Stem cells, immortality, and the evolution of metastatic properties in breast cancer: Telomere maintenance mechanisms and metastatic evolution. In addition to endowing transformed cells with replicative immortality, telomerase also regulates multiple processes of tumor formation and progression by acting as a TF (Figure 3). In addition, telomerase possesses a host of extratelomeric (i.e., telomere-independent) functions that influence telomere homeostasis, as well as signal transduction, cellular energetics, and transcriptional regulation of gene expression [60]. ({"type":"entrez-nucleotide","attrs":{"text":"CA236273","term_id":"35305639","term_text":"CA236273"}}CA236273) and N.J.R. 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. The makings of TERRA R-loops at chromosome ends. Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. 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]. 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. Relatedly, the presence of mutations, rearrangements, or duplications that hyperactivate telomerase are pathognomonic in numerous cancers, where they upregulate TERT through a variety of genetic and epigenetic mechanisms [187,188]. Teixeira L., Medioni J., Garibal J., Adotevi O., Doucet L., Durey M.D., Ghrieb Z., Kiladjian J.J., Brizard M., Laheurte C., et al. FOIA Watson J.D. Gallicchio L., Gadalla S.M., Murphy J.D., Simonds N.I. In preclinical [211] and clinical studies [212], TERT DC vaccines stimulated cytotoxic T cell responses and induced immune memory. Similar approaches can be employed to quantify TERRA expression, whose decreased expression is associated with poor survival and increased progression to metastasis across multiple cancer types [184,185,186]. It also maintains the genomic integrity and chromosomal stability. HHS Vulnerability Disclosure, Help In addition to transcription, TERT abundance is heavily influenced by post-transcriptional regulatory mechanisms. Telomeres buffer against the loss of genetic information during DNA replication and cell division by serving as a medium for genomic attrition. Constitutive activation of STAT3 signaling regulates hTERT and promotes stem cell-like traits in human breast cancer cells. 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]. Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. These changes are mediated in part by the induction of replicative immortality that is accompanied by active telomere elongation. Tools Versions Telomerase is commonly expressed in human cancer cells. Go to: Abstract There is mounting evidence for the existence of an important relationship between telomeres and telomerase and cellular aging and cancer. Soudet J., Jolivet P., Teixeira M.T. Gazzaniga F.S., Blackburn E.H. An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity. 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. Finally, we examine how these mechanistic insights can facilitate the development of telomere-directed cancer therapies. Means to the ends: The role of telomeres and telomere processing machinery in metastasis. Importantly, these mechanisms also play a central role in TR processing and function (Figure 2). Typically, cognate miRNAs bind the TERT 3-UTR to suppress its expression via RNA degradation or repression of translation. Furthermore, TERT is capable of binding to mitochondrial DNA (mtDNA) and maintaining genome integrity under oxidative stress, in part by shielding mtDNA from oxidative damage [154] as well as alleviating reactive oxygen species (ROS) production through upregulation of superoxide dismutase [158] and components of the electron transport chain [159]. Both transcriptional and posttranscriptional mechanisms regulate human telomerase template RNA levels. Effect of pseudouridylation on the structure and activity of the catalytically essential P6.1 hairpin in human telomerase RNA. A First-in-Human Phase I Study of INVAC-1, an Optimized Human Telomerase DNA Vaccine in Patients with Advanced Solid Tumors. 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. Thus, it is conceivable that expression of these factors is less stringently regulated than TERT and TR, or alternatively, that the mechanisms governing the expression of these factors is disjoint from those overseeing TERT and TR. Palm W., Hockemeyer D., Kibe T., de Lange T. Functional dissection of human and mouse POT1 proteins. The enzyme has recently been found in many human tumors. High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells. 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]. The multifaceted nature of telomerase recruitment and catalytic activity can be viewed as a series of bifurcation points, at which the constituents of telomerase can either (i) assemble sequentially into active holoenzyme units, (ii) adopt and execute alternative functions via recruitment to other genomic loci, or (iii) form complexes with discrete binding partners throughout the cell. Both TERT and TR undergo substantial post-transcriptional processing that is required for telomerase maturation and activity. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Importantly, multiple clinical trials have revealed that these vaccines are generally safe and well-tolerated; they also yield survival benefits for patients across a host of tumor types that correlate with the strength of antitumor immune responses [206]. Kar A., Saha D., Purohit G., Singh A., Kumar P., Yadav V.K., Kumar P., Thakur R.K., Chowdhury S. Metastases suppressor NME2 associates with telomere ends and telomerase and reduces telomerase activity within cells. The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Hamma T., Ferre-DAmare A.R. Bermudez Y., Yang H., Cheng J.Q., Kruk P.A. Biol. 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. These include (i) alternative telomere dsDNA-binding proteins, such as TERB1/TERB2 [32] and TZAP, which preferentially binds to long telomeres and institutes an upper limit to telomere length via initiation of telomere trimming [33]; (ii) proteins involved in modulating DDRs, including the exonuclease Apollo, which processes telomere overhangs and prevents aberrant recombination-based DNA repair [34,35]; NBS1 and Ku70/Ku80, which collectively sense DSBs and coordinate end-resection and diminution of DSB repair at telomeres [24,36]; and the structure-specific endonuclease scaffold SLX4 together with its associated nucleases [37]; (iii) proteins that exert temporal control and impart strand specificity during telomere replication, namely the CTC1-STN1-TEN1 (CST) and DNA polymerase -DNA primase (pol -primase) complexes [38], as well as the DNA helicase RTEL1 [39]; and (iv) the poly(ADP-ribose) polymerase (PARP) homologs tankyrase 1 and tankyrase 2, which promote telomere maintenance by modifying TRF1 and liberating it from telomeres [40,41]. Cytokines modulate telomerase activity in a human multiple myeloma cell line. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. McClintock B. Hastie N.D., Dempster M., Dunlop M.G., Thompson A.M., Green D.K., Allshire R.C. TFs shown above and below the chromosome (rectangle) have binding motifs located on overlapping segment of the TERT promoter, rather than binding in opposing orientations. Avin B.A., Umbricht C.B., Zeiger M.A. Guilleret I., Yan P., Grange F., Braunschweig R., Bosman F.T., Benhattar J. Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity. In addition, TERT binds to the promoters of genes that encode key growth factors (EGF, VEGF), as well as secondary effectors of tumor-promoting signaling pathways (Wnt, NF-B, TGF-), thereby positively or negatively regulating their expression. 3 terminal diversity of MRP RNA and other human noncoding RNAs revealed by deep sequencing. PARP1 Regulates the Biogenesis and Activity of Telomerase Complex Through Modification of H/ACA-Proteins. Qin Y., Tang B., Hu C.J., Xiao Y.F., Xie R., Yong X., Wu Y.Y., Dong H., Yang S.M. (A) TERT transcription is mediated by the coordinated actions of myriad intracellular signaling pathways that are initiated by specific ligands (e.g., growth factors, cytokines). Telomerase, a eukaryotic ribonucleoprotein (RNP) complex, contains both an essential RNA and a protein reverse transcriptase subunit. Venteicher A.S., Abreu E.B., Meng Z., McCann K.E., Terns R.M., Veenstra T.D., Terns M.P., Artandi S.E. Sharma S., Mukherjee A.K., Roy S.S., Bagri S., Lier S., Verma M., Sengupta A., Kumar M., Nesse G., Pandey D.P., et al. 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. This process has long been viewed as an unwanted side-effect of aging, but a recent study shows it is in fact good for you. Inhibition of telomerase induces alternative lengthening of telomeres during human esophageal carcinogenesis. Baudino T.A., McKay C., Pendeville-Samain H., Nilsson J.A., Maclean K.H., White E.L., Davis A.C., Ihle J.N., Cleveland J.L. 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). Sfeir A., Kosiyatrakul S.T., Hockemeyer D., MacRae S.L., Karlseder J., Schildkraut C.L., de Lange T. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. TERT is expressed as multiple alternatively spliced isoforms, most notably the catalytically inactive - and - variants. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. Listerman I., Sun J., Gazzaniga F.S., Lukas J.L., Blackburn E.H. It's unclear. Telomeres, repetitive (TTAGGG) DNA-protein complexes at the ends of chromosomes, are crucial for the survival of cancer cells. Saha D., Singh A., Hussain T., Srivastava V., Sengupta S., Kar A., Dhapola P., Dhople V., Ummanni R., Chowdhury S. Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex-dependent fashion. SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Telomere lengthening early in development. Introduction. Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer. An hTERT/ZEB1 complex directly regulates E-cadherin to promote epithelial-to-mesenchymal transition (EMT) in colorectal cancer. Pathol. Lamb R., Ozsvari B., Bonuccelli G., Smith D.L., Pestell R.G., Martinez-Outschoorn U.E., Clarke R.B., Sotgia F., Lisanti M.P. Telomerase can be viewed as a tumor-associated neoantigen that, when leveraged therapeutically, may elicit potent anti-tumor immune responses. Soc. Notably, this transcriptional function of NME2 is augmented by its direct association with the telomerase holoenzyme and inhibition of telomerase activity [98]. ; figure preparation, N.J.R. Human telomerase and its regulation. 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. Moreover, c-Myc sits at the convergence of multiple signaling pathways, which allows for fine-tuning of TERT expression and telomerase activity in response to specific cellular and environmental cues. 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. Lorbeer F.K., Hockemeyer D. TERT promoter mutations and telomeres during tumorigenesis. Zhang X.L., Xu L.L., Wang F. Hsa_circ_0020397 regulates colorectal cancer cell viability, apoptosis and invasion by promoting the expression of the miR-138 targets TERT and PD-L1. Liu H., Yang Y., Ge Y., Liu J., Zhao Y. TERC promotes cellular inflammatory response independent of telomerase. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Hochreiter A.E., Xiao H., Goldblatt E.M., Gryaznov S.M., Miller K.D., Badve S., Sledge G.W., Herbert B.S. 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. Before Telomerase defects may lead to aging and cancer. Moreover, NF-B acts in conjunction with TGF- to drive cancer cell dissemination and disease progression, which is potentiated by TERT through its interaction with the TGF--responsive TF, ZEB1 [148,149]. Suram A., Kaplunov J., Patel P.L., Ruan H., Cerutti A., Boccardi V., Fumagalli M., Di Micco R., Mirani N., Gurung R.L., et al. and W.P.S. Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Moving forward, significant attention should be devoted to (i) developing improved methods for measuring and understanding patient telomere length and TMM status, both at the time of diagnosis and longitudinally; (ii) exploring improved therapies that target the canonical and extratelomeric functions of telomerase; and (iii) propelling these therapies into clinical trials. 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]. It all comes together at the ends: Telomerase structure, function, and biogenesis. Interestingly, other TERT variants that lack catalytic activity can still stimulate cell proliferation [9]. 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. After all, a cancer cell is one that can keep dividing forever. Importantly, TRF1 aids in DNA replication through G-rich telomeric sequences [23]. Park J.I., Venteicher A.S., Hong J.Y., Choi J., Jun S., Shkreli M., Chang W., Meng Z., Cheung P., Ji H., et al. ; writingoriginal draft preparation, N.J.R. Telomere length maintenance in stem cell populations. As we get older, our blood stem cells slow down because their telomeres are too short. 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. Moving forward, more research is needed to better determine the in vivo pharmacokinetic and pharmacodynamic properties of these agents, as well as their safety and efficacy in patients. 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. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): An open-label, randomised, phase 3 trial. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Cerezo A., Kalthoff H., Schuermann M., Schafer B., Boukamp P. Dual regulation of telomerase activity through c-Myc-dependent inhibition and alternative splicing of hTERT. Taken together, these findings highlight the ability to TERT to oversee multiple metabolic and cellular detoxification functions that substantially influence cancer cell survival, adaptation, and dissemination. 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. Post-transcriptional regulation of TERT and TR. Denchi E.L., de Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. 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. Li S., Rosenberg J.E., Donjacour A.A., Botchkina I.L., Hom Y.K., Cunha G.R., Blackburn E.H. 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. This metabolic derangement of cell bioenergetics is mediated by altered mitochondrial function, which impacts cancer cell redox homeostasis, intracellular signaling, and survival [153]. 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. 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]. Over the past few years there has been significant progress in identifying the components of the . At least six nucleotides in TR undergo pseudouridylation, including two sites that lie within a highly conserved domain essential for telomerase catalytic activity. Off. Nava-Parada P., Emens L.A. GV-1001, an injectable telomerase peptide vaccine for the treatment of solid cancers. Intriguingly, this DNA repair deficiency is independent of alterations in telomere length. Along these lines, TR mutants deficient in TERT binding still protect cells against drug-induced apoptosis via hTERP production. Telomeres are dynamically extended during embryonic development and in germ cell and stem cell populations postnatally but are otherwise not maintained in most cell types [50,51,52]. ; supervision, W.P.S. Enter telomerase, a specialised telomere repair enzyme in two parts - able to add DNA to the chromosome tips. 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. Cao Y., Li H., Deb S., Liu J.P. TERT regulates cell survival independent of telomerase enzymatic activity. Cancer cells may reactivate telomerase by changing the DNA around one of the genes that makes telomerase, called TERT.
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