Abstract
Telomerase is a ribonucleoprotein complex, the catalytic core of which includes the telomerase reverse transcriptase (TERT) and the non-coding human telomerase RNA (hTR), which serves as a template for the addition of telomeric repeats to chromosome ends. Telomerase expression is restricted in humans to certain cell types, and telomerase levels are tightly controlled in normal conditions. Increased levels of telomerase are found in the vast majority of human cancers, and we have recently begun to understand the mechanisms by which cancer cells increase telomerase activity. Conversely, germline mutations in telomerase-relevant genes that decrease telomerase function cause a range of genetic disorders, including dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure. In this Review, we discuss the transcriptional regulation of human TERT, hTR processing, assembly of the telomerase complex, the cellular localization of telomerase and its recruitment to telomeres, and the regulation of telomerase activity. We also discuss the disease relevance of each of these steps of telomerase biogenesis.
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References
Palm, W. & de Lange, T. How shelterin protects mammalian telomeres. Annu. Rev. Genet. 41, 301–334 (2008).
Lazzerini-Denchi, E. & Sfeir, A. Stop pulling my strings — what telomeres taught us about the DNA damage response. Nat. Rev. Mol. Cell Biol. 17, 364–378 (2016).
Grolimund, L. et al. A quantitative telomeric chromatin isolation protocol identifies different telomeric states. Nat. Commun. 4, 2848 (2013).
Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).
Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992).
Chiba, K. et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science 357, 1416–1420 (2017).
Romanov, S. R. et al. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409, 633–637 (2001).
Kiyono, T. et al. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396, 84–88 (1998).
Weng, N. P., Levine, B. L., June, C. H. & Hodes, R. J. Regulated expression of telomerase activity in human T lymphocyte development and activation. J. Exp. Med. 183, 2471–2479 (1996).
Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).
Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996).
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Chiu, C. P. et al. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cell 14, 239–248 (1996).
Chiba, K. et al. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife 4, e07918 (2015).
Prowse, K. R. & Greider, C. W. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl Acad. Sci. USA 92, 4818–4822 (1995).
Meier, B. et al. trt-1 is the Caenorhabditis elegans catalytic subunit of telomerase. PLoS Genet. 2, e18 (2006).
Harel, I. et al. A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Cell 160, 1013–1026 (2015).
Pech, M. F. et al. High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells. Genes Dev. 29, 2420–2434 (2015).
Garbuzov, A. et al. Purification of GFRα1+ and GFRα1– spermatogonial stem cells reveals a niche-dependent mechanism for fate determination. Stem Cell Rep. 10, 553–567 (2018).
Montgomery, R. K. et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc. Natl Acad. Sci. USA 108, 179–184 (2011).
Lin, S. et al. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 556, 244–248 (2018).
Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002).
Allsopp, R. C., Morin, G. B., DePinho, R., Harley, C. B. & Weissman, I. L. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102, 517–520 (2003).
Gunes, C. & Rudolph, K. L. The role of telomeres in stem cells and cancer. Cell 152, 390–393 (2013).
Aubert, G. Telomere dynamics and aging. Prog. Mol. Biol. Transl Sci. 125, 89–111 (2014).
Amit, M. et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev. Biol. 227, 271–278 (2000).
Yui, J., Chiu, C. P. & Lansdorp, P. M. Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood 91, 3255–3262 (1998).
Morrison, S. J., Prowse, K. R., Ho, P. & Weissman, I. L. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5, 207–216 (1996).
Schepers, A. G., Vries, R., van den Born, M., van de Wetering, M. & Clevers, H. Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J. 30, 1104–1109 (2011).
Wick, M., Zubov, D. & Hagen, G. Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT). Gene 232, 97–106 (1999).
Takakura, M. et al. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 59, 551–557 (1999).
Horikawa, I., Cable, P. L., Afshari, C. & Barrett, J. C. Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res. 59, 826–830 (1999).
Wu, K. J. et al. Direct activation of TERT transcription by c-MYC. Nat. Genet. 21, 220–224 (1999).
Greenberg, R. A. et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18, 1219–1226 (1999).
Goueli, B. S. & Janknecht, R. Regulation of telomerase reverse transcriptase gene activity by upstream stimulatory factor. Oncogene 22, 8042–8047 (2003).
Kyo, S. et al. Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic Acids Res. 28, 669–677 (2000).
Harle-Bachor, C. & Boukamp, P. Telomerase activity in the regenerative basal layer of the epidermis inhuman skin and in immortal and carcinoma-derived skin keratinocytes. Proc. Natl Acad. Sci. USA 93, 6476–6481 (1996).
Gomes, N. M. et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 10, 761–768 (2011).
Bachand, F., Kukolj, G. & Autexier, C. Expression of hTERT and hTR in cis reconstitutes and active human telomerase ribonucleoprotein. RNA 6, 778–784 (2000).
Weinrich, S. L. et al. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat. Genet. 17, 498–502 (1997).
Beattie, T. L., Zhou, W., Robinson, M. O. & Harrington, L. Reconstitution of human telomerase activity in vitro. Curr. Biol. 8, 177–180 (1998).
Feng, J. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).
Blasco, M. A., Funk, W., Villeponteau, B. & Greider, C. W. Functional characterization and developmental regulation of mouse telomerase RNA. Science 269, 1267–1270 (1995).
Kiss, T., Fayet, E., Jady, B. E., Richard, P. & Weber, M. Biogenesis and intranuclear trafficking of human box C/D and H/ACA RNPs. Cold Spring Harb. Symp. Quant. Biol. 71, 407–417 (2006).
Mitchell, J. R., Cheng, J. & Collins, K. A box H/ACA small nucleolar RNA-like domain at the human telomerase RNA 3′ end. Mol. Cell Biol. 19, 567–576 (1999).
Matera, A. G., Terns, R. M. & Terns, M. P. Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs. Nat. Rev. Mol. Cell Biol. 8, 209–220 (2007).
Kim, N. K., Theimer, C. A., Mitchell, J. R., Collins, K. & Feigon, J. Effect of pseudouridylation on the structure and activity of the catalytically essential P6.1 hairpin in human telomerase RNA. Nucleic Acids Res. 38, 6746–6756 (2010).
Nguyen, T. H. D. et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature 557, 190–195 (2018).
Venteicher, A. S. et al. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323, 644–648 (2009).
Jamonnak, N. et al. Yeast Nrd1, Nab3, and Sen1 transcriptome-wide binding maps suggest multiple roles in post-transcriptional RNA processing. RNA 17, 2011–2025 (2011).
Kuehner, J. N., Pearson, E. L. & Moore, C. Unravelling the means to an end: RNA polymerase II transcription termination. Nat. Rev. Mol. Cell Biol. 12, 283–294 (2011).
Noel, J. F., Larose, S., Abou Elela, S. & Wellinger, R. J. Budding yeast telomerase RNA transcription termination is dictated by the Nrd1/Nab3 non-coding RNA termination pathway. Nucleic Acids Res. 40, 5625–5636 (2012).
Baillat, D. et al. Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 123, 265–276 (2005).
Rubtsova, M. P. et al. Integrator is a key component of human telomerase RNA biogenesis. Sci. Rep. 9, 1701 (2019).
Stadelmayer, B. et al. Integrator complex regulates NELF-mediated RNA polymerase II pause/release and processivity at coding genes. Nat. Commun. 5, 5531–5531 (2014).
Tudek, A. et al. Molecular basis for coordinating transcription termination with noncoding RNA degradation. Mol. Cell 55, 467–481 (2014).
Lubas, M. et al. Interaction profiling identifies the human nuclear exosome targeting complex. Mol. Cell 43, 624–637 (2011).
Schilders, G., van Dijk, E. & Pruijn, G. J. C1D and hMtr4p associate with the human exosome subunit PM/Scl-100 and are involved in pre-rRNA processing. Nucleic Acids Res. 35, 2564–2572 (2007).
Goldfarb, K. C. & Cech, T. R. 3′ terminal diversity of MRP RNA and other human noncoding RNAs revealed by deep sequencing. BMC Mol. Biol. 14, 23 (2013).
Roake, C. M. et al. Disruption of telomerase RNA maturation kinetics precipitates disease. Mol. Cell 74, 688–700 (2019).
Tseng, C. K., Wang, H. F., Schroeder, M. R. & Baumann, P. The H/ACA complex disrupts triplex in hTR precursor to permit processing by RRP6 and PARN. Nat. Commun. 9, 5430 (2018).
Tseng, C. K. et al. Human telomerase RNA processing and quality control. Cell Rep. 13, 2232–2243 (2015).
Moon, D. H. et al. Poly(A)-specific ribonuclease (PARN) mediates 3′-end maturation of the telomerase RNA component. Nat. Genet. 47, 1482–1488 (2015).
Henriksson, N., Nilsson, P., Wu, M., Song, H. & Virtanen, A. Recognition of adenosine residues by the active site of poly(A)-specific ribonuclease. J. Biol. Chem. 285, 163–170 (2010).
Wu, M. et al. Structural insight into poly(A) binding and catalytic mechanism of human PARN. EMBO J. 24, 4082–4093 (2005).
Lardelli, R. M. et al. Biallelic mutations in the 3′ exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat. Genet. 49, 457–464 (2017).
Son, A., Park, J. E. & Kim, V. N. PARN and TOE1 constitute a 3′ end maturation module for nuclear non-coding RNAs. Cell Rep. 23, 888–898 (2018).
Deng, T. et al. TOE1 acts as a 3′ exonuclease for telomerase RNA and regulates telomere maintenance. Nucleic Acids Res. 47, 391–405 (2019).
Nguyen, D. et al. A polyadenylation-dependent 3′ end maturation pathway is required for the synthesis of the human telomerase RNA. Cell Rep. 13, 2244–2257 (2015).
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. Nat. Struct. Mol. Biol. 23, 286–292 (2016).
Boyraz, B. et al. Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease. J. Clin. Invest. 126, 3377–3382 (2016).
Fok, W. C. et al. Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita. Blood 133, 1308–1312 (2019).
Mouaikel, J., Verheggen, C., Bertrand, E., Tazi, J. & Bordonne, R. Hypermethylation of the cap structure of both yeast snRNAs and snoRNAs requires a conserved methyltransferase that is localized to the nucleolus. Mol. Cell 9, 891–901 (2002).
Tang, W., Kannan, R., Blanchette, M. & Baumann, P. Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes. Nature 484, 260–264 (2012).
Chen, L. et al. Loss of human TGS1 hypermethylase promotes increased telomerase RNA and telomere elongation. Cell Rep. 30, 1358–1372.e5 (2020).
Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in tetrahymena extracts. Cell 43, 405–413 (1985).
Lingner, J. & Cech, T. R. Purification of telomerase from euplotes aediculatus: requirement of a primer 3′ overhang. Proc. Natl Acad. Sci. USA 93, 10712–10717 (1996).
Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959 (1997).
Tesmer, V. M. et al. Two inactive fragments of the integral RNA cooperate to assemble active telomerase with the human protein catalytic subunit (hTERT) in vitro. Mol. Cell Biol. 19, 6207–6216 (1999).
Mitchell, J. R. & Collins, K. Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase. Mol. Cell 6, 361–371 (2000).
Jiang, J. et al. Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions. Science 350, aab4070 (2015).
Jiang, J. et al. Structure of telomerase with telomeric DNA. Cell 173, 1179–1190 (2018).
Chen, J. L., Opperman, K. K. & Greider, C. W. A critical stem–loop structure in the CR4–CR5 domain of mammalian telomerase RNA. Nucleic Acids Res. 30, 592–597 (2002).
Robart, A. R. & Collins, K. Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants. J. Biol. Chem. 285, 4375–4386 (2010).
Schnapp, G., Rodi, H. P., Rettig, W. J., Schnapp, A. & Damm, K. One-step affinity purification protocol for human telomerase. Nucleic Acids Res. 26, 3311–3313 (1998).
Xin, H. et al. TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. Nature 445, 559–562 (2007).
Venteicher, A. S., Meng, Z., Mason, P. J., Veenstra, T. D. & Artandi, S. E. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell 132, 945–957 (2008).
Cohen, S. B. et al. Protein composition of catalytically active human telomerase from immortal cells. Science 315, 1850–1853 (2007).
Fu, D. & Collins, K. Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation. Mol. Cell 28, 773–785 (2007).
Egan, E. D. & Collins, K. An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. Mol. Cell Biol. 32, 2428–2439 (2012).
Egan, E. D. & Collins, K. Biogenesis of telomerase ribonucleoproteins. RNA 18, 1747–1759 (2012).
Jady, B. E., Bertrand, E. & Kiss, T. Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body-specific localization signal. J. Cell Biol. 164, 647–652 (2004).
Zhu, Y., Tomlinson, R. L., Lukowiak, A. A., Terns, R. M. & Terns, M. P. Telomerase RNA accumulates in Cajal bodies in human cancer cells. Mol. Biol. Cell 15, 81–90 (2004).
Chang, B. D. et al. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 59, 3761–3767 (1999).
Darzacq, X. et al. Stepwise RNP assembly at the site of H/ACA RNA transcription in human cells. J. Cell Biol. 173, 207–218 (2006).
Wang, C. & Meier, U. T. Architecture and assembly of mammalian H/ACA small nucleolar and telomerase ribonucleoproteins. EMBO J. 23, 1857–1867 (2004).
Hoareau-Aveilla, C., Bonoli, M., Caizergues-Ferrer, M. & Henry, Y. hNaf1 is required for accumulation of human box H/ACA snoRNPs, scaRNPs, and telomerase. RNA 12, 832–840 (2006).
Grozdanov, P. N., Roy, S., Kittur, N. & Meier, U. T. SHQ1 is required prior to NAF1 for assembly of H/ACA small nucleolar and telomerase RNPs. RNA 15, 1188–1197 (2009).
Holt, S. E. et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. 13, 817–826 (1999).
Toogun, O. A., Dezwaan, D. C. & Freeman, B. C. The hsp90 molecular chaperone modulates multiple telomerase activities. Mol. Cell. Biol. 28, 457–467 (2008).
Keppler, B. R., Grady, A. T. & Jarstfer, M. B. The biochemical role of the heat shock protein 90 chaperone complex in establishing human telomerase activity. J. Biol. Chem. 281, 19840–19848 (2006).
Freund, A. et al. Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1. Cell 159, 1389–1403 (2014).
Cristofari, G. et al. Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation. Mol. Cell 27, 882–889 (2007).
Stern, J. L., Zyner, K. G., Pickett, H. A., Cohen, S. B. & Bryan, T. M. Telomerase recruitment requires both TCAB1 and cajal bodies independently. Mol. Cell Biol. 32, 2384–2395 (2012).
Zhong, F. L. et al. TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends. Cell 150, 481–494 (2012).
Zhong, F. et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25, 11–16 (2011).
Tycowski, K. T., Shu, M. D., Kukoyi, A. & Steitz, J. A. A conserved WD40 protein binds the Cajal body localization signal of scaRNP particles. Mol. Cell 34, 47–57 (2009).
Schmidt, J. C., Zaug, A. J. & Cech, T. R. Live cell imaging reveals the dynamics of telomerase recruitment to telomeres. Cell 166, 1188–1197 e1189 (2016).
Chen, L. et al. An activity switch in human telomerase based on RNA conformation and shaped by TCAB1. Cell 174, 218–230 (2018).
Tomlinson, R. L., Li, J., Culp, B. R., Terns, R. M. & Terns, M. P. A Cajal body-independent pathway for telomerase trafficking in mice. Exp. Cell Res. 316, 2797–2809 (2010).
Broccoli, D., Smogorzewska, A., Chong, L. & de Lange, T. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat. Genet. 17, 231–235 (1997).
Chong, L. et al. A human telomeric protein. Science 270, 1663–1667 (1995).
Baumann, P. & Cech, T. R. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292, 1171–1175 (2001).
Abreu, E. et al. TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol. Cell Biol. 30, 2971–2982 (2010).
Nandakumar, J. et al. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492, 285–289 (2012).
Sexton, A. N. et al. Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes Dev. 28, 1885–1899 (2014).
Kocak, H. et al. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev. 28, 2090–2102 (2014).
Houghtaling, B. R., Cuttonaro, L., Chang, W. & Smith, S. A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr. Biol. 14, 1621–1631 (2004).
Ye, J. Z. et al. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 18, 1649–1654 (2004).
Liu, D. et al. PTOP interacts with POT1 and regulates its localization to telomeres. Nat. Cell Biol. 6, 673–680 (2004).
Kim, S. H., Kaminker, P. & Campisi, J. TIN2, a new regulator of telomere length in human cells. Nat. Genet. 23, 405–412 (1999).
Takai, K. K., Kibe, T., Donigian, J. R., Frescas, D. & de Lange, T. Telomere protection by TPP1/POT1 requires tethering to TIN2. Mol. Cell 44, 647–659 (2011).
Savage, S. A. et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82, 501–509 (2008).
Walne, A. J., Vulliamy, T., Beswick, R., Kirwan, M. & Dokal, I. TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 112, 3594–3600 (2008).
Frank, A. K. et al. The shelterin TIN2 subunit mediates recruitment of telomerase to telomeres. PLoS Genet. 11, e1005410 (2015).
Yang, D., He, Q., Kim, H., Ma, W. & Songyang, Z. TIN2 protein dyskeratosis congenita missense mutants are defective in association with telomerase. J. Biol. Chem. 286, 23022–23030 (2011).
Frescas, D. & de Lange, T. A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice. Genes Dev. 28, 153–166 (2014).
Miyake, Y. et al. RPA-like mammalian Ctc1–Stn1–Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol. Cell 36, 193–206 (2009).
Surovtseva, Y. V. et al. Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes. Mol. Cell 36, 207–218 (2009).
Casteel, D. E. et al. A DNA polymerase-α·primase cofactor with homology to replication protein A-32 regulates DNA replication in mammalian cells. J. Biol. Chem. 284, 5807–5818 (2009).
Chen, L. Y., Redon, S. & Lingner, J. The human CST complex is a terminator of telomerase activity. Nature 488, 540–544 (2012).
Nandakumar, J. & Cech, T. R. Finding the end: recruitment of telomerase to telomeres. Nat. Rev. Mol. Cell Biol. 14, 69–82 (2013).
Jady, B. E., Richard, P., Bertrand, E. & Kiss, T. Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres. Mol. Biol. Cell 17, 944–954 (2006).
Tomlinson, R. L., Ziegler, T. D., Supakorndej, T., Terns, R. M. & Terns, M. P. Cell cycle-regulated trafficking of human telomerase to telomeres. Mol. Biol. Cell 17, 955–965 (2006).
Vogan, J. M. et al. Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies. eLife 5, e18221 (2016).
Loayza, D. & de Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 424, 1013–1018 (2003).
Latrick, C. M. & Cech, T. R. POT1–TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. EMBO J. 29, 924–933 (2010).
Wang, F. et al. The POT1–TPP1 telomere complex is a telomerase processivity factor. Nature 445, 506–510 (2007).
Zaug, A. J., Podell, E. R., Nandakumar, J. & Cech, T. R. Functional interaction between telomere protein TPP1 and telomerase. Genes Dev. 24, 613–622 (2010).
Pike, A. M., Strong, M. A., Ouyang, J. P. T. & Greider, C. W. TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. Mol. Cell Biol. 39, e00593–18 (2019).
Greider, C. W. & Blackburn, E. H. Telomeres, telomerase and cancer. Sci. Am. 274, 92–97 (1996).
Counter, C. M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 (1992).
Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).
Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).
d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).
Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).
Davoli, T., Denchi, E. L. & de Lange, T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 141, 81–93 (2010).
Nassour, J. et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature 565, 659–663 (2019).
Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013).
Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. USA 110, 6021–6026 (2013).
Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013).
Kinde, I. et al. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 73, 7162–7167 (2013).
Vinagre, J. et al. Frequency of TERT promoter mutations in human cancers. Nat. Commun. 4, 2185 (2013).
Weinhold, N., Jacobsen, A., Schultz, N., Sander, C. & Lee, W. Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet https://doi.org/10.1038/ng.3101 (2014).
Borah, S. et al. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347, 1006–1010 (2015).
Bell, R. J. et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348, 1036–1039 (2015).
Stern, J. L., Theodorescu, D., Vogelstein, B., Papadopoulos, N. & Cech, T. R. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 29, 2219–2224 (2015).
Xi, L., Schmidt, J. C., Zaug, A. J., Ascarrunz, D. R. & Cech, T. R. A novel two-step genome editing strategy with CRISPR–Cas9 provides new insights into telomerase action and TERT gene expression. Genome Biol. 16, 231 (2015).
Akincilar, S. C. et al. Long-range chromatin interactions drive mutant TERT promoter activation. Cancer Discov. 6, 1276–1291 (2016).
Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. USA 110, 6021–6026 (2013).
Nault, J. C. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 4, 2218 (2013).
Shain, A. H. et al. The genetic evolution of melanoma from precursor lesions. N. Engl. J. Med. 373, 1926–1936 (2015).
Heidenreich, B., Rachakonda, P. S., Hemminki, K. & Kumar, R. TERT promoter mutations in cancer development. Curr. Opin. Genet. Dev. 24, 30–37 (2014).
Ferber, M. J. et al. Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene 22, 3813–3820 (2003).
Paterlini-Bréchot, P. et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene 22, 3911–3916 (2003).
Bellon, M. & Nicot, C. Regulation of telomerase and telomeres: human tumor viruses take control. J. Natl Cancer Inst. 100, 98–108 (2008).
Kawai-Kitahata, F. et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J. Gastroenterol. 51, 473–486 (2016).
Valentijn, L. J. et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat. Genet. 47, 1411–1414 (2015).
Peifer, M. et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526, 700–704 (2015).
Barthel, F. P. et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat. Genet. 49, 349–357 (2017).
Pickett, H. A. & Reddel, R. R. Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. Nat. Struct. Mol. Biol. 22, 875–880 (2015).
Dilley, R. L. & Greenberg, R. A. ALTernative telomere maintenance and cancer. Trends Cancer 1, 145–156 (2015).
Soder, A. I. et al. Amplification, increased dosage and in situ expression of the telomerase RNA gene in human cancer. Oncogene 14, 1013–1021 (1997).
Sugita, M. et al. Molecular definition of a small amplification domain within 3q26 in tumors of cervix, ovary, and lung. Cancer Genet. Cytogenet. 117, 9–18 (2000).
Yuan, X., Larsson, C. & Xu, D. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene 38, 6172–6183 (2019).
Kim, W. et al. Regulation of the human telomerase gene TERT by telomere position effect-over long distances (TPE-OLD): implications for aging and cancer. PLoS Biol. 14, e2000016 (2016).
Armanios, M. & Blackburn, E. H. The telomere syndromes. Nat. Rev. Genet. 13, 693–704 (2012).
Brown, Y. et al. A critical three-way junction is conserved in budding yeast and vertebrate telomerase RNAs. Nucleic Acids Res. 35, 6280–6289 (2007).
Trahan, C. & Dragon, F. Dyskeratosis congenita mutations in the H/ACA domain of human telomerase RNA affect its assembly into a pre-RNP. RNA 15, 235–243 (2009).
Zaug, A. J., Crary, S. M., Jesse Fioravanti, M., Campbell, K. & Cech, T. R. Many disease-associated variants of hTERT retain high telomerase enzymatic activity. Nucleic Acids Res. 41, 8969–8978 (2013).
Mitchell, J. R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).
Vulliamy, T. J. et al. Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 107, 2680–2685 (2006).
Stanley, S. E. et al. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci. Transl Med. 8, 351ra107 (2016).
Walne, A. J. et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum. Mol. Genet. 16, 1619–1629 (2007).
Stuart, B. D. et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat. Genet. 47, 512–517 (2015).
Batista, L. F. et al. Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474, 399–402 (2011).
Walne, A. J. et al. Mutations in the telomere capping complex in bone marrow failure and related syndromes. Haematologica 98, 334–338 (2013).
Walne, A. J., Vulliamy, T., Kirwan, M., Plagnol, V. & Dokal, I. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am. J. Hum. Genet. 92, 448–453 (2013).
Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001).
Vulliamy, T., Marrone, A., Dokal, I. & Mason, P. J. Association between aplastic anaemia and mutations in telomerase RNA. Lancet 359, 2168–2170 (2002).
Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).
Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005).
Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005).
Heiss, N. S. et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat. Genet. 19, 32–38 (1998).
Alder, J. K. et al. Diagnostic utility of telomere length testing in a hospital-based setting. Proc. Natl Acad. Sci. USA 115, E2358–e2365 (2018).
Anderson, B. H. et al. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat. Genet. 44, 338–342 (2012).
Vulliamy, T. et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc. Natl Acad. Sci. USA 105, 8073–8078 (2008).
Guo, Y. et al. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. Blood 124, 2767–2774 (2014).
Gable, D. L. et al. ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. Genes Dev. 33, 1381–1396 (2019).
Acknowledgements
This work was supported by NIH grants CA197563 and AG056575 to S.E.A. C.M.R. was supported by MSTP Training Grant GM007365 and by a Gerald J. Lieberman Fellowship.
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Glossary
- TERT-CreER
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A mouse strain engineered to induce the expression of the recombinase CreERT2, which enables fluorescence labelling of telomerase-expressing cells in vivo.
- Pseudouridylation
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Enzymatic alteration of the linkage between the uracil base and the ribose sugar moiety of uridine to create its isomer pseudouridine.
- WD40 repeat
-
A protein domain of 44–60 amino acids, which often mediates protein–protein or protein–RNA interactions.
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Roake, C.M., Artandi, S.E. Regulation of human telomerase in homeostasis and disease. Nat Rev Mol Cell Biol 21, 384–397 (2020). https://doi.org/10.1038/s41580-020-0234-z
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DOI: https://doi.org/10.1038/s41580-020-0234-z
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