telomerase and cancer ppt

Telomerase Structure: RNA dependent DNA Polymerase Two Subunits: hTERT and hTR [1] Mutations eliminate activity figure [2] Overview of Telomeres and Telomerase Telomerase Function: Maintain Telomeres! Therefore, novel fast-acting therapeutic agents that can inhibit telomerase activity would be highly desirable. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Isolation and characterization of human recombinant antibodies endowed with the antigen-specific, major histocompatibility complex-restricted specificity of T cells directed toward the widely expressed tumor T-cell epitopes of the telomerase catalytic subunit. Masutomi K, Kaneko S, Hayashi N, Yamashita T, Shirota Y, Kobayashi K, Murakami S. Telomerase activity reconstituted in vitro with purified human telomerase reverse transcriptase and human telomerase RNA component. Lev A, Denkberg G, Cohen CJ, Tzukerman M, Skorecki KL, Chames P, et al. However, a subset of cancer/immortalized cells lack telomerase activity and maintain telomere length by alternative mechanisms, probably involving genetic (homologous) recombination , which is elevated in most immortal/cancer cell lines . Granulocytemonocyte colony-stimulating factor (GM-CSF) or TLR7 is used as adjuvant to carry GV1001. However, TERT promoter mutations have not been detected in prostate cancer, a cancer of low self-renewing tissue, suggesting that alterations within the core promoter of the TERT gene do not play an important role in prostate carcinogenesis [52]. Frescas D, de Lange T. TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1. Moreover, there are many other unresolved questions regarding telomeres and telomerase function that deserve further investigation (Box 2). Article Cells that gain additional oncogenic changes (p53 loss) can bypass senescence and continue to divide until multiple critically shortened telomeres initiate crisis, a period of increased chromosome end-to-end fusions and extensive cell death. Telomerase promoter mutations in cancer: an emerging molecular biomarker? Curr Opin Genet Dev. Imetelstat has been undergoing clinical trials for several years, and while some trials have already been completed, some were discontinued (breast and lung cancer, lymphoproliferative disorders and polycythemia vera) because the US FDA put these on hold due to hematological toxicity, but a few are still continuing (Table2). This complex then undergoes Reptin and Pontin (ATPases)-mediated binding to hTERT+p23+HSP90 complex. Thus, inhibition of telomerase recruitment may result in cell death [94]. Hayashi MT, Cesare AJ, Rivera T, Karlseder J. Although telomerase maintains telomere length in the majority of cancer cells, the ALT mechanism is also employed by 1015% of tumors [27]. Large multicenter studies are required to determine long-term toxicities in patients. Telomerase: Blackburn and Carol Greider, at Berkeley in 1985, identified an enzymatic activity capable of extending telomeric sequences. 2014;9:e85155. Jerry W. Shay. These non-canonical putative telomerase functions may be mediated through a network of feed forward signaling loops [95]. Genetics. 2009;323:6448. Shay JW, Wright WE. Nat Commun. 2015;4:e176. Article The following sections will cover recent developments in the area of telomere and telomerase biology, their implications for understanding mechanisms underlying cancer and for the development of cancer therapies, as well as outstanding questions for the field. 2015;36:118092. For example, TRF2 is required for T-loop formation and maintenance of ATM-mediated DDR suppression and repression from non-homologous end joining [11]. While these non-coding hTERT promoter mutations are the most frequent promoter mutations in cancer, the level and frequency varies with cancer types (Table1). Importantly, with direct telomerase inhibitors, if the patient has hematological or any other toxicities (for example, one concern with imetelstat is the development of hematological toxicities requiring drug holidays), then going off treatment for a few weeks would reverse some of the benefits already obtainedthe decision about treatment termination or stopping treatment for a short duration may depend upon the riskbenefit ratio in terms of efficacy and manifested toxicity. 1961;25:585621. In 1994, Jerry Shay and colleagues showed telomerase activity in ~90% of human cancers and cell lines [89], and in 1998 the same team demonstrated that introduction of hTERT (the catalytic protein reverse transcriptase component of telomerase) into normal human cells was sufficient to immortalize cells [90]. 2011;108:2032532. of Genetics, HUJI 2 The Telomerase RNP complex adds short DNA repeats to the end of the chromosome 3 The Telomerase RNP complex adds short DNA repeats to the end of the chromosome 4 The Telomerase RNP complex adds short DNA repeats to the end of the chromosome 5 Rapid fusions of telomeres uncapped by mutant template telomerase RNA. 2006;26:186578. For this reason, some have called telomerase the "immortality enzyme." Nevertheless, the telomeres in cancer cells are generally shorter than telomeres in normal cells. He also demonstrated that human telomeres consisted of the repeated sequence TTAGGG [88]. These three proteins are interconnected by three additional shelterin proteins, TIN2, TPP1 and RAP1, forming a complex that enables the DNA damage response surveillance machinery to distinguish telomere DNA from sites of genomic DNA damage. Although binding of TFs is essential for hTERT transcription, in addition a permissive chromatin microenvironment is required. 1 of 33 Telomerase its role in aging and cancer Feb. 17, 2018 0 likes 6,653 views Download Now Download to read offline Health & Medicine A brief review on Telomerase and its importance in aging and cancer. Recruitment of human telomerase to telomeres in cancer cells: The recruitment of telomerase to telomeres is highly regulated and occurs only after the replication fork remodels protected DNA 3 ends during the S phase of the cell cycle. Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems. Nat Cell Biol. 2). 2014;33:1495505. Koh CM, Khattar E, Leow SC, Liu CY, Muller J, Ang WX, et al. Telomeric DNA contains a variable number of G-rich, non-coding, tandem repeats (1015 kilobases (kb) long in humans at birth) of double-stranded DNA sequence, 5-(TTAGGG) The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Several pathways that regulate telomere length have . Is telomerase a viable target in cancer? Human Telomerase and Its Regulation - PMC - National Center for However, it was then discovered that the use of chick embryo extract to culture these cells was actually re-seeding fetal cells and thus the immortality reported by the Carrel laboratory has been largely discounted. The hTERT promoter core also contains a single TSS that binds the multifunctional transcription factor TFII-I. Hockemeyer D, Collins K. Control of telomerase action at human telomeres. Telomeres and telomerase in oncogenesis (Review) - Spandidos Publications Google Scholar. However, knockdown of ATRX is not sufficient to trigger the ALT pathway in telomerase-positive cell lines or to directly activate ALT in normal somatic cells, implying the existence of other necessary contributing factors involved in activation of ALT in cancer cells [92, 93]. In the cells undergoing replicative senescence, the p53 and p16RB pathways are often activated leading to essentially irreversible growth arrest. Telomerase-specific epitopes can induce CD4+ or CD8+ cytotoxic T-lymphocyte responses or stimulate antigen-presenting cells capable of attacking tumors [71] (Fig. One possible explanation for these observations could be that incipient cancer cells, originating from rapidly self-renewing telomerase-competent cells, do not require TERT promoter mutations to regulate TL maintenance. Targeting telomerase for cancer therapy | Oncogene - Nature How does ATRX/DAXX repress ALT and what is the molecular basis of its activation in cancer cells with wild-type ATRX/DAXX? Article Telomeres and Telomerase in Cancer. Do they have hTERT promoter mutations? Therefore, the rationale for anti-telomerase immunotherapy is to sensitize the immune system to tumor cells expressing hTERT peptides to activate and generate hTERT-specific CD8+ cells to produce enhanced anti-tumor effects. However, a rare clone (1 in 100,000 to 1 in 10 million cells) can progress towards the acquisition of cell immortality [25]. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2-deoxyguanosine. The telomerase recruitment process is likely regulated by as yet unknown signaling pathways. At this point, a mechanism must be engaged to maintain these very short telomeres, and this occurs by either increasing or reactivating telomerase expression, or by acquiring a much rarer telomerase-independent ALT mechanism, thus bypassing crisis and ultimately leading to cell immortalization [26] (Fig. Allory Y, Beukers W, Sagrera A, Flandez M, Marquez M, van der Keur KA, et al. During this treatment period, most tumor cells will continue to grow, which may require the use of other treatment modalities for successful clinical outcomes. 5a). Identification of human TERT elements necessary for telomerase recruitment to telomeres. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Reversible cellular senescence: implications for immortalization of normal human diploid fibroblasts. Article Although hTERT is usually silenced in almost all somatic cells, it is significantly expressed in ~90% of human cancers. 2015;1:14556. Telomeres protect chromosome ends from undergoing fusions and recombination by masking telomeric DNA with shelterin protein protective caps, preventing the ends from being recognized by the DNA damage surveillance pathways. This differential role makes telomerase and its regulatory mechanisms attractive cancer biomarkers with relevant implications in clinical practice [ 3 ]. Why do incipient cancer cells during crisis acquire stem cell-like properties? Telomerase action involves multiple steps including assembly of the telomerase complex, its intracellular trafficking and finally recruitment to telomeres. Morin GB. Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. Rarely, another DNA recombination mechanism termed alternative lengthening of telomeres (ALT) reverses telomere attrition in order to bypass senescence. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. It is still not established whether telomerase expression has any oncogenic characteristics or is simply required for the maintenance of sustained tumor growth (that is, whether it is permissive). Answers to these questions may facilitate development of mechanism-based inhibitors for ALT-positive cancers. PubMed Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Oncotarget. Google Scholar. Jansson LI, Akiyama BM, Ooms A, Lu C, Rubin SM, Stone MD. Science. Mutat Res. By contrast, cancer-initiating cells originating from cells with low self-renewing capability may require TERT promoter mutations to overcome the short-telomere-dependent proliferative barrier. Exploiting the high telomerase of cancer cells to make toxic telomeric DNA. Imetelstat binds to the hTR template region at the hTERT active site with high affinity and blocks its recruitment to telomeric DNA. Telomeres are maintained by telomerase, a multisubunit enzyme comprised of an RNA component, hTR, 2 which provides the template for the synthesis of telomeric repeats and a protein reverse transcriptase component, hTERT, which catalyzes the synthesis reaction (3). 2015;51:96976. Telomerase is not usually active in most somatic cells (cells of the body), but it's active in germ cells (the cells that make sperm and eggs) and some adult stem cells. Telomeres comprise a specialized nucleoprotein-capping structure consisting of DNA and shelterin protein complexes. Bell RJA, Rube HT, Kreig A, Mancini A, Fouse SD, Nagarajan RP, et al. Senescence Crisis and the Hayflick Limit Strong Selection in Cancer [9] Overview of Telomeres and Telomerase Dysfunctional telomeres, arising by critical shortening of telomeres in normal somatic cells during progressive cell divisions, elicit DNA damage responses (DDRs) that trigger cellular senescence. Jafri, M.A., Ansari, S.A., Alqahtani, M.H. WT wild type; WT1 Wilms tumor protein1; MZF2 myeloid zinc finger protein 2. However, many molecular details remain unclear. Telomerase RNA - PowerPoint PPT Presentation - PowerShow.com However, it is not clear what effects targeting shelterin proteins would have on normal cells. Science. In the large majority of cancer cells, telomere length is maintained by telomerase. One working model of human telomerase biogenesis is that dyskerin, pontin and reptin form a scaffold and create an assembly platform for nascent hTR transcripts. Telomere maintenance has been extensively studied, and our understanding of the role of telomerase and ALT in cancer has improved remarkably in recent years. However, the signaling pathways that regulate telomerase recruitment in human cancer cells are not clearly understood. TERRA has been implicated in telomerase regulation, organization of heterochromatin at telomeres, regulation of gene expression, and in DDR triggered by dysfunctional telomeres [19]. They protect genome from Nucleolytic degradation Unnecessary recombination Interchromosomal fusion A small portion of telomeric DNA is lost with each . Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. 2013;126:90715. PubMed Central Additionally, a less frequent hTERT promoter mutation, 57bp upstream from the ATG start site, resulting in an A>C transition, and other less frequent but recurrent mutations in cancer are found on chromosome 5 at the following positions: 1,295,228 C>A; 1,295,2481,295,243 CC>TT; and 1,295,161 A>C [46]. Lee JH, Jeong SA, Khadka P, Hong J, Chung IK. Proc Natl Acad Sci U S A. Several telomerase-based vaccines have been developed, which sensitize immune cells to cancer cells expressing hTERT peptides as surface antigens via the human leukocyte antigen (HLA) class I and class II pathways. TERT promoter mutations in familial and sporadic melanoma. It contains at least five GC boxes (GGGCGG), which are binding sites for the zinc finger transcription factor SP1, and are essential for hTERT promoter activity. Schematic representation of telomeric DNA and components of the shelterin complex. Article Targeting Telomerase for Cancer Therapeutics A dual role of telomere shortening and telomerase activation in tumor initiation and progression. J Cancer Sci Ther. -3, followed by a terminal 3 G-rich single-stranded overhang (150200 nucleotides (nt) long). jshay@mednet.swmed.edu, University of Texas, Southwestern Medical Center . This review focuses on the current knowledge of the dual role of telomeres in cancer and suggests a new perspective to reconcile the paradox of telomeres and their implications in cancer etiology. Imetelstat is a competitive telomerase template antagonist (not antisense that targets mRNA). Furthermore, telomerase activity in differentiated fibroblasts carrying hTERT promoter mutations was comparable to that observed in cancer cell lines. Inhibition of TERT RNA-binding domain (tTRBD): TERT protein binds to the template boundary element of TR (TERC), crucial for the recognition of the precise telomere sequence to be reverse transcribed by TERT [99]. Microbiol Mol Biol Rev. J Biol Chem. Genes Dev. PubMed Central Additionally, mice treated with 6-thio-dG at effective doses for a month did not show any hematological, hepatic or renal side effects. The recruitment of telomerase to telomeres occurs only after the replication fork remodels the protected DNA 3 ends during the S phase of the cell cycle. In tumors, however, telomerase is active and may be required for the growth of cancer cells. Proc Natl Acad Sci U S A. However, the mechanisms governing hTERT expression in cancer remain incompletely understood. Cell death during crisis is mediated by mitotic telomere deprotection. Telomerase. Telomerase holoenzyme assembly: Although there has recently been progress on determining the yeast and ciliate telomerase structure, the processes of assembly and function of telomerase in human cancer cells remain poorly understood. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 2015;522:4926. PPT - Telomeres and Telomerase PowerPoint Presentation, free download During anaphase, the sister chromatids are drawn apart owing to movement towards opposite poles, resulting in the formation of uneven derivative chromosomes, leading to genomic instability. Imetelstat is a competitive inhibitor of telomerase activity, and was developed for the intravenous treatment of various cancers. In the presence of cancer-initiating changes, M1 can be bypassed, providing an extended cell division period. Telomerase is a reverse transcriptase that consists of a catalytic protein subunit called telomerase reverse transcriptase (TERT), encoded by the hTERT gene in humans that is positioned at chromosome 5p15.33, and an essential RNA component known as human telomerase RNA (hTR) or human telomerase RNA component (hTERC), encoded by the hTERC gene found on chromosomal region 3q26. Google Scholar. In humans, telomerase enzyme activity is absent in most normal cells but present . The 3 G-rich overhang facilitates telomeric DNA in forming a higher-order structure in which the 3 single-stranded overhang folds back and invades the homologous double-stranded TTAGGG region, forming a telomeric loop (T-loop) that provides 3-end protection by sequestering it from recognition by the DDR machinery [10]. These are cell types that need to undergo many divisions, or, in the case of germ cells, give rise to a new organism with its telomeric "clock" reset 5 ^5 5 start . Binding of imetelstat to hTR results in telomerase inhibition leading to progressively shortened telomeres. These cells have telomerase reactivated, allowing them to maintain telomere length. Telomerase-based therapeutic cancer vaccines (TCVs) have been under clinical investigation for the past two decades. Next, hTR removes NAF1 and attaches GAR1, leading to the formation of a physiologically stable hTR-H/ACA-RNP complex. Imetelstat has been extensively evaluated for its activity and efficacy against multiple cancer cell lines and in mouse xenograft models in preclinical studies. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized. However, the molecular mechanisms of telomerase activation by ETS are not clearly understood. Telomere shortening requires a series of cell division cycles to become apparent, and treatment may have to be given continuously for months to induce therapeutically relevant tumor reduction effects. Greider CW, Blackburn EH. 2012;7:e50062. Mender and colleagues [79] have recently demonstrated that, in telomerase-positive cells, 6-thio-2-deoxyguanosine (6-thio-dG), a nucleoside analogue of 6-thioguanine (an approved drug), is recognized by telomerase and incorporated into telomeres. Oncogenesis. Vinagre J, Pinto V, Celestino R, Reis M, Populo H, Boaventura P, et al. Telomerase has been a prime target for the development of effective therapeutics against cancer as it is expressed in the majority of cancer types as well as in cancer stem or stem-like cells. Additionally, development of G-quadruplex stabilizers, tankyrase (which has an important role in telomere homeostasis, mitotic spindle formation and WNT/-catenin signaling) inhibitors and HSP90 (involved in signal transduction, intracellular transport and protein degradation) inhibitors targeting telomere and telomerase assembly, and T-oligo (DNA oligonucleotide homologous to the telomere 3 overhang region, which causes cytotoxic effects by inducing DDR) have also been explored to selectively kill cancer cells [59]. Imetelstat does not behave like a typical antisense oligonucleotide as it does not bind to mRNA to inactivate it; rather its sequence (5-palmitate-TAGGGTTAGACAA-NH2-3) binds to a complementary 13-nucleotide region of hTR that has high affinity and specificity at the active site of the telomerase holoenzyme, thus leading to complete inhibition of enzyme activity (Fig. The genetic abrogation of TRF1 leads to a marked reduction in lung carcinoma tumor growth in the K-Ras Telomerase - SlideShare statement and

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