International Journal of Molecular Sciences

Research

Jump to: Review, Other

21 pages, 2401 KiB

Open AccessArticle

Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs

by Aina Bernal, Elisenda Zafon, Daniel Domínguez, Enric Bertran and Laura Tusell

Int. J. Mol. Sci. 2018, 19(7), 2078; https://doi.org/10.3390/ijms19072078 - 17 Jul 2018

Cited by 3 | Viewed by 4009

Abstract

Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse [...] Read more.

Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre-malignant immortalised cells, we ectopically expressed telomerase in telomere-compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period—aggravated by p53 deficiency—and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy. Full article

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

► Show Figures

Figure 1

14 pages, 15646 KiB

Open AccessArticle

Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine

by Sakineh Kazemi Noureini, Mitra Kheirabadi, Fatima Masoumi, Farve Khosrogerdi, Younes Zarei, Cristian Suárez-Rozas, Julio Salas-Norambuena and Bruce Kennedy Cassels

Int. J. Mol. Sci. 2018, 19(4), 1239; https://doi.org/10.3390/ijms19041239 - 19 Apr 2018

Cited by 13 | Viewed by 5425

Abstract

Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, [...] Read more.

Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum, was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC₅₀ value of about 0.17 ± 0.1 µM for BSB, roughly 400 times stronger than boldine, while the LD₅₀ in the cytotoxicity assays were 12.5 and 21.88 µM, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC₅₀ for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations. Full article

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

► Show Figures

Figure 1

13 pages, 1268 KiB

Open AccessArticle

Presence of TERT Promoter Mutations is a Secondary Event and Associates with Elongated Telomere Length in Myxoid Liposarcomas

by Monica S. Ventura Ferreira, Martina Crysandt, Till Braunschweig, Edgar Jost, Barbara Voss, Anne-Sophie Bouillon, Ruth Knuechel, Tim H. Brümmendorf and Fabian Beier

Int. J. Mol. Sci. 2018, 19(2), 608; https://doi.org/10.3390/ijms19020608 - 18 Feb 2018

Cited by 13 | Viewed by 4959

Abstract

The occurrence of TERT promoter mutations has been well described in soft tissue sarcomas (STS). However, the biological role of these mutations as well as their impact on telomere length in STS is still unclear. We analyzed 116 patient samples diagnosed with 22 [...] Read more.

The occurrence of TERT promoter mutations has been well described in soft tissue sarcomas (STS). However, the biological role of these mutations as well as their impact on telomere length in STS is still unclear. We analyzed 116 patient samples diagnosed with 22 distinct histological subtypes of bone and STS for the occurrence of TERT promoter mutations by Sanger sequencing. We observed TERT promoter mutations at an overall frequency of 9.5% distributed over 7 different sarcoma subtypes. Except for one chondrosarcoma case harboring a C250T mutation, all other mutations were detected at location C228T. By far the far highest frequency of TERT promoter mutations was found in myxoid liposarcoma (MLS) (4 out of 9 cases studied, i.e., 44%). Assessment of telomere length from tumor biopsies revealed that TERT promoter-mutated MLSs had significantly fewer shortened telomeres in comparison to TERT wildtype MLSs. Based on the frequency of TERT promoter mutations and the elongated telomere length in mutated compared to wildtype MLS, we hypothesize that occurrence of TERT promoter mutations has a pivotal role in the disease progression as a secondary genetic event at a time when tumor cells face the need for telomere elongation to allow further proliferation. Full article

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

► Show Figures

Figure 1

12 pages, 1498 KiB

Open AccessArticle

Telomeric Repeat-Containing RNAs (TERRA) Decrease in Squamous Cell Carcinoma of the Head and Neck Is Associated with Worsened Clinical Outcome

by Valerio Vitelli, Paolo Falvo, Solomon G. Nergadze, Marco Santagostino, Lela Khoriauli, Paola Pellanda, Giulia Bertino, Antonio Occhini, Marco Benazzo, Patrizia Morbini, Marco Paulli, Camillo Porta and Elena Giulotto

Int. J. Mol. Sci. 2018, 19(1), 274; https://doi.org/10.3390/ijms19010274 - 17 Jan 2018

Cited by 14 | Viewed by 4572

Abstract

Telomeres are transcribed into noncoding telomeric repeat-containing RNAs (TERRA), which are essential for telomere maintenance. Deregulation of TERRA transcription impairs telomere metabolism and a role in tumorigenesis has been proposed. Head and neck cancer (HNC) is one of the most frequent cancers worldwide, [...] Read more.

Telomeres are transcribed into noncoding telomeric repeat-containing RNAs (TERRA), which are essential for telomere maintenance. Deregulation of TERRA transcription impairs telomere metabolism and a role in tumorigenesis has been proposed. Head and neck cancer (HNC) is one of the most frequent cancers worldwide, with head and neck squamous cell carcinoma (HNSCC) being the predominant type. Since HNSCC patients are characterized by altered telomere maintenance, a dysfunction in telomere transcription can be hypothesized. In this prospective study, we compared TERRA levels in the tumor and matched normal tissue from 23 HNSCC patients. We then classified patients in two categories according to the level of TERRA expression in the tumor compared to the normal tissue: (1) lower expression in the tumor, (2) higher or similar expression in tumor. A significant proportion of patients in the first group died of the disease within less than 34 months postsurgery, while the majority of patients in the second group were alive and disease-free. Our results highlight a striking correlation between TERRA expression and tumor aggressiveness in HNSCC suggesting that TERRA levels may be proposed as a novel molecular prognostic marker for HNSCC. Full article

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

► Show Figures

Figure 1

1541 KiB

Open AccessArticle

Measurement of Telomere Length in Colorectal Cancers for Improved Molecular Diagnosis

by Eric Le Balc’h, Nathalie Grandin, Marie-Véronique Demattei, Serge Guyétant, Anne Tallet, Jean-Christophe Pagès, Mehdi Ouaissi, Thierry Lecomte and Michel Charbonneau

Int. J. Mol. Sci. 2017, 18(9), 1871; https://doi.org/10.3390/ijms18091871 - 29 Aug 2017

Cited by 17 | Viewed by 5283

Abstract

All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs) using [...] Read more.

All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs) using TRF (Telomere Restriction Fragment) analysis. Telomeric DNA content was also quantified as the ratio of total telomeric (TTAGGG) sequences over that of the invariable Alu sequences. In most of the 125 CRCs analyzed, there was a significant diminution in telomere length compared with that in control healthy tissue. Only 34 tumors exhibited no telomere erosion and, in some cases, a slight telomere lengthening. Telomere length did not correlate with age, gender, tumor stage, tumor localization or stage of tumor differentiation. In addition, while telomere length did not correlate with the presence of a mutation in BRAF (V-raf murine sarcoma viral oncogene homolog B), PIK3CA (phosphatidylinositol 3-kinase catalytic subunit), or MSI status, it was significantly associated with the occurrence of a mutation in KRAS. Interestingly, we found that the shorter the telomeres in healthy tissue of a patient, the larger an increase in telomere length in the tumor. Our study points to the existence of two types of CRCs based on telomere length and reveals that telomere length in healthy tissue might influence telomere maintenance mechanisms in the tumor. Full article

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

► Show Figures

Graphical abstract

599 KiB

Open AccessArticle

Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives

by Payal P. Khincha, Casey L. Dagnall, Belynda Hicks, Kristine Jones, Abraham Aviv, Masayuki Kimura, Hormuzd Katki, Geraldine Aubert, Neelam Giri, Blanche P. Alter, Sharon A. Savage and Shahinaz M. Gadalla

Int. J. Mol. Sci. 2017, 18(8), 1765; https://doi.org/10.3390/ijms18081765 - 13 Aug 2017

Cited by 33 | Viewed by 4825

Abstract

Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three [...] Read more.

Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three most commonly used methods, quantitative polymerase chain reaction (qPCR), flow cytometry with fluorescence in situ hybridization (flow FISH) and Southern blot, in a cohort of patients with the telomere biology disorder dyskeratosis congenita (DC) and in their unaffected relatives (controls). We observed a strong correlation between the Southern blot average TL and the flow FISH total lymphocyte TL in both the DC patients and their unaffected relatives (R² of 0.68 and 0.73, respectively). The correlation between the qPCR average TL and that of the Southern blot method was modest (R² of 0.54 in DC patients and of 0.43 in unaffected relatives). Similar results were noted when comparing the qPCR average TL and the flow FISH total lymphocyte TL (R² of 0.49 in DC patients and of 0.42 in unaffected relatives). In conclusion, the strengths of the correlations between the three widely used TL assays (qPCR, flow FISH, and Southern blot) were significantly different. Careful consideration is warranted when selecting the method of TL measurement for research and for clinical studies. Full article

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

► Show Figures

Figure 1

Review

Jump to: Research, Other

12 pages, 1146 KiB

Open AccessReview

MicroRNA Regulation of Telomerase Reverse Transcriptase (TERT): Micro Machines Pull Strings of Papier-Mâché Puppets

by Ammad Ahmad Farooqi, Qaisar Mansoor, Nada Alaaeddine and Baojun Xu

Int. J. Mol. Sci. 2018, 19(4), 1051; https://doi.org/10.3390/ijms19041051 - 1 Apr 2018

Cited by 22 | Viewed by 5821

Abstract

Substantial fraction of high-quality information is continuously being added into the existing pool of knowledge related to the biology of telomeres. Based on the insights gleaned from decades of research, it is clear that chromosomal stability needs a highly controlled and dynamic balance [...] Read more.

Substantial fraction of high-quality information is continuously being added into the existing pool of knowledge related to the biology of telomeres. Based on the insights gleaned from decades of research, it is clear that chromosomal stability needs a highly controlled and dynamic balance of DNA gain and loss in each terminal tract of telomeric repeats. Telomeres are formed by tandem repeats of TTAGGG sequences, which are gradually lost with each round of division of the cells. Targeted inhibition of telomerase to effectively induce apoptosis in cancer cells has attracted tremendous attention and overwhelmingly increasingly list of telomerase inhibitors truthfully advocates pharmacological significance of telomerase. Telomerase reverse transcriptase (TERT) is a multi-talented and catalytically active component of the telomerase-associated protein machinery. Different proteins of telomerase-associated machinery work in a synchronized and orchestrated manner to ensure proper maintenance of telomeric length of chromosomes. Rapidly emerging scientific findings about regulation of TERT by microRNAs has revolutionized our understanding related to the biology of telomeres and telomerase. In this review, we have comprehensively discussed how different miRNAs regulate TERT in different cancers. Use of miRNA-based therapeutics against TERT in different cancers needs detailed research in preclinical models for effective translation of laboratory findings to clinically effective therapeutics. Full article

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

► Show Figures

Figure 1

32 pages, 2085 KiB

Open AccessReview

Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection—The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress

by Nabeel Quryshi, Laura E. Norwood Toro, Karima Ait-Aissa, Amanda Kong and Andreas M. Beyer

Int. J. Mol. Sci. 2018, 19(3), 797; https://doi.org/10.3390/ijms19030797 - 10 Mar 2018

Cited by 15 | Viewed by 6710

Abstract

Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive [...] Read more.

Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage (_mtDNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects. Telomerase, originally discovered to promote cellular proliferation, has recently emerged as a potential mechanism to counteract mitochondrial defects and restore healthy mitochondrial vascular phenotypes. This review details mechanisms currently used to assess cardiovascular damage, such as C-reactive protein (CRP) and troponin levels, while also unearthing recently researched biomarkers, including circulating _mtDNA, telomere length and telomerase activity. Further, we explore a potential role of telomerase in the mitigation of mitochondrial reactive oxygen species and maintenance of _mtDNA integrity. Telomerase activity presents a promising indicator for the early detection and treatment of chemotherapy-derived cardiac damage. Full article

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

► Show Figures

Graphical abstract

15 pages, 736 KiB

Open AccessReview

Telomere Length Maintenance in Cancer: At the Crossroad between Telomerase and Alternative Lengthening of Telomeres (ALT)

by Marco De Vitis, Francesco Berardinelli and Antonella Sgura

Int. J. Mol. Sci. 2018, 19(2), 606; https://doi.org/10.3390/ijms19020606 - 18 Feb 2018

Cited by 121 | Viewed by 14789

Abstract

Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated [...] Read more.

Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated senescence and/or apoptosis. For this reason, telomere maintenance is an essential step in cancer progression. Most human tumors maintain their telomeres expressing telomerase, whereas a lower but significant proportion activates the alternative lengthening of telomeres (ALT) pathway. However, evidence about the coexistence of ALT and telomerase has been found both in vivo in the same cancer populations and in vitro in engineered cellular models, making the distinction between telomerase- and ALT-positive tumors elusive. Indeed, after the development of drugs able to target telomerase, the capability for some cancer cells to escape death, switching from telomerase to ALT, was highlighted. Unfortunately, to date, the mechanism underlying the possible switching or the coexistence of telomerase and ALT within the same cell or populations is not completely understood and different factors could be involved. In recent years, different studies have tried to shed light on the complex regulation network that controls the transition between the two TMMs, suggesting a role for embryonic cancer origin, epigenetic modifications, and specific genes activation—both in vivo and in vitro. In this review, we examine recent findings about the cancer-associated differential activation of the two known TMMs and the possible factors implicated in this process. Furthermore, some studies on cancers are also described that did not display any TMM. Full article

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

► Show Figures

Figure 1

17 pages, 2449 KiB

Open AccessReview

Telomere Length Dynamics and the Evolution of Cancer Genome Architecture

by Kez Cleal, Kevin Norris and Duncan Baird

Int. J. Mol. Sci. 2018, 19(2), 482; https://doi.org/10.3390/ijms19020482 - 6 Feb 2018

Cited by 51 | Viewed by 11135

Abstract

Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass [...] Read more.

Telomeres are progressively eroded during repeated rounds of cell division due to the end replication problem but also undergo additional more substantial stochastic shortening events. In most cases, shortened telomeres induce a cell-cycle arrest or trigger apoptosis, although for those cells that bypass such signals during tumour progression, a critical length threshold is reached at which telomere dysfunction may ensue. Dysfunction of the telomere nucleoprotein complex can expose free chromosome ends to the DNA double-strand break (DSB) repair machinery, leading to telomere fusion with both telomeric and non-telomeric loci. The consequences of telomere fusions in promoting genome instability have long been appreciated through the breakage–fusion–bridge (BFB) cycle mechanism, although recent studies using high-throughput sequencing technologies have uncovered evidence of involvement in a wider spectrum of genomic rearrangements including chromothripsis. A critical step in cancer progression is the transition of a clone to immortality, through the stabilisation of the telomere repeat array. This can be achieved via the reactivation of telomerase, or the induction of the alternative lengthening of telomeres (ALT) pathway. Whilst telomere dysfunction may promote genome instability and tumour progression, by limiting the replicative potential of a cell and enforcing senescence, telomere shortening can act as a tumour suppressor mechanism. However, the burden of senescent cells has also been implicated as a driver of ageing and age-related pathology, and in the promotion of cancer through inflammatory signalling. Considering the critical role of telomere length in governing cancer biology, we review questions related to the prognostic value of studying the dynamics of telomere shortening and fusion, and discuss mechanisms and consequences of telomere-induced genome rearrangements. Full article

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

► Show Figures

Figure 1

18 pages, 854 KiB

Open AccessReview

Modulation of Telomerase Activity in Cancer Cells by Dietary Compounds: A Review

by Takahiro Eitsuka, Kiyotaka Nakagawa, Shunji Kato, Junya Ito, Yurika Otoki, Soo Takasu, Naoki Shimizu, Takumi Takahashi and Teruo Miyazawa

Int. J. Mol. Sci. 2018, 19(2), 478; https://doi.org/10.3390/ijms19020478 - 6 Feb 2018

Cited by 33 | Viewed by 7719

Abstract

Telomerase is expressed in ~90% of human cancer cell lines and tumor specimens, whereas its enzymatic activity is not detectable in most human somatic cells, suggesting that telomerase represents a highly attractive target for selective cancer treatment. Accordingly, various classes of telomerase inhibitors [...] Read more.

Telomerase is expressed in ~90% of human cancer cell lines and tumor specimens, whereas its enzymatic activity is not detectable in most human somatic cells, suggesting that telomerase represents a highly attractive target for selective cancer treatment. Accordingly, various classes of telomerase inhibitors have been screened and developed in recent years. We and other researchers have successfully found that some dietary compounds can modulate telomerase activity in cancer cells. Telomerase inhibitors derived from food are subdivided into two groups: one group directly blocks the enzymatic activity of telomerase (e.g., catechin and sulfoquinovosyldiacylglycerol), and the other downregulates the expression of human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, via signal transduction pathways (e.g., retinoic acid and tocotrienol). In contrast, a few dietary components, including genistein and glycated lipid, induce cellular telomerase activity in several types of cancer cells, suggesting that they may be involved in tumor progression. This review summarizes the current knowledge about the effects of dietary factors on telomerase regulation in cancer cells and discusses their molecular mechanisms of action. Full article

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

► Show Figures

Graphical abstract

28 pages, 5965 KiB

Open AccessReview

Current Perspectives of Telomerase Structure and Function in Eukaryotes with Emerging Views on Telomerase in Human Parasites

by Abhishek Dey and Kausik Chakrabarti

Int. J. Mol. Sci. 2018, 19(2), 333; https://doi.org/10.3390/ijms19020333 - 24 Jan 2018

Cited by 23 | Viewed by 8157

Abstract

Replicative capacity of a cell is strongly correlated with telomere length regulation. Aberrant lengthening or reduction in the length of telomeres can lead to health anomalies, such as cancer or premature aging. Telomerase is a master regulator for maintaining replicative potential in most [...] Read more.

Replicative capacity of a cell is strongly correlated with telomere length regulation. Aberrant lengthening or reduction in the length of telomeres can lead to health anomalies, such as cancer or premature aging. Telomerase is a master regulator for maintaining replicative potential in most eukaryotic cells. It does so by controlling telomere length at chromosome ends. Akin to cancer cells, most single-cell eukaryotic pathogens are highly proliferative and require persistent telomerase activity to maintain constant length of telomere and propagation within their host. Although telomerase is key to unlimited cellular proliferation in both cases, not much was known about the role of telomerase in human parasites (malaria, Trypanosoma, etc.) until recently. Since telomerase regulation is mediated via its own structural components, interactions with catalytic reverse transcriptase and several factors that can recruit and assemble telomerase to telomeres in a cell cycle-dependent manner, we compare and discuss here recent findings in telomerase biology in cancer, aging and parasitic diseases to give a broader perspective of telomerase function in human diseases. Full article

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

► Show Figures

Figure 1

21 pages, 673 KiB

Open AccessReview

Telomeres: Implications for Cancer Development

by Aina Bernal and Laura Tusell

Int. J. Mol. Sci. 2018, 19(1), 294; https://doi.org/10.3390/ijms19010294 - 19 Jan 2018

Cited by 61 | Viewed by 10064

Abstract

Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR). This is most likely achieved by a lariat structure that hides the linear telomeric DNA through protein-protein and protein-DNA interactions. The telomere shortening associated with [...] Read more.

Telomeres facilitate the protection of natural ends of chromosomes from constitutive exposure to the DNA damage response (DDR). This is most likely achieved by a lariat structure that hides the linear telomeric DNA through protein-protein and protein-DNA interactions. The telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in unmasked telomeres. Then, the subsequent activation of the DDR will define the fate of cells according to the functionality of cell cycle checkpoints. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptotic pathways, but they can also promote tumour initiation. Studies in telomere dynamics and karyotype analysis underpin telomere crisis as a key event driving genomic instability. Significant attainment of telomerase or alternative lengthening of telomeres (ALT)-pathway to maintain telomere length may be permissive and required for clonal evolution of genomically-unstable cells during progression to malignancy. We summarise current knowledge of the role of telomeres in the maintenance of chromosomal stability and carcinogenesis. Full article

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

► Show Figures

Graphical abstract

16 pages, 941 KiB

Open AccessReview

Telomere Homeostasis: Interplay with Magnesium

by Donogh Maguire, Ognian Neytchev, Dinesh Talwar, Donald McMillan and Paul G. Shiels

Int. J. Mol. Sci. 2018, 19(1), 157; https://doi.org/10.3390/ijms19010157 - 5 Jan 2018

Cited by 29 | Viewed by 10173

Abstract

Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished [...] Read more.

Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished during cellular senescence and normative physiological ageing. Inherent in the biochemistry of these processes is the role of magnesium, one of the main cellular ions and an essential cofactor in all reactions that use ATP. Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. This review explores the mechanisms that maintain telomere structure and function, their influence on circadian rhythms and their impact on health and age-related disease. The pervasive role of magnesium in telomere homeostasis is also highlighted. Full article

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

► Show Figures

Graphical abstract

1327 KiB

Open AccessReview

Telomere Biology and Thoracic Aortic Aneurysm

by Thomas Aschacher, Olivia Salameh, Florian Enzmann, Barbara Messner and Michael Bergmann

Int. J. Mol. Sci. 2018, 19(1), 3; https://doi.org/10.3390/ijms19010003 - 21 Dec 2017

Cited by 16 | Viewed by 6921

Abstract

Ascending aortic aneurysms are mostly asymptomatic and present a great risk of aortic dissection or perforation. Consequently, ascending aortic aneurysms are a source of lethality with increased age. Biological aging results in progressive attrition of telomeres, which are the repetitive DNA sequences at [...] Read more.

Ascending aortic aneurysms are mostly asymptomatic and present a great risk of aortic dissection or perforation. Consequently, ascending aortic aneurysms are a source of lethality with increased age. Biological aging results in progressive attrition of telomeres, which are the repetitive DNA sequences at the end of chromosomes. These telomeres play an important role in protection of genomic DNA from end-to-end fusions. Telomere maintenance and telomere attrition-associated senescence of endothelial and smooth muscle cells have been indicated to be part of the pathogenesis of degenerative vascular diseases. This systematic review provides an overview of telomeres, telomere-associated proteins and telomerase to the formation and progression of aneurysms of the thoracic ascending aorta. A better understanding of telomere regulation in the vascular pathology might provide new therapeutic approaches. Measurements of telomere length and telomerase activity could be potential prognostic biomarkers for increased risk of death in elderly patients suffering from an aortic aneurysm. Full article

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

► Show Figures

Figure 1

815 KiB

Open AccessReview

Telomerase Inhibitors from Natural Products and Their Anticancer Potential

by Kumar Ganesan and Baojun Xu

Int. J. Mol. Sci. 2018, 19(1), 13; https://doi.org/10.3390/ijms19010013 - 21 Dec 2017

Cited by 90 | Viewed by 14845

Abstract

Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite [...] Read more.

Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy—a hallmark of cancer—and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transcriptional levels. This extensive understanding of telomerase biology will provide indispensable information for enhancing the efficiency of rational anti-cancer drug design. Full article

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

► Show Figures

Graphical abstract

379 KiB

Open AccessReview

Telomeres, Aging and Exercise: Guilty by Association?

by Warrick Chilton, Brendan O’Brien and Fadi Charchar

Int. J. Mol. Sci. 2017, 18(12), 2573; https://doi.org/10.3390/ijms18122573 - 29 Nov 2017

Cited by 30 | Viewed by 9516

Abstract

Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse [...] Read more.

Telomeres are repetitive tandem DNA sequences that cap chromosomal ends protecting genomic DNA from enzymatic degradation. Telomeres progressively shorten with cellular replication and are therefore assumed to correlate with biological and chronological age. An expanding body of evidence suggests (i) a predictable inverse association between telomere length, aging and age-related diseases and (ii) a positive association between physical activity and telomere length. Both hypotheses have garnered tremendous research attention and broad consensus; however, the evidence for each proposition is inconsistent and equivocal at best. Telomere length does not meet the basic criteria for an aging biomarker and at least 50% of key studies fail to find associations with physical activity. In this review, we address the evidence in support and refutation of the putative associations between telomere length, aging and physical activity. We finish with a brief review of plausible mechanisms and potential future research directions. Full article

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

238 KiB

Open AccessReview

Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions

by Theresa Vasko, Andrea Kaifie, Matthias B. Stope, Thomas Kraus and Patrick Ziegler

Int. J. Mol. Sci. 2017, 18(11), 2267; https://doi.org/10.3390/ijms18112267 - 28 Oct 2017

Cited by 18 | Viewed by 5424

Abstract

Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able [...] Read more.

Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML), indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions. Full article

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

Other

Jump to: Research, Review

1554 KiB

Open AccessBrief Report

Effects of Highly Polluted Environment on Sperm Telomere Length: A Pilot Study

by Cecilia Vecoli, Luigi Montano, Andrea Borghini, Tiziana Notari, Antonino Guglielmino, Antonella Mercuri, Stefano Turchi and Maria Grazia Andreassi

Int. J. Mol. Sci. 2017, 18(8), 1703; https://doi.org/10.3390/ijms18081703 - 4 Aug 2017

Cited by 28 | Viewed by 6325

Abstract

High environmental pressure may impair male fertility by affecting sperm quality, but the real effect remains controversial. Herein, we assessed the influence of environmental exposure on telomere length (TL) in both leukocytes (LTL) and sperm cells (STL). A pilot biomonitoring study was conducted [...] Read more.

High environmental pressure may impair male fertility by affecting sperm quality, but the real effect remains controversial. Herein, we assessed the influence of environmental exposure on telomere length (TL) in both leukocytes (LTL) and sperm cells (STL). A pilot biomonitoring study was conducted in 112 clinically healthy, normospermic men living in various areas of Campania region (South of Italy) with high (n = 57, High Group) or low (n = 55, Low Group) environmental pressure. TL analysis was assessed by quantitative real time-PCR. STL was not significantly correlated with either age (p = 0.6) or LTL (p = 0.7), but was significantly longer in the High Group compared with the Low Group (p = 0.04). No significant difference was observed between leukocyte TL in the High or Low Group. Our results showed that male residents in areas with high environment exposure had a significant increase in STL. This finding supports the view that the human semen is a sentinel biomarker of environmental exposure. Full article

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

► Show Figures

Figure 1

Journal Menu

Journal Browser

Role of Telomeres and Telomerase in Cancer and Aging

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (19 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI