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The Dual Roles of Telomeres and Telomerase in Aging and...
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The Dual Roles of Telomeres and Telomerase in Aging and Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (22 March 2023) | Viewed by 31778

Special Issue Editor

Prof. Dr. Cagatay Günes

E-Mail Website
Guest Editor
Department of Urology, Medical Faculty, Universität Ulm, Ulm, Germany
Interests: telomeres; telomerase; stem cells; aging; cancer

Special Issue Information

Dear Colleagues,

Studies over the past three decades have revealed the dual role of both telomeres and telomerase in aging and disease. While the activity of telomerase is necessary for the long-term replicative potential of eukaryotic cells, devoted to maintaining the integrity of genetic material, it is also required for the sustained proliferation of cancer cells. Consequently, telomerase activity is shut down in adult human tissues, and only a few cell types with high proliferation capacity and stem cells maintain telomerase activity throughout their life span. Absent or insufficient telomerase activity results in telomere shortening and consequently in the activation of tumor suppressor checkpoints, preventing tumorigenesis. As a trade-off, telomere shortening limits organismal life span and promotes aging syndromes. In cells with defective check-point activation, aging-associated telomere shortening can promote genome instability and cancer formation.

Increasing evidence indicates that both telomeres and telomerase contribute to cell survival and cancer via mechanisms that go beyond mere telomere length regulation. There is compelling evidence for additional, length-independent roles of telomerase, including gene regulation. Regarding telomeres, it has been shown that telomeres can induce senescence in a length-independent manner and may thus suppress tumorigenesis. This new role of telomeres is ascribed to sensing replication stress that results from aneuploidy or sustained oncogenic signals. Interestingly, telomerase activity abrogates replication-stress-induced senescence independent of its role in telomere elongation and promotes tumorigenesis. The exact nature of telomeric-replication stress and the role of telomerase in this context are two questions remaining to be elucidated experimentally.

Given their pivotal roles in cancer and aging, much hope has been kindled in telomerase inhibition or activation. Nevertheless, a telomerase inhibitor is still not in sight for effective cancer treatment. Regardless, though, can we assess the potential risk that anti-telomerase treatment may provoke alternative lengthening (ALT) of telomeres in cancer cells? On the other hand, may a telomerase activator be useful in attenuating age-related decline in tissue function and improving tissue regeneration? Finally, can we deal with the cancer-promoting features of activated telomerase? New findings may reveal new and safe therapeutic opportunities.

Prof. Dr. Cagatay Günes
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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • telomerase
  • telomere
  • shelterin
  • stem cells
  • cancer
  • aging
  • telomeropathies
  • ALT
  • replication stress
  • G-quadruplex structures

Published Papers (10 papers)

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12 pages, 1765 KiB  
Article
Genetic Polymorphisms of the Telomerase Reverse Transcriptase Gene in Relation to Prostate Tumorigenesis, Aggressiveness and Mortality: A Cross-Ancestry Analysis
by Yongle Zhan, Xiaohao Ruan, Jiacheng Liu, Da Huang, Jingyi Huang, Jinlun Huang, Tsun Tsun Stacia Chun, Ada Tsui-Lin Ng, Yishuo Wu, Gonghong Wei, Haowen Jiang, Danfeng Xu and Rong Na
Cancers 2023, 15(9), 2650; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15092650 - 08 May 2023
Cited by 1 | Viewed by 1350
Abstract
Background: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank and a Chinese PCa [...] Read more.
Background: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). Results: A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12–1.20, p = 4.12 × 10−16) and rs11291391 (OR = 1.73, 95%CI:1.34–2.25, p = 3.04 × 10−5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31–1.71, p = 2.91 × 10−9) and rs2853677 (OR = 1.74, 95%CI:1.52–1.98, p = 3.52 × 10−16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04–2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10−15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171). Conclusion: TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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18 pages, 3678 KiB  
Article
Targeted Long-Read Bisulfite Sequencing Identifies Differences in the TERT Promoter Methylation Profiles between TERT Wild-Type and TERT Mutant Cancer Cells
by Seungjae Lee, Ti-Cheng Chang, Patrick Schreiner, Yiping Fan, Neeraj Agarwal, Charles Owens, Reinhard Dummer, John M. Kirkwood, Raymond L. Barnhill, Dan Theodorescu, Gang Wu and Armita Bahrami
Cancers 2022, 14(16), 4018; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14164018 - 19 Aug 2022
Cited by 3 | Viewed by 1973
Abstract
Background: TERT promoter methylation, located several hundred base pairs upstream of the transcriptional start site, is cancer specific and correlates with increased TERT mRNA expression and poorer patient outcome. Promoter methylation, however, is not mutually exclusive to TERT activating genetic alterations, as predicted [...] Read more.
Background: TERT promoter methylation, located several hundred base pairs upstream of the transcriptional start site, is cancer specific and correlates with increased TERT mRNA expression and poorer patient outcome. Promoter methylation, however, is not mutually exclusive to TERT activating genetic alterations, as predicted for functionally redundant mechanisms. To annotate the altered patterns of TERT promoter methylation and their relationship with gene expression, we applied a Pacific Biosciences-based, long-read, bisulfite-sequencing technology and compared the differences in the methylation marks between wild-type and mutant cancers in an allele-specific manner. Results: We cataloged TERT genetic alterations (i.e., promoter point mutations or structural variations), allele-specific promoter methylation patterns, and allele-specific expression levels in a cohort of 54 cancer cell lines. In heterozygous mutant cell lines, the mutant alleles were significantly less methylated than their silent, mutation-free alleles (p < 0.05). In wild-type cell lines, by contrast, both epialleles were equally methylated to high levels at the TERT distal promoter, but differentially methylated in the proximal regions. ChIP analysis showed that epialleles with the hypomethylated proximal and core promoter were enriched in the active histone mark H3K4me2/3, whereas epialleles that were methylated in those regions were enriched in the repressive histone mark H3K27me3. Decitabine therapy induced biallelic expression in the wild-type cancer cells, whereas the mutant cell lines were unaffected. Conclusions: Long-read bisulfite sequencing analysis revealed differences in the methylation profiles and responses to demethylating agents between TERT wild-type and genetically altered cancer cell lines. The causal relation between TERT promoter methylation and gene expression remains to be established. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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19 pages, 3674 KiB  
Article
Relative Telomere Length Change in Colorectal Carcinoma and Its Association with Tumor Characteristics, Gene Expression and Microsatellite Instability
by Muhammad G. Kibriya, Maruf Raza, Mohammed Kamal, Zahidul Haq, Rupash Paul, Andrew Mareczko, Brandon L. Pierce, Habibul Ahsan and Farzana Jasmine
Cancers 2022, 14(9), 2250; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092250 - 30 Apr 2022
Cited by 11 | Viewed by 1960
Abstract
We compared tumor and adjacent normal tissue samples from 165 colorectal carcinoma (CRC) patients to study change in relative telomere length (RTL) and its association with different histological and molecular features. To measure RTL, we used a Luminex-based assay. We observed shorter RTL [...] Read more.
We compared tumor and adjacent normal tissue samples from 165 colorectal carcinoma (CRC) patients to study change in relative telomere length (RTL) and its association with different histological and molecular features. To measure RTL, we used a Luminex-based assay. We observed shorter RTL in the CRC tissue compared to paired normal tissue (RTL 0.722 ± SD 0.277 vs. 0.809 ± SD 0.242, p = 0.00012). This magnitude of RTL shortening (by ~0.08) in tumor tissue is equivalent to RTL shortening seen in human leukocytes over 10 years of aging measured by the same assay. RTL was shorter in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. RTL shortening was more prominent in low-grade CRC and in the presence of microsatellite instability (MSI). In a subset of patients, we also examined differential gene expression of (a) telomere-related genes, (b) genes in selected cancer-related pathways and (c) genes at the genome-wide level in CRC tissues to determine the association between gene expression and RTL changes. RTL shortening in CRC was associated with (a) upregulation of DNA replication genes, cyclin dependent-kinase genes (anti-tumor suppressor) and (b) downregulation of “caspase executor”, reducing apoptosis. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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21 pages, 6590 KiB  
Article
A Comparative Assessment of Replication Stress Markers in the Context of Telomerase
by Sabine Meessen, Gregoire Najjar, Anca Azoitei, Sebastian Iben, Christian Bolenz and Cagatay Günes
Cancers 2022, 14(9), 2205; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092205 - 28 Apr 2022
Cited by 1 | Viewed by 2320
Abstract
Aberrant replication stress (RS) is a source of genome instability and has serious implications for cell survival and tumourigenesis. Therefore, the detection of RS and the identification of the underlying molecular mechanisms are crucial for the understanding of tumourigenesis. Currently, three protein markers—p33-phosphorylated [...] Read more.
Aberrant replication stress (RS) is a source of genome instability and has serious implications for cell survival and tumourigenesis. Therefore, the detection of RS and the identification of the underlying molecular mechanisms are crucial for the understanding of tumourigenesis. Currently, three protein markers—p33-phosphorylated replication protein A2 (pRPA2), γ-phosphorylated H2AX (γ-H2AX), and Tumor Protein P53 Binding Protein 1 (53BP1)—are frequently used to detect RS. However, to our knowledge, there is no report that compares their suitability for the detection of different sources of RS. Therefore, in this study, we evaluate the suitability of pRPA2, γ-H2AX, and 53BP1 for the detection of RS caused by different sources of RS. In addition, we examine their suitability as markers of the telomerase-mediated alleviation of RS. For these purposes, we use here telomerase-negative human fibroblasts (BJ) and their telomerase-immortalized counterparts (BJ-hTERT). Replication stress was induced by the ectopic expression of the oncogenic RAS mutant RASG12V (OI-RS), by the knockdown of ploidy-control genes ORP3 or MAD2 (AI-RS), and by treatment with hydrogen peroxide (ROS-induced RS). The level of RS was determined by immunofluorescence staining for pRPA2, γ-H2AX, and 53BP1. Evaluation of the staining results revealed that pRPA2- and γ-H2AX provide a significant and reliable assessment of OI-RS and AI-RS compared to 53BP1. On the other hand, 53BP1 and pRPA2 proved to be superior to γ-H2AX for the evaluation of ROS-induced RS. Moreover, the data showed that among the tested markers, pRPA2 is best suited to evaluate the telomerase-mediated suppression of all three types of RS. In summary, the data indicate that the choice of marker is important for the evaluation of RS activated through different conditions. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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22 pages, 4055 KiB  
Article
CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome
by Jessica Merkle, Markus Breunig, Maximilian Schmid, Chantal Allgöwer, Jana Krüger, Michael K. Melzer, Susanne Bens, Reiner Siebert, Lukas Perkhofer, Ninel Azoitei, Thomas Seufferlein, Sandra Heller, Matthias Meier, Martin Müller, Alexander Kleger and Meike Hohwieler
Cancers 2021, 13(20), 5139; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205139 - 13 Oct 2021
Cited by 16 | Viewed by 2488
Abstract
Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human [...] Read more.
Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRASG12Dusing a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A-mutated KRASG12DPDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A-mutated pluripotent stem cells. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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16 pages, 1541 KiB  
Article
Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma
by Xi Zheng, Felix Wezel, Anca Azoitei, Sabine Meessen, Wenya Wang, Gregoire Najjar, Xue Wang, Johann M. Kraus, Hans A. Kestler, Axel John, Friedemann Zengerling, Christian Bolenz and Cagatay Günes
Cancers 2021, 13(15), 3774; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153774 - 27 Jul 2021
Cited by 4 | Viewed by 2225
Abstract
Background: Telomeres are protein–DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres [...] Read more.
Background: Telomeres are protein–DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres of peripheral blood leukocyte (PBL) cells can serve as prognostic biomarkers for cancer risk and may be associated with survival of patients with solid cancers. Telomere length in PBL cells could also be a potential prognostic biomarker for survival in bladder cancer (BC) or renal cell carcinoma (RCC). Methods: The relative telomere length (RTL) of PBL cells was assessed in patients with BC (n = 144) and RCC (n = 144) by using qPCR. A control population of patients without malignant disease (NC, n = 73) was included for comparison. The correlation and association of RTL with histopathological parameters and overall survival (OS) were evaluated. Results: Patients with BC and RCC had significantly shorter telomeres compared to patients without malignant disease. Within the cancer cohorts, multivariate analysis revealed that short RTL is an independent predictor of worse survival in BC (p = 0.039) and RCC (p = 0.041). Conclusion: Patients with BC and RCC had significantly shorter telomeres compared to the normal population. Shorter RTL in BC and RCC was an independent predictor of reduced survival. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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18 pages, 4106 KiB  
Article
Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells
by Karolin Walter, Eva Rodriguez-Aznar, Monica S. Ventura Ferreira, Pierre-Olivier Frappart, Tabea Dittrich, Kanishka Tiwary, Sabine Meessen, Laura Lerma, Nora Daiss, Lucas-Alexander Schulte, Zeynab Najafova, Frank Arnold, Valentyn Usachov, Ninel Azoitei, Mert Erkan, Andre Lechel, Tim H. Brümmendorf, Thomas Seufferlein, Alexander Kleger, Enrique Tabarés, Cagatay Günes, Steven A. Johnsen, Fabian Beier, Bruno Sainz, Jr. and Patrick C. Hermannadd Show full author list remove Hide full author list
Cancers 2021, 13(13), 3145; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133145 - 23 Jun 2021
Cited by 13 | Viewed by 4082
Abstract
To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor [...] Read more.
To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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18 pages, 4271 KiB  
Article
A Prospective Feasibility Trial to Challenge Patient–Derived Pancreatic Cancer Organoids in Predicting Treatment Response
by Alica K. Beutel, Lena Schütte, Jeanette Scheible, Elodie Roger, Martin Müller, Lukas Perkhofer, Annika M. T. U. Kestler, Johann M. Kraus, Hans A. Kestler, Thomas F. E. Barth, Johannes Lemke, Marko Kornmann, Thomas J. Ettrich, Johann Gout, Thomas Seufferlein and Alexander Kleger
Cancers 2021, 13(11), 2539; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112539 - 21 May 2021
Cited by 26 | Viewed by 3945
Abstract
Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective [...] Read more.
Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay. Areas under the curves (AUC) are clustered for each drug, and a prediction score is developed for combined regimens. Pharmacotyping profiles are obtained from 28 PDOs (efficacy 63.6%) after a median of 53 days (range 21–126 days). PDOs exhibit heterogeneous responses to the standard-of-care drugs, and are classified into high, intermediate, or low responder categories. Our developed prediction model allows a successful response prediction in treatment-naïve patients with an accuracy of 91.1% for first-line and 80.0% for second-line regimens, respectively. The power of prediction declines in pretreated patients (accuracy 40.0%), particularly with more than one prior line of chemotherapy. Progression-free survival (PFS) is significantly longer in previously treatment-naïve patients receiving a predicted tumor sensitive compared to a predicted tumor resistant regimen (mPFS 141 vs. 46 days; p = 0.0048). In conclusion, generation and pharmacotyping of PDOs is feasible in clinical routine and may provide substantial benefit. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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Review

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22 pages, 1400 KiB  
Review
Telomerase in Cancer: Function, Regulation, and Clinical Translation
by Nathaniel J. Robinson and William P. Schiemann
Cancers 2022, 14(3), 808; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030808 - 05 Feb 2022
Cited by 25 | Viewed by 6867
Abstract
During the process of malignant transformation, cells undergo a series of genetic, epigenetic, and phenotypic alterations, including the acquisition and propagation of genomic aberrations that impart survival and proliferative advantages. These changes are mediated in part by the induction of replicative immortality that [...] Read more.
During the process of malignant transformation, cells undergo a series of genetic, epigenetic, and phenotypic alterations, including the acquisition and propagation of genomic aberrations that impart survival and proliferative advantages. These changes are mediated in part by the induction of replicative immortality that is accompanied by active telomere elongation. Indeed, telomeres undergo dynamic changes to their lengths and higher-order structures throughout tumor formation and progression, processes overseen in most cancers by telomerase. Telomerase is a multimeric enzyme whose function is exquisitely regulated through diverse transcriptional, post-transcriptional, and post-translational mechanisms to facilitate telomere extension. In turn, telomerase function depends not only on its core components, but also on a suite of binding partners, transcription factors, and intra- and extracellular signaling effectors. Additionally, telomerase exhibits telomere-independent regulation of cancer cell growth by participating directly in cellular metabolism, signal transduction, and the regulation of gene expression in ways that are critical for tumorigenesis. In this review, we summarize the complex mechanisms underlying telomere maintenance, with a particular focus on both the telomeric and extratelomeric functions of telomerase. We also explore the clinical utility of telomeres and telomerase in the diagnosis, prognosis, and development of targeted therapies for primary, metastatic, and recurrent cancers. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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17 pages, 1582 KiB  
Review
RAP1/TERF2IP—A Multifunctional Player in Cancer Development
by Anna Deregowska and Maciej Wnuk
Cancers 2021, 13(23), 5970; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235970 - 27 Nov 2021
Cited by 13 | Viewed by 2916
Abstract
Mammalian RAP1 (TERF2IP), the most conserved shelterin component, plays a pleiotropic role in the regulation of a variety of cellular processes, including cell metabolism, DNA damage response, and NF-κB signaling, beyond its canonical telomeric role. Moreover, it has been demonstrated to be involved [...] Read more.
Mammalian RAP1 (TERF2IP), the most conserved shelterin component, plays a pleiotropic role in the regulation of a variety of cellular processes, including cell metabolism, DNA damage response, and NF-κB signaling, beyond its canonical telomeric role. Moreover, it has been demonstrated to be involved in oncogenesis, progression, and chemoresistance in human cancers. Several mutations and different expression patterns of RAP1 in cancers have been reported. However, the functions and mechanisms of RAP1 in various cancers have not been extensively studied, suggesting the necessity of further investigations. In this review, we summarize the main roles of RAP1 in different mechanisms of cancer development and chemoresistance, with special emphasis on the contribution of RAP1 mutations, expression patterns, and regulation by non-coding RNA, and briefly discuss telomeric and non-telomeric functions. Full article
(This article belongs to the Special Issue The Dual Roles of Telomeres and Telomerase in Aging and Cancer)
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