stimulatory effect on TLR2, TLR3, TLR4, TLR5, TLR7, or TLR9. This result was not surprising since the structure of imetelstat does not meet the reported minimal structural requirements for TLR9 activation. Furthermore, imetelstat treatment of the MPN cell line HEL did not impact the expression of TLR signaling pathway target genes that are commonly induced by activation of different TLRs, whereas it significantly reduced its target gene hTERT, human telomerase reverse transcriptase, in a dose- and time-dependent manner. Hence, cytopenias, especially thrombocytopenia observed in some patients treated with imetelstat, are not mediated by off-target interactions with TLRs. Full article
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2020)
Show Figures

Graphical abstract

Review

Jump to: Research

22 pages, 1532 KiB  
Review
Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging
by Barbara Jacczak, Błażej Rubiś and Ewa Totoń
Int. J. Mol. Sci. 2021, 22(12), 6381; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126381 - 15 Jun 2021
Cited by 13 | Viewed by 7564
Abstract
Proper functioning of cells—their ability to divide, differentiate, and regenerate—is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science [...] Read more.
Proper functioning of cells—their ability to divide, differentiate, and regenerate—is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science fields for years, including the study of both cancer and of senescence and aging. All these processes are accompanied by telomere-length modulation. Maintaining the key levels of telomerase component (hTERT) expression and telomerase activity that provide optimal telomere length as well as some nontelomeric functions represents a promising step in advanced anti-aging strategies, especially in dermocosmetics. Some known naturally derived compounds contribute significantly to telomere and telomerase metabolism. However, before they can be safely used, it is necessary to assess their mechanisms of action and potential side effects. This paper focuses on the metabolic potential of natural compounds to modulate telomerase and telomere biology and thus prevent senescence and skin aging. Full article
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging 2020)
Show Figures

Figure 1

Back to TopTop