Li S, Rosenberg JE, Donjacour AA, et al. Telomerase activation: a potential key modulator for human healthspan and longevity. 2019 Jan 4;2(1):e186967. Inhibiting telomerase, an enzyme that rescues malignant cells from destruction by extending the protective caps on the ends of chromosomes, kills tumor cells but also triggers resistance pathways that allow cancer to survive and spread, scientists report in the . 2021 Sep 10;11(19):12908-12922. doi: 10.1002/ece3.7931. Transcription factors such as p53 (also known as TP53; represses transcription in an SP1-dependent manner), MAD (transcription factor involved in a network controlling cell cycle progression), WT1, MZF-2, SIP1 and menin have been shown to downregulate hTERT transcription. Although the oligonucleotide imetelstat (GRN163L) appears to be the most promising telomerase inhibitor, Bryan and colleagues [58] have reported a novel telomerase inhibitor, BIBR1532, that binds to the thumb domain of TERT, disrupting TERTRNA binding (telomerase ribonucleoprotein assembly), leading to the inhibition of enzyme activity. Extension of short telomeres is one of the outcomes, but we cannot dismiss novel roles for telomerase in distinct networks [55]. . Introduction dsRNA 3, a hybrid consisting of a sense and antisense strand of an endogenous mRNA, can initiate a cellular response that results in the sequence-specific degradation of homologous single-stranded RNA. We did something somewhat different: We knocked down the telomerase RNA levels so that now, not only was there less telomerase enzymatic activity but also the cell was depleted of telomerase ribonucleoprotein itself. As described above, the telomeric DNA sequence is specified by copying the telomerase RNA template. Telomerase recruitment to telomeres takes place during the S phase of the cell cycle through interactions between the shelterin complex components TPP1 and POT1 and the DAT domain of hTERT. 2021 Dec 28;12(1):39. doi: 10.3390/biom12010039. He also demonstrated that human telomeres consisted of the repeated sequence TTAGGG [88]. Identification of a specific telomere terminal transferase activity in. The period of crisis results in extensive cell death. The https:// ensures that you are connecting to the Vx001 action is mediated by CD8+ T cells. What is the function of variant DNA repeats in ALT? Telomeres, repetitive (TTAGGG) DNAprotein complexes at the ends of chromosomes, are crucial for the survival of cancer cells. Thus, a telomerase-mediated telomere-disrupting approach may provide a safe and efficacious option for the treatment of cancer [80]. The period of cellular senescence, also known as mortality stage 1 (M1), is characterized by inhibition of cellular proliferation, probably due to the uncapping of one or a few shortened telomeres. Completed and ongoing clinical trials of imetelstat in cancer patients, ADR adverse drug reaction, aPTT activated partial thromboplastin time, DLT dose-limiting toxicity, MTD maximum tolerated dose, OS overall survival, PFS progression-free survival, TL telomere length. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, 21589 Kingdom of Saudi Arabia, Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 USA. Imetelstat is a lipid-conjugated 13-mer oligonucleotide sequence with a thio-phosphoramidate backbone. In in-vivo studies, 6-thio-dG treatment caused significant reduction in tumor growth rates and was superior to 6-thioguanine treatment. Imetelstat is a competitive inhibitor of telomerase activity, and was developed for the intravenous treatment of various cancers. Therapeutic interventions aimed to increase the quality of life at advanced age are visualized as important demands for the future, both at the level of individuals and society. The nucleoside analogue 6-thio-dG has been evaluated against cell lines and in vivo. 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]. The site is secure. Cancer vaccination with telomerase peptide. It is becoming clear how cancer cells regulate different molecular events involved in telomere maintenance to expand their proliferative capacity. Increased telomerase activity and comprehensive lifestyle changes: a An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. 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)n-3, followed by a terminal 3 G-rich single-stranded overhang (150200 nucleotide long). Determining mechanism(s) of escape from crisis: Cells in crisis undergo tremendous genomic instability due to bridgefusionbreakage cycles. Interestingly, despite being continually serially passaged for months, we never observed any reversion or any fast-growing resistant subpopulations growing out from 80 to 100 different clonal lines that were followed. In contrast to the effects of mutant-template telomerase RNA expression on telomerase RNA knockdown, no telomere shortening or telomere uncapping, or DNA damage response, accompanied the cell growth rate decrease. The rapid inhibition of cell growth seen on knockdown of telomerase indicated that cancer cells are particularly susceptible to its depletion. The enzymatic activity of telomerase is related but not equivalent to the expression of TERT, the. Answers to these questions may facilitate development of mechanism-based inhibitors for ALT-positive cancers. Liu H, Liu Q, Ge Y, Zhao Q, Zheng X, Zhao Y. hTERT promotes cell adhesion and migration independent of telomerase activity. However, a rare clone (1 in 100,000 to 1 in 10 million cells) can progress towards the acquisition of cell immortality [25]. Although binding of TFs is essential for hTERT transcription, in addition a permissive chromatin microenvironment is required. Imetelstat 2h intravenous Infusion on day 1 and day 8 of a 28-day cycle, Eighteen patients, all with positive hematologic response. Kotsakis A, Papadimitraki E, Vetsika EK, Aggouraki D, Dermitzaki EK, Hatzidaki D, et al. Unable to load your collection due to an error, Unable to load your delegates due to an error. The template is only a minor part of the entire telomerase RNA molecule. In the large majority of cancer cells, telomere length is maintained by telomerase. We are very interested in understanding the signaling pathways leading to the apoptosis, which is under active investigation right now. Aging: Too Much Telomerase Can Be As Bad As Too Little Therapies involving telomerase expression in adult tissues have demonstrated a potential impact in rescuing of age-associated degenerative pathologies [21,49]. Human Rifl protein binds aberrant telomeres and aligns along anaphase midzone microtubules. In vivo inhibition of lung cancer by GRN163L: a novel telomerase inhibitor. The vaccine shows high affinity for HLA class I and has demonstrated a significant immune response rate in cancer patients [75, 76]. Thus, there exists a puzzle that the abundant telomerase activity is apparently not there to make long telomeres. Architecture of human telomerase RNA. Imetelstat has been extensively evaluated for its activity and efficacy against multiple cancer cell lines and in mouse xenograft models in preclinical studies. Role of telomeres and telomerase in cancer. Nevertheless, the increase in telomerase activity seems transient after acute exercise. The common hTERT promoter mutations have been detected across all stages and grades in most cancers, suggesting that hTERT mutations are generally an early event in the process of carcinogenesis [49]. The mechanisms underlying telomere length (TL) maintenance and telomerase expression involve transcriptional, post-transcriptional and epigenetic regulation, and in-depth understanding of these mechanisms may provide novel biomarkers and targets for early detection of disease, determination of disease prognosis, and the development of therapeutics [1]. In collaboration with Jerry Cunha's lab at University of California, San Francisco, human bladder tumor cells were xenografted under the renal capsule in a mouse. Huang FW, Bielski CM, Rinne ML, Hahn WC, Seller WR, Stegmeier F, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. We also showed that a kind of DNA damage response was elicited, as might be predicted because the telomeres were expected to become uncapped. The https:// ensures that you are connecting to the NOTE: Comparison of human cancer cell growth inhibitory effects predicted and observed when telomerase enzymatic activity was only inhibited (Old) versus those observed in cells in which total telomerase RNA levels were knocked down (New). This eventually results in chromosome end-to-end fusions and extensive cell death (apoptosis) [24]. 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. Georgoulias V, Douillard JY, Khayat D, Manegold C, Rosell A, Menez-Jamet J, et al. How does RAD51 interact with the 5 overhang of ALT telomeric DNA to facilitate its invasion into homologous DNA, and how are shelterin proteins organized in ALT telomeres? Epub 2014 Feb 19. Koelsche C, Renner M, Hartmann W, Brandt R, Lehner B, Waldburger N, et al. Careers, Unable to load your collection due to an error. Furthermore, telomerase activity in differentiated fibroblasts carrying hTERT promoter mutations was comparable to that observed in cancer cell lines. Completed and ongoing clinical trials of anti-telomerase vaccines: current status. See this image and copyright information in PMC. However, it is not clear what effects targeting shelterin proteins would have on normal cells. Although hTERT is usually silenced in almost all somatic cells, it is significantly expressed in ~90% of human cancers. Here, we summarize telomere organization and function and its role in oncogenesis. Novel advances in telomerase function from several independent laboratories have resulted in potential new therapeutic strategies which appear as promising new venues to prevent cellular and tissue dysfunction and organismal decline, thereby increasing the so-called "health span". In addition, a WD-repeat-containing protein 79 called TCAB1 binds to the CAB-box sequence within hTR and directs the telomerase holoenzyme to localize at Cajal bodies bound to the nucleolus [37]. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2-deoxyguanosine. Telomerase is silenced in most normal cells but is active in an estimated 85% to 95% of human cancer cells. Roles of telomeres and telomerase in cancer, and advances in telomerase In cancer cells, the degradation of telomerase by proteasomes results in the formation of protein fragments or peptides of telomerase that are expressed on the tumor cell surface as antigens by the human leukocyte antigen (HLA) class I pathway [68, 69], and these telomerase antigenic epitopes can be targeted by cytotoxic T cells to destroy the tumor cells [70]. With its different RNA template sequence, it makes the sequence at the ends of our chromosomes, T2AG3 repeats, which is very much like that of some ciliated protozoans, T2G4 repeats. 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. The serial cultivation of human diploid cell strains. 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. Watson predicted, based on the asymmetry of how linear duplex DNA is copied, that each cell division would result in the extreme termini of chromosomes being lost. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. {"type":"clinical-trial","attrs":{"text":"NCT00594126","term_id":"NCT00594126"}}, {"type":"clinical-trial","attrs":{"text":"NCT00732056","term_id":"NCT00732056"}}, {"type":"clinical-trial","attrs":{"text":"NCT00310895","term_id":"NCT00310895"}}, {"type":"clinical-trial","attrs":{"text":"NCT00124189","term_id":"NCT00124189"}}, {"type":"clinical-trial","attrs":{"text":"NCT00510445","term_id":"NCT00510445"}}, {"type":"clinical-trial","attrs":{"text":"NCT01265927","term_id":"NCT01265927"}}, {"type":"clinical-trial","attrs":{"text":"NCT01242930","term_id":"NCT01242930"}}, {"type":"clinical-trial","attrs":{"text":"NCT02598661","term_id":"NCT02598661"}}, {"type":"clinical-trial","attrs":{"text":"NCT02426086","term_id":"NCT02426086"}}, {"type":"clinical-trial","attrs":{"text":"NCT01243073","term_id":"NCT01243073"}}, {"type":"clinical-trial","attrs":{"text":"NCT01731951","term_id":"NCT01731951"}}, {"type":"clinical-trial","attrs":{"text":"NCT00510133","term_id":"NCT00510133"}}, {"type":"clinical-trial","attrs":{"text":"NCT01579188","term_id":"NCT01579188"}}, {"type":"clinical-trial","attrs":{"text":"NCT00425360","term_id":"NCT00425360"}}, {"type":"clinical-trial","attrs":{"text":"NCT01935154","term_id":"NCT01935154"}}. The effects of telomerase inhibition on prostate tumor-initiating cells. Effect of comprehensive lifestyle changes on telomerase activity and Adding GV1001 vaccination to chemotherapy did not improve overall survival. Hence, the telomeric structure is continually being assembled and disassembled. (7)]. In vivo preclinical studies in mouse models of human tumor xenografts showed that the compound was well tolerated and highly efficacious in inducing telomerase inhibition, leading to reduced tumor growth, prevention of metastasis, and sensitization of tumors to standard chemotherapy [65]. Therefore, they introduced three common hTERT promoter mutations (57 A>C, 124 C>T, 146 C>T) into isogenic human embryonic stem cells (hESCs) using CRISPR/Cas9 genome editing, and observed that in undifferentiated hESCs the presence of 124 C>T caused a 2- to 3-fold increase in hTERT mRNA while neither the 57 A>C nor 146 C>T mutation had any effect on hTERT transcription and none of the three mutations had a major influence on telomerase activity. Wong MS, Wright WE, Shay JW. Arora R, Lee Y, Wischnewski H, Brun CM, Schwarz T, Azzalin CM. Imetelstat binds to the hTR template region at the hTERT active site with high affinity and blocks its recruitment to telomeric DNA. DLT: thrombocytopenia, neutropenia, anemia, aPTT prolongation, fatigue, nausea, anorexia and dizziness. Telomeres are the protective caps on the ends of chromosomes that affect how quickly cells age. Origin of concatemeric T7 DNA. Recent studies also suggest that telomerase is implicated in tumor progression in unexpected ways. Science. Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Elizabeth H. Blackburn; Telomerase and Cancer: Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture. Ghosh A, Saginc G, Leow SC, Khattar E, Shin EM, Yan TD, et al. 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 DNA damage response machinery. FOIA Many of these factors are thought to be involved in the assembly of a functional telomerase holoenzyme in vivo but the actual mechanisms by which they interact with telomerase remain poorly understood. 8600 Rockville Pike In control cells, the wild-type telomerase RNA was introduced, and big robust tumors formed. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, et al. The mutated sequence could not bind the DNA sequencespecific protective proteins. Lu R, Pal J, Buon L, Nanjappa P, Shi J, Fulciniti M, et al. In addition, higher-order DNA conformations, such as the T-loop and G-quadruplexes (G-rich four-stranded non-helical structures) are thought to contribute to normal telomere function. http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, http://asteriasbiotherapeutics.com/pipeline/ast-vac1/, Thyroid cancer (papillary and poorly differentiated carcinomas), Breast cancer, colorectal cancer, medullary thyroid carcinoma, ovarian cancer, esophageal adenocarcinoma, acute myeloid leukemia, chronic lymphoid leukemia, pancreatic cancer, prostate cancer, testicular carcinoma, uterine cervix cancer. Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. The telomerase activator TA65 elongates short telomeres and increases 1 C).The TERT gene length is 40 kbs that is located at chromosome 5p15.33 [67].Any point mutation or non-synonymous mutations in the TERT gene or on the regulatory . Klewes L, Vallente R, Dupas E, Brand C, Gru D, Guffei A, et al. 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. Do they have hTERT promoter mutations? Thus, inhibition of telomerase recruitment may result in cell death [94]. This results in altered telomere organization and activation of telomere-associated DNA damage signals called telomere dysfunction-induced foci, and rapid cell death. Growth Inhibitory Effects of Knocking Down Telomerase in Cancer Cells. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. A multicenter randomized phase IIb efficacy study of Vx-001, a peptide-based cancer vaccine as maintenance treatment in advanced non-small-cell lung cancer: treatment rationale and protocol dynamics. GFP lane, Northern blot analysis of RNA from cells expressing GFP alone from the control lentiviral vector [adapted from Li et al. The human telomerase enzyme is a DNA polymerase consisting of two subunits known as telomerase reverse transcriptase (hTERT, the catalytic subunit encoded by the TERT gene, located on chromosome 5p15.33) and telomerase RNA component (hTERC or hTR, encoded by the TERC gene positioned on chromosomal region 3q26) [ 2, 3 ]. Effect of a Qigong Intervention on Telomerase Activity and Mental Health in Chinese Women Survivors of Intimate Partner Violence: A Randomized Clinical Trial. Bourgeron T, Xu Z, Doumic M, Teixeira MT. For example, in the earliest experiments we did, we transfected the mutant template telomerase RNA constructs into human cancer cell lines and selected for cells that stably expressed the mutant-template telomerase RNA (5). Telomerase and Cancer | Molecular Cancer Research | American Recent advances in telomere biology are beginning to unravel potential new telomerase targets (Box 3) for the design of novel molecules targeting the activity of this key enzyme. Similarly, Huang and colleagues [48] also demonstrated that hTERT promoter mutations C228T and C250T caused a 2.8-fold to 5.3-fold increase in transcription (using a luciferase reporter assay in U87-MG cells) and telomerase activation using the telomere repeat amplification protocol (TRAP) assay in both xenografts and primary tumor tissues. Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. Epigenetic mechanisms such as chromatin remodeling, DNA methylation and histone modifications for regulation of hTERT transcription have also been described [54, 55]. Increased expression of hTERT gene or its reactivation is required for limitless cellular proliferation in immortal malignant cells. Thus, the shortest telomere is critically important for cell viability and chromosomal stability as it may be a sole contributor to the senescence onset signal [22]. Clipboard, Search History, and several other advanced features are temporarily unavailable. Identification of human TERT elements necessary for telomerase recruitment to telomeres. eCollection 2021 Oct. Guinobert I, Blondeau C, Colicchio B, Oudrhiri N, Dieterlen A, Jeandidier E, Deschenes G, Bardot V, Cotte C, Ripoche I, Carde P, Berthomier L, M'Kacher R. Biomedicines. Once again, the effects did not require p53 (7). Telomerase, the enzyme that reduces telomere shortening in certain cells, is reactivated or increased in more than 90 percent of cancers, found a 2016 study. Interventions targeting the molecules involved in non-telomeric functions of telomerase may be a rational approach for cancer treatment. RESULTS: TERT promoter mutations and telomerase reactivation in urothelial cancer. Vonderheide RH, Hahn WC, Schultze JL, Nadler LM. Frescas D, de Lange T. Binding of TPP1 protein to TIN2 protein is required for POT1 protein-mediated telomere protection. Recent reports have implicated two cancer-specific hTERT promoter mutations (mainly CT transitions) in the activation of telomerase in cancer cells [3, 4]. Increased telomerase expression produces vulnerability of cancer cells, distinguishing them from normal cells in the body, although normal cells do also have some active telomerase. Inhibition of the Tel patch to block telomerase recruitment to telomeres: The Tel patch, a specific amino acid sequence in the OB-fold domain of shelterin complex protein TPP1, is involved in telomerase binding, recruitment, enzyme processivity and telomere elongation. 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]. Picariello L, Grappone C, Polvani S, Galli A. Telomerase activity: an attractive target for cancer therapeutics. Stoer R, Taubert H, Zinnall U, Giedl J, Gaisa NT, Burger M, et al. Structural basis of template-boundary definition in Tetrahymena telomerase. The time point at which any chromosome end will become uncapped depends on the specific TL shortening rate in each cell type or tissue. 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. 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. Telomeres consist of a capping structure, which is a specialized nucleoprotein structure consisting of DNA and shelterin protein complexes. However, at present, it is not certain if any of these vaccine candidates will progress to registration studies to get approval for clinical application. Bookshelf This work comprises one approach by which one might exploit the increased expression of telomerase, which is so common in cancer cells by forcing them to make toxic telomeres. Involvement of SRSF 11 in cell cycle-specific recruitment of telomerase to telomeres at nuclear speckles. elomerase inhibitors and activators in aging and cancer: A systematic Nosrati M, Li S, Bagheri S, et al. The component of the telomerase ribonucleoprotein we targeted for knockdown by RNA interference (short interfering RNA or siRNA) was the telomerase RNA. This response does not require the telomeres to shorten. Chan AK, Yao Y, Zhenyu Z, Chung NY, Liu JS, Ka-Wai, et al. ATRX represses alternative lengthening of telomeres. These three proteins are interconnected by three additional shelterin proteins, TIN2, TPP1 and RAP1, forming a complex that enables DDR surveillance machinery to distinguish telomere DNA from sites of genomic DNA damage (Fig. Koelsche C, Sahm F, Capper D, Reuss D, Stum D, Jones DT, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer: an open-label, randomised, phase 3 trial. Telomeres therefore play a vital role in preserving the information in our genome. In the presence of cancer-initiating changes, M1 can be bypassed, providing an extended cell division period. Vonderheide RH. Wu L, Xie X, Liang T, Ma J, Yang L, Yang J, Li L, Xi Y, Li H, Zhang J, Chen X, Ding Y, Wu Q. Biomolecules. Alternative splicing regulation of telomerase: a new paradigm. Clinical trial results have demonstrated that GRNVAC1, Vx001 and GV1001 are promising telomerase-targeting vaccines capable of stimulating CD4+ and CD8+ responses in telomerase-positive tumors, showing minimal effects on normal cells and no autoimmunity. This inactive complex swamps out the endogenous telomerase. Cells that gain oncogenic changes bypass senescence and continue to divide (extended lifespan period) until multiple critically shortened telomeres initiate crisis (a period of complete replicative senescence, chromosome end-to-end fusions, and extensive apoptosis). Are short telomeres predictive of advanced cancer? The solution to this theoretical problem was the enzyme telomerase (1). Ouellette MM, Wright WE, Shay JW. Shang Li and Lifeng Xu showed that when we expressed the mutant-template telomerase RNA, even as early as 3 or 4 days after infection, DNA damage foci appeared at the telomeres, as visualized by immunostaining of the telomere-specific protein TRF2. Arnoult N, Karlseder J. It has recently been reported that epidermal growth factor (EGF)-mediated activation of telomerase activity in lung cancer is associated with direct binding of ETS-2 to the hTERT promoter [43]. Each ribozyme was delivered systemically after B16 cells had been introduced into mice by tail-vein injection. Extension of lifespan by introduction of telomerase in normal human cells. Immunostaining was done for telomere-protective protein TRF2 (green) and for the DNA damage response protein hRif1 (red). A major challenge for anti-telomerase-directed therapy is the long lag period required to observe enough TL attrition to induce cell death. The presence of telomerase activity may indicate the ability of a cell to bypass the telomeric "clock" that limits the proliferative capacity of normal somatic cells and may reflect the presence of immortalized or cancer cells. The unexpectedly rapid response to telomerase knockdown prompted us to carry out many controls to rule out possibilities such as targets other than the telomerase RNA being responsible for the effects on cell growth. The authors declare that they have no competing interests. Cellular immortality in culture: Alex Carrel, recipient of the 1912 Nobel Prize in physiology, working at the Rockefeller Institute demonstrated that chick heart tissue culture cells can be maintained in long-term cultures by replenishing with fresh culture medium. Effects of low-level expression of mutant-template telomerase RNA in MCF-7 breast cancer cells. Telomerase gene therapy in adult and old mice delays aging and They are combinations of DNA and protein that protect the ends of chromosomes and help them remain stable. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, et al. 2023 Jun 9;380(6649):eabn9257. Finally, AAV9-mTERT treatment was able to increase telomerase activity as measured by TRAP assay 2-year old mice in vivo in a number of mouse tissues, such as lungs, liver, kidney and heart (Fig 1D; Supporting Information Fig S3D-F).
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