Collectively, shelterin and other telomere-binding proteins act as critical mediators to combat the end-replication and end-protection problems, thereby orchestrating the events that govern telomere homeostasis. Moreover, telomere lengths in tumors and surrogate tissues may be employed to predict patient survival [180], as well as to assess patient response to therapy [181]. Telomeres act as caps that protect the internal regions of the chromosomes, and they're worn down a small amount in each round of DNA replication. Haendeler J., Drose S., Buchner N., Jakob S., Altschmied J., Goy C., Spyridopoulos I., Zeiher A.M., Brandt U., Dimmeler S. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Barthel F.P., Wei W., Tang M., Martinez-Ledesma E., Hu X., Amin S.B., Akdemir K.C., Seth S., Song X., Wang Q., et al. Indeed, in clinical trials involving multiple cancer types, patients achieved an immunologic response [206], with further analyses revealing putative disease stabilization and increased disease-free survival [213,214,215]. Patente T.A., Pinho M.P., Oliveira A.A., Evangelista G.C.M., Bergami-Santos P.C., Barbuto J.A.M. ({"type":"entrez-nucleotide","attrs":{"text":"CA236273","term_id":"35305639","term_text":"CA236273"}}CA236273) and N.J.R. Gonzalo S., Garcia-Cao M., Fraga M.F., Schotta G., Peters A.H., Cotter S.E., Eguia R., Dean D.C., Esteller M., Jenuwein T., et al. Akiyama M., Hideshima T., Hayashi T., Tai Y.T., Mitsiades C.S., Mitsiades N., Chauhan D., Richardson P., Munshi N.C., Anderson K.C. Saretzki G. Extra-telomeric functions of human telomerase: Cancer, mitochondria and oxidative stress. Elucidation of the DNA end-replication problem in Saccharomyces cerevisiae. Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1. Zhang C., Chen X., Li L., Zhou Y., Wang C., Hou S. The Association between Telomere Length and Cancer Prognosis: Evidence from a Meta-Analysis. Telomerase inhibition by stable RNA interference impairs tumor growth and angiogenesis in glioblastoma xenografts. Li J.S., Miralles Fuste J., Simavorian T., Bartocci C., Tsai J., Karlseder J., Lazzerini Denchi E. TZAP: A telomere-associated protein involved in telomere length control. Intriguingly, given the presence of histone proteins in the telomerase holoenzyme structure [49], histone modification may play an as-yet-unexplored role in telomerase regulation at the post-translational level as well. Hamma T., Ferre-DAmare A.R. In the absence of de-adenylation, TR intermediates initially accumulate and are subsequently degraded within RNA exosomes [122], resulting in reduced telomerase activity. Wu Z., Liu J., Zhang Q.D., Lv D.K., Wu N.F., Zhou J.Q. Too much telomerase can help confer . Wu P., van Overbeek M., Rooney S., de Lange T. Apollo contributes to G overhang maintenance and protects leading-end telomeres. Given that telomerase-mediated telomere elongation is important for the infinite proliferation of TERT-positive cancer cells, genetic or pharmacological inhibition of telomerase activity in cancer cells induces gradual shortening of telomeres and eventual cell senescence or apoptosis [109,110,111]. Cells undergoing malignant transformation must circumvent replicative senescence and eventual cell death associated with progressive telomere shortening that occurs through successive cell division. Extratelomeric functions of TERT. (T32 GM007250 and F30 CA213892). A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. sharing sensitive information, make sure youre on a federal Tools Versions Telomerase is commonly expressed in human cancer cells. Cook B.D., Dynek J.N., Chang W., Shostak G., Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Active and Passive Destabilization of G-Quadruplex DNA by the Telomere POT1-TPP1 Complex. Thus, TR harbors many of the same extratelomeric functions as TERT, but the mechanisms underlying these functions may be distinct and complementary. Lenain C., Bauwens S., Amiard S., Brunori M., Giraud-Panis M.J., Gilson E. The Apollo 5 exonuclease functions together with TRF2 to protect telomeres from DNA repair. J. In addition, TERRA has been shown to form DNA-RNA hybrid structures, known as R-loops, at telomeres [111]. Mitochondrial Telomerase Reverse Transcriptase Protects From Myocardial Ischemia/Reperfusion Injury by Improving Complex I Composition and Function. This dismal statistic has increased efforts to prevent the disease or to detect it early, when treatment is less invasive, relatively . The first part is a protein called TERT that does the . An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity. Yi X., Tesmer V.M., Savre-Train I., Shay J.W., Wright W.E. Kroupa M., Rachakonda S.K., Liska V., Srinivas N., Urbanova M., Jiraskova K., Schneiderova M., Vycital O., Vymetalkova V., Vodickova L., et al. Robinson N.J., Miyagi M., Scarborough J.A., Scott J.G., Taylor D.J., Schiemann W.P. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Taken together, these findings underscore the ability of TERT to function within a transcriptional nexus controlled by numerous oncogenic signaling inputs. Nava-Parada P., Emens L.A. GV-1001, an injectable telomerase peptide vaccine for the treatment of solid cancers. Azzalin C.M., Reichenbach P., Khoriauli L., Giulotto E., Lingner J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Regulating telomere length from the inside out: The replication fork model. Likewise, TERT expression can be indirectly influenced by miRNAs through alterations in the abundance of TERT transcriptional regulators [106]. TERT peptide vaccines, including GV1001 [207], GX301 [208], and Vx-001 [209], are displayed on the surface of antigen-presenting cells, which express major histocompatibility complex class II (MHCII) proteins that are responsible for coordinating robust, antigen-specific cell-mediated and humoral immune responses through the activation of CD4+ T cells and B cells, respectively. Denchi E.L., de Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Importantly, these mechanisms also play a central role in TR processing and function (Figure 2). Qin Y., Tang B., Hu C.J., Xiao Y.F., Xie R., Yong X., Wu Y.Y., Dong H., Yang S.M. In spite of the mechanistic insights gained through molecular interrogations of telomerase, much work remains to translate these insights into clinical action. Yuan X., Larsson C., Xu D. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: Old actors and new players. Ghosh A., Saginc G., Leow S.C., Khattar E., Shin E.M., Yan T.D., Wong M., Zhang Z., Li G., Sung W.K., et al. In human somatic cells proliferation potential is strictly limited and senescence follows approximately 50-70 cell divisions. Pathol. Rice C., Shastrula P.K., Kossenkov A.V., Hills R., Baird D.M., Showe L.C., Doukov T., Janicki S., Skordalakes E. Structural and functional analysis of the human POT1-TPP1 telomeric complex. They are maintained by an enzyme called telomerase in the vast majority of tumors. Non-canonical NF-kappaB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Regulation of telomerase expression, assembly, and function occur at all levels of gene expression and is governed by a range of intracellular and environmental stimuli that share substantial overlap with pathways that control malignant transformation and tumor progression. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. In higher eukaryotes, somatic cells undergo a finite number of divisions before entering senescence and ultimately undergoing apoptosis, thereby preventing the generation and accumulation of pathologic genetic anomalies [1]. Nevertheless, the determination of telomere homeostatic mechanisms in individual tumors presents a promising avenue for improved cancer diagnosis, prognosis, and therapy. Importantly, the presence of specific TMMs and their underlying genomic aberrations may presage potential therapeutic vulnerabilities. Theoretically, the anticancer effect of . Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Fed. Telomere maintenance in telomerase-positive human ovarian SKOV-3 cells cannot be retarded by complete inhibition of telomerase. Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. What does this mean? Lorbeer F.K., Hockemeyer D. TERT promoter mutations and telomeres during tumorigenesis. 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. Abstract. Go to: Abstract The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. The box H/ACA ribonucleoprotein complex: Interplay of RNA and protein structures in post-transcriptional RNA modification. Fenoglio D., Parodi A., Lavieri R., Kalli F., Ferrera F., Tagliamacco A., Guastalla A., Lamperti M.G., Giacomini M., Filaci G. Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one. For instance, NF-B functions broadly during malignant transformation, tumor progression, and modulation of the tumor immune milieu; it also directly stimulates TERT expression [67,72] and upregulates c-Myc, thereby potentiating the transcriptional effects of c-Myc on TERT [66]. Notably, telomere homeostatic factors act cooperatively with DDR proteins to bypass apoptosis secondary to telomere crisis, such that many cancers exhibit telomeres that are stably maintained close to their critical length [57,58]. First, TERT mRNA is subject to extensive alternative splicing, with the functions of many of these splice variants remaining to be elucidated [100]. Thus, genomic instability can be viewed as a wellspring for many of the remaining cancer hallmarks, with the attainment of replicative immortality serving as a necessary condition for the propagation of tumor-promoting genomic aberrations. On the other hand, DC vaccines introduce a concentrated population of dendritic cells that have been engineered to express, process, and present specific tumor-associated antigens. This process ensures to limit proliferation of somatic cells to avoid malignant proliferation; however, it leads to proliferative senescence. The abundance of these components and their ability to be assembled into telomerase holoenzyme units significantly impacts telomere homeostasis and the acquisition of cancer phenotypes. An hTERT/ZEB1 complex directly regulates E-cadherin to promote epithelial-to-mesenchymal transition (EMT) in colorectal cancer. Structure of human telomerase holoenzyme with bound telomeric DNA. The https:// ensures that you are connecting to the Mahmoudi S., Henriksson S., Weibrecht I., Smith S., Soderberg O., Stromblad S., Wiman K.G., Farnebo M. WRAP53 is essential for Cajal body formation and for targeting the survival of motor neuron complex to Cajal bodies. Sotillo-Pineiro E., Sierrasesumaga L., Patinno-Garcia A. Telomerase activity and telomere length in primary and metastatic tumors from pediatric bone cancer patients. Hiyama E., Tatsumoto N., Kodama T., Hiyama K., Shay J., Yokoyama T. Telomerase activity in human intestine. Beneke S., Cohausz O., Malanga M., Boukamp P., Althaus F., Burkle A. Relatedly, the TERT promoter undergoes extensive DNA methylation, which quite paradoxically stimulates gene expression. The mechanisms that dictate TERT expression are reminiscent of those that regulate TR, with TR undergoing additional post-transcriptional processing as well (Figure 2) [115]. Roake C.M., Chen L., Chakravarthy A.L., Ferrell J.E., Jr., Raffa G.D., Artandi S.E. These include enzymes that modify both DNA and histones with an assortment of chemical moieties (Figure 1). Ding D., Xi P., Zhou J., Wang M., Cong Y.S. Clin. ; supervision, W.P.S. Conversely, effectors that diminish TERT expression, which include several important tumor suppressors, become dysregulated in cancer cells as a means of de-repressing telomerase activity. Stampfer M.R., Garbe J., Levine G., Lichtsteiner S., Vasserot A.P., Yaswen P. Expression of the telomerase catalytic subunit, hTERT, induces resistance to transforming growth factor beta growth inhibition in p16INK4A(-) human mammary epithelial cells. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, telomeres, telomerase, TERT, TR, extratelomeric, targeted therapy, treatment resistance, {"type":"entrez-nucleotide","attrs":{"text":"CA236273","term_id":"35305639","term_text":"CA236273"}}. Inhibition of telomerase induces alternative lengthening of telomeres during human esophageal carcinogenesis. Liu Z., Li Q., Li K., Chen L., Li W., Hou M., Liu T., Yang J., Lindvall C., Bjorkholm M., et al. https://creativecommons.org/licenses/by/4.0/. Conceptualization, N.J.R. Telomere length maintenance in stem cell populations. Watson J.D. Griffith J.K., Bryant J.E., Fordyce C.A., Gilliland F.D., Joste N.E., Moyzis R.K. Vannier J.B., Pavicic-Kaltenbrunner V., Petalcorin M.I., Ding H., Boulton S.J. Arora R., Lee Y., Wischnewski H., Brun C.M., Schwarz T., Azzalin C.M. TERRA recruitment of polycomb to telomeres is essential for histone trymethylation marks at telomeric heterochromatin. Nascent linear chromosomes, however, have created many additional challenges. Telomerase is a ribonucleoprotein complex, which is made of a reverse transcriptase enzyme subunit and a long non-coding RNA which contains the template sequence for telomere synthesis. Telomerase, also called terminal transferase, [1] is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. Porporato P.E., Filigheddu N., Pedro J.M.B., Kroemer G., Galluzzi L. Mitochondrial metabolism and cancer. Avin B.A., Umbricht C.B., Zeiger M.A. Additional support was graciously provided by the Case Comprehensive Cancer Centers Research Innovation Fund, which is supported by the Case Council and Friends of the Case Comprehensive Cancer Center (to W.P.S.). J. U. S. Can. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Assoc. FASEB J. Ale-Agha N., Jakobs P., Goy C., Zurek M., Rosen J., Dyballa-Rukes N., Metzger S., Greulich J., von Ameln F., Eckermann O., et al. Importantly, mitochondrial function is reliant upon the expression and subcellular localization of TERT, which shields the mitochondrial genome from damage and buffers cells against oxidative stress (Figure 3; [154,155]). George J., Banik N.L., Ray S.K. These structures may play a dual role in blocking telomerase by (i) recruiting histone-modifying enzymes that induce telomeric heterochromatin [112], which can attenuate extension by telomerase [113]; and (ii) promoting telomere extension by homologous recombination (i.e., ALT) [114]. Normal human chromosomes have long G-rich telomeric overhangs at one end. Thalmensi J., Pliquet E., Liard C., Escande M., Bestetti T., Julithe M., Kostrzak A., Pailhes-Jimenez A.S., Bourges E., Loustau M., et al. By reverse transcription, the telomerase RNP maintains telomere length stability in almost all cancer cells. Chow T.T., Shi X., Wei J.H., Guan J., Stadler G., Huang B., Blackburn E.H. Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection. Li Y., Zhou Q.L., Sun W., Chandrasekharan P., Cheng H.S., Ying Z., Lakshmanan M., Raju A., Tenen D.G., Cheng S.Y., et al. Seimiya H., Muramatsu Y., Ohishi T., Tsuruo T. Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics. Indran I.R., Hande M.P., Pervaiz S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Lilleby W., Gaudernack G., Brunsvig P.F., Vlatkovic L., Schulz M., Mills K., Hole K.H., Inderberg E.M. Xu D., Popov N., Hou M., Wang Q., Bjorkholm M., Gruber A., Menkel A.R., Henriksson M. Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. TERT plays a key role in cancer formation, ensuring chromosomal stability by maintaining telomere length, and allowing cells to avert senescence. Teixeira L., Medioni J., Garibal J., Adotevi O., Doucet L., Durey M.D., Ghrieb Z., Kiladjian J.J., Brizard M., Laheurte C., et al. Accordingly, telomerase recruitment and processivity are dictated by the presence of specific telomere-binding proteinsnamely, the shelterin components POT1 [131,132], TPP1 [133], and TIN2 [134], and by the resolution of higher-order telomere DNA structures through differential protein binding [135,136] or post-translational modification [137]. This metabolic derangement of cell bioenergetics is mediated by altered mitochondrial function, which impacts cancer cell redox homeostasis, intracellular signaling, and survival [153]. Greider C.W. Middleton G., Silcocks P., Cox T., Valle J., Wadsley J., Propper D., Coxon F., Ross P., Madhusudan S., Roques T., et al. Wang F., Podell E.R., Zaug A.J., Yang Y., Baciu P., Cech T.R., Lei M. The POT1-TPP1 telomere complex is a telomerase processivity factor. Importantly, this approach has a distinct advantage over traditional pharmacologic inhibition of telomerase in that therapy-induced cell death occurs much faster, thereby minimizing the risk of developing resistance. However, given that TERT frequently operates within transcriptional feedback loops, it is conceivable that signals that activate these loops simultaneously promote the extratelomeric functions of TERT. TERT is expressed as multiple alternatively spliced isoforms, most notably the catalytically inactive - and - variants. Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion. Queisser A., Heeg S., Thaler M., von Werder A., Opitz O.G. Specifically, NME2 recruits the RE1-silencing transcription factor (REST)lysine-specific histone demethylase 1 (LSD1) co-repressor complex to the TERT promoter, where it erases activating methyl marks on histones to transcriptionally silence TERT [97]. Dilley R.L., Verma P., Cho N.W., Winters H.D., Wondisford A.R., Greenberg R.A. Break-induced telomere synthesis underlies alternative telomere maintenance. Telomeres are nucleoprotein structures composed of tandem DNA repeats ((TTAGGG)n, average length of ~10 kb [16] in humans) and a core six-member protein complex known as shelterin [17,18]. Of note, aberrant overexpression from the mutant TERT promoter is further enhanced by the upregulation of several ETS TFs through mitogen-activated protein kinase (MAPK) signaling [87,88]. de Lange T. Shelterin-Mediated Telomere Protection. More recently, the effectiveness of telomerase DNA vaccines has been examined [218,219], as has the feasibility of adoptive transfer of anti-telomerase chimeric antigen receptor (CAR) T cells [220]. Oh B.K., Kim H., Park Y.N., Yoo J.E., Choi J., Kim K.S., Lee J.J., Park C. High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis. Moreover, TR can also be trafficked into mitochondria, where it is nucleolytically processed and re-exported into the cytosol [174]. In contrast, the existence and nature of extratelomeric functions for TR are not well-understood but are beginning to be uncovered. Venteicher A.S., Abreu E.B., Meng Z., McCann K.E., Terns R.M., Veenstra T.D., Terns M.P., Artandi S.E. Nair S.K., Heiser A., Boczkowski D., Majumdar A., Naoe M., Lebkowski J.S., Vieweg J., Gilboa E. Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. In line with this, TERT binds to the VEGF promoter [139] and functions as a downstream effector of VEGF signaling [140], while inhibition of telomerase abrogates VEGF expression and angiogenesis [141,142]. Kyo S., Takakura M., Taira T., Kanaya T., Itoh H., Yutsudo M., Ariga H., Inoue M. Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT), Beishline K., Azizkhan-Clifford J. Sp1 and the hallmarks of cancer. 190 Citations 10 Altmetric Metrics Abstract Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres,. In addition, TR undergoes addition and removal of a 5 cap (represented by the yellow G) and 3 oligo-adenosine tail (represented by the green A sequence), whose presence or absence dictate TR stability and dramatically influence telomerase function. The enzyme has recently been found in many human tumors. Typically, cognate miRNAs bind the TERT 3-UTR to suppress its expression via RNA degradation or repression of translation. In addition to the core TERT:TR dimer, telomerase is composed of (i) the dyskerin-NOP10-NHP2-GAR1 tetramer (also known as the H/ACA RNP complex) that functions in telomerase RNP biogenesis [61]; (ii) TCAB1, which recruits the telomerase core to subnuclear Cajal bodies (CBs) for further processing by the H/ACA complex [62]; and (iii) the histone proteins H2A and H2B, which stabilize a critical TERT-interacting domain in TR during holoenzyme assembly [49]. As noted above, telomere crisis is a necessary step not only in TMM reactivation and tumorigenesis, but also in the acquisition of metastatic phenotypes [198,199]. The site is secure. Ohira T., Naohiro S., Nakayama Y., Osaki M., Okada F., Oshimura M., Kugoh H. miR-19b regulates hTERT mRNA expression through targeting PITX1 mRNA in melanoma cells. Hiyama K., Hirai Y., Kyoizumi S., Akiyama M., Hiyama E., Piatyszek M.A., Shay J.W., Ishioka S., Yamakido M. Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. The most well-characterized of these is the Myc/Max/Mad1 family of TFs, which bind to specific sequences in the TERT promoter and coordinate the recruitment of additional TFs and chromatin-modifying enzymes that modulate TERT promoter accessibility and gene expression [70,71]. Treatment involves a combination of surgery, chemotherapy, and radiation therapy. In fact, increasing telomerase levels ought to lengthen telomeres but in the case of cancer, too much telomerase can be just as bad as too little telomeres. Zeng X., Hernandez-Sanchez W., Xu M., Whited T.L., Baus D., Zhang J., Berdis A.J., Taylor D.J. It's unclear. Soc. 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. Telomeres are exquisitely complex structures whose composition and length are dynamically organized by a host of factors, notably the core and accessory components of telomerase. Gazzaniga F.S., Blackburn E.H. An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity. Conversely, TERT expression is reciprocally regulated by -catenin [146], which may sustain a positive feedback loop between Wnt signaling and TERT transcriptional activity. Careers, Unable to load your collection due to an error. Liu R., Zhang T., Zhu G., Xing M. Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer. When a cell starts to make telomerase when it shouldn't, bad things like cancer can happen. In addition to telomere length, TMM identity can be directly assayed in individual tumors and associated with pathologic and clinical features, including survival and metastasis [182,183]. Indeed, studies examining the relationship between telomerase activity and transcriptomic alterations in cancer cells have revealed a host of genes whose transcription appears to be directly overseen by TERT, including EGFR and VEGF [12,138]. Rennoll S., Yochum G. Regulation of MYC gene expression by aberrant Wnt/beta-catenin signaling in colorectal cancer. Causes Cancer is caused by changes (mutations) to the DNA within cells. Recent work has confirmed these observations in both solid and hematopoietic cancers , leading to the proposal that telomerase expression may prove to be an important diagnostic tool as well as a novel target for cancer therapy. In vivo inhibition of lung cancer by GRN163L: A novel human telomerase inhibitor. As we get older, our blood stem cells slow down because their telomeres are too short. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. The DNA inside a cell is packaged into a large number of individual genes, each of which contains a set of instructions telling the cell what functions to perform, as well as how to grow and divide. While the identity of TERT transcriptional regulators can be highly cancer-specific [69], there exists a set of shared TFs that serve to influence TERT expression across numerous cancer types. Similarly, Wnt ligands released within the tumor microenvironment [151] may drive TERT expression without compensatory upregulation of other telomerase components [146]. and W.P.S. Exp. Zhang X., Gaspard J.P., Chung D.C. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Consequently, aberrant telomere homeostasis imparts cells with replicative immortality [5]. Drugs that inhibit telomerase activity, or kill telomerase-producing cells, may potentially stop and kill cancer cells in their tracks. Yin L., Hubbard A.K., Giardina C. NF-kappa B regulates transcription of the mouse telomerase catalytic subunit. Naturally, in somatic cells chromosome ends (telomeres) shorten during each cell division. In contrast, TR is synthesized as a pool of alternative transcripts (represented in blue, green, and purple). Future studies need to examine whether, and by what means, accessory proteins function as regulatory nodes for telomerase biogenesis in a manner akin to TERT and TR. The authors declare no conflict of interest. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy. Coupled with the presence of histone proteins in the telomerase holoenzyme, these findings emphasize the critical functional diversity of all of the telomerase accessory components. For example, two members of the H/ACA RNP complex, dyskerin and GAR1, are post-translationally modified by PARP1, an event that may promote telomerase assembly and activity [125,126]. The mechanism for this is incompletely understood but may involve blocking CTCF recruitment secondary to methylation of CG-rich DNA sequences in the TERT promoter [92,99]. Importantly, the functional versatility of telomeres is determined by their structural dynamics and the regulatory mechanisms that exist to maintain them. In a similar vein, telomere destabilization can be accomplished by introducing mutant-template TR, which causes misincorporation during telomere DNA synthesis that results in cell death or increased sensitivity to other anti-cancer agents [204,205]. Telomerase activity in human germline and embryonic tissues and cells. Telomerase contains the reverse transcriptase TERT, which together with the TERC component, is responsible for protection of genome integrity by preventing . Indeed, upregulation of TR during tumorigenesis can occur in the absence of increased telomerase activity [171], suggesting that TR possesses telomerase-independent functions in cancer cells (Figure 3). Collectively, the covalent modification of DNA and histones exerts powerful control over the set of TFs bound at the TERT genomic locus, which in turn dictates TERT expression and telomerase function. Introduction. Off. Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. Shukla S., Schmidt J.C., Goldfarb K.C., Cech T.R., Parker R. Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects. To date, these trials have revealed modest benefit over standard-of-care, although a handful of trials have demonstrated a potential telomere length-dependent therapeutic effect [194], an effect that is likely attributable to the inherently complex relationship between telomere length and tumor progression.

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