Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.
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Greider, C. W. Telomeres. Curr. Opin. Cell Biol. 3, 444–451 (1991).
de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005).
Maciejowski, J. & de Lange, T. Telomeres in cancer: tumour suppression and genome instability. Nat. Rev. Mol. Cell. Biol. 18, 175–186 (2017).
Shay, J. W. Role of telomeres and telomerase in aging and cancer. Cancer Discov. 6, 584–593 (2016).
Shay, J. W., Wright, W. E. & Werbin, H. Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta 1072, 1–7 (1991).
Hemann, M. T., Strong, M. A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).
Zou, Y., Sfeir, A., Gryaznov, S. M., Shay, J. W. & Wright, W. E. Does a sentinel or a subset of short telomeres determine replicative senescence? Mol. Biol. Cell 15, 3709–3718 (2004).
Lai, T.-P., Wright, W. E. & Shay, J. W. Comparison of telomere length measurement methods. Phil. Trans. R. Soc. B 373, 20160451 (2018).
Aubert, G., Hills, M. & Lansdorp, P. M. Telomere length measurement-caveats and a critical assessment of the available technologies and tools. Mutat. Res. 730, 59–67 (2012).
Lai, T.-P. et al. A method for measuring the distribution of the shortest telomeres in cells and tissues. Nat. Commun. 8, 1356 (2017).
Bendix, L., Horn, P. B., Jensen, U. B., Rubelj, I. & Kolvraa, S. The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells. Aging Cell 9, 383–397 (2010).
Wright, W. E., Pereira-Smith, O. M. & Shay, J. W. Reversible cellular senescence: a two-stage model for the immortalization of normal human diploid fibroblasts. Mol. Cell. Biol. 9, 3088–3092 (1989).
Wright, W. E. & Shay, J. W. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 27, 383–389 (1992).
Bryan, T. M., Englezou, A., Dalla-Pozza, L., Dunham, M. A. & Reddel, R. R. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat. Med. 3, 1271–1274 (1997).
Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).
Shay, J. W. & Bacchetti, S. A survey of telomerase activity in human cancer. Eur. J. Cancer 33, 787–791 (1997).
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).
Ulaner, G. A., Hu, J. F., Vu, T. H., Giudice, L. C. & Hoffman, A. R. Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development. Int. J. Cancer 91, 644–649 (2001).
Wong, M. S., Wright, W. E. & Shay, J. W. Alternative splicing regulation of telomerase: a new paradigm? Trends Genet. 30, 430–438 (2014).
Blasco, M. A. The epigenetic regulation of mammalian telomeres. Nat. Rev. Genet. 8, 299–309 (2007).
Robin, J. D. et al. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev. 28, 2464–2476 (2014).
Kim, W. et al. Regulation of the human telomerase gene TERT by telomere position effect over long distance (TPE-OLD): implications for aging and cancer. PLOS Biol. 14, 2000016 (2016).
Robin, J. D. & Magdinier, F. Physiological and pathological aging affects chromatin dynamics, structure and function at the nuclear edge. Front. Genet. 7, 153 (2016).
Kim, W. & Shay, J. W. Long-range telomere regulation of gene expression: telomere looping and telomere position effect over long distances (TPE-OLD). Differentiation 99, 1–9 (2018).
Lou, Z. et al. Endogenous genes near telomeres regulated by telomere length in human cells. Aging 1, 608–621 (2009).
Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985).
Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959 (1997).
Feng, J. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).
Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).
Holohan, B., Wright, W. E. & Shay, J. W. Impaired telomere maintenance spectrum disorders. J. Cell Biol. 205, 289–229 (2014).
Calado, R. T. & Young, N. S. Telomere diseases. N. Eng. J. Med. 361, 2353–2365 (2009).
Mender, I. et al. Telomerase-mediated strategy for overcoming non-small cell lung cancer targeted therapy and chemotherapy resistance. Neoplasia 20, 826–837 (2018).
Shay, J. W. & Wright, W. E. Telomerase therapeutics for cancer: challenges and new directions. Nat. Rev. Drug Discov. 5, 477–584 (2006).
Shay, J. W. & Wright, W. E. Mechanism-based combination telomerase inhibition therapy. Cancer Cell 7, 1–2 (2005).
Herbert, B.-S. et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl Acad. Sci. USA 96, 14276–14281 (1999).
Mender, I., Gryaznov, S., Dikmen, Z. G., Wright, W. E. & Shay, J. W. Induction of telomere dysfunction mediated by the telomerase substrate precursor, 6-thio-2-deoxyguanosine. Cancer Discov. 5, 82–95 (2015).
Wood, A. M. et al. TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends. Nat. Commun. 5, 5467 (2014).
Robin, J. D. et al. SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy. Genome Res. 25, 1781–1790 (2015).
Wood, A. M., Laster, K., Rice, E. I. & Kosak, S. T. A beginning of the end: new insights into the functional organization of telomeres. Nucleus 6, 172–178 (2015).
Stadler, G. et al. Human disease and telomere position effect (TPE): The regulation of DUX4 expression in facioscapulohumeral muscular dystrophy (FSHD). Nat. Struct. Mol. Biol. 20, 671–678 (2013).
Morgan, T. H. Random segregation versus coupling in Mendelian inheritance. Science 34, 384 (1911).
Muller, H. J. The remaking of chromosomes. Collect. Net 8, 182–195 (1938).
Creighton, H. B. & McClintock, B. A correlation of cytological and genetical crossing-over in Zea mays. Proc. Natl Acad. Sci. USA 17, 492–497 (1931).
McClintock, B. The stability of broken ends of chromosomes in Zea mays. Genetics 26, 234–282 (1941).
McClintock, B. The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc. Natl Acad. Sci. USA 25, 405–416 (1939).
McClintock, B. Profiles in science. Letter from Barbara McClintock to Elizabeth H. Blackburn. NIH https://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/LLBBDW (1983).
Weismann, A. Collected Essays Upon Heredity and Kindred Biological Problems (eds Poulton, E. B., Schönland, S. & Shipley, A. E.) (Clarendon Press, Oxford, 1889).
Carrel, A. & Ebeling, A. H. Age and multiplication of fibroblasts. J. Exp. Med. 34, 599–606 (1921).
Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).
Rubin, H. Telomerase and cellular lifespan: ending the debate? Nat. Biotechnol. 16, 396–397 (1998).
Shay, J. W. & Wright, W. E. Hayflick, his limit, and cellular ageing. Nat. Rev. Mol. Cell. Biol. 1, 72–76 (2000).
Watson, J. D. Origin of concatemeric T7 DNA. Nat. New Biol. 239, 197–201 (1972).
Olovnikov, A. M. A theory of marginotomy. The incomplete copying of template margin in enzymatic synthesis of polynucleotides and biological significance of the phenomenon. J. Theor. Biol. 41, 181–190 (1973).
Blackburn, E. H. & Gall, J. G. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J. Mol. Biol. 120, 33–53 (1978).
Szostak, J. W. & Blackburn, E. H. Cloning yeast telomeres on linear plasmid vectors. Cell 29, 245–255 (1982).
Shampay, J., Szostak, J. W. & Blackburn, E. H. DNA sequences of telomeres maintained in yeast. Nature 310, 154–157 (1984).
Cooke, H. J. & Smith, B. A. Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harb. Symp. Quant. Biol. 51, 213–219 (1986).
Moyzis, R. K. et al. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc. Natl Acad. Sci. USA 85, 6622–6626 (1988).
Meyne, J., Ratliff, R. L. & Moyzis, R. K. Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc. Natl Acad. Sci. USA 86, 7049–7053 (1989).
Gomes, N. M. V. et al. The comparative biology of mammalian telomeres: ancestral states and functional transitions. Aging Cell 10, 761–768 (2011).
Klobutcher, L. A., Swanton, M. T., Donini, P. & Prescott, D. M. All gene-szied DNA molecules in four specific of hypotrich have the same terminal sequence and an unusual 3’ terminus. Proc. Natl Acad. Sci. USA 78, 3015–3019 (1981).
Gottschling, D. E. & Zakian, V. A. Telomere proteins: specific recognition and protection of the natural termini of Oxytricha macronuclear DNA. Cell 47, 195–205 (1986).
Lin, J. J. & Zakian, V. A. The Saccharomyces CDC13 protein is a single-strand TG1-3 telomeric DNA-binding protein in vitro that affects telomere behavior in vivo. Proc. Natl Acad. Sci. USA 93, 13760–13765 (1996).
Nugent, C. I., Hughes, T. R., Lue, N. F. & Lundblad, V. Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance. Science 274, 249–252 (1996).
Baumann, P. & Cech, T. R. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292, 1171–1175 (2001).
Buchman, A. R., Kimmerly, W. J., Rine, J. & Kornberg, R. D. Two DNA-binding factors recognize specific sequences at silencers, upstream activating sequences, autonomously replicating sequences, and telomeres in Saccharomyces cerevisiae. Mol. Cell. Biol. 8, 210–225 (1988).
Conrad, M. N., Wright, J. H., Wolf, A. J. & Zakian, V. A. RAP1 protein interacts with yeast telomeres in vivo: overproduction alters telomere structure and decreases chromosome stability. Cell 63, 739–750 (1990).
Lustig, A. J., Kurtz, S. & Shore, D. Involvement of the silencer and UAS binding protein RAP1 in regulation of telomere length. Science 250, 549–553 (1990).
Krauskopf, A. & Blackburn, E. H. Control of telomere growth by interactions of RAP1 with the most distal telomeric repeats. Nature 383, 354–357 (1996).
Marcand, S., Wotton, D., Gilson, E. & Shore, D. Rap1p and telomere length regulation in yeast. Ciba Found. Symp. 211, 76–93; discussion 93–103 (1997).
Chong, L. et al. A human telomeric protein. Science 270, 1663–1667 (1995).
van Steensel, B. & de Lange, T. Control of telomere length by the human telomeric protein TRF1. Nature 385, 740–743 (1997).
Bilaud, T. et al. Telomeric localization of TRF2, a novel human telobox protein. Nat. Genet. 17, 236–239 (1997).
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).
Smogorzewska, A. et al. Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol. 20, 1659–1668 (2000).
van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998).
Kim, S. H., Kaminker, P. & Campisi, J. TIN2, a new regulator of telomere length in human cells. Nat. Genet. 23, 405–412 (1999).
National Center for Biotechnology Information. ACD, shelterin complex subunit and telomerase recruitment factor [Homo sapiens (human)]. NCBI Gene https://www.ncbi.nlm.nih.gov/gene/65057 (2018).
O’Connor, M. S., Safari, A., Xin, H., Liu, D. & Songyang, Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc. Natl Acad. Sci. USA 103, 11874–11879 (2006).
Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999).
Lundblad, V. & Szostak, J. W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57, 633–643 (1989).
Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).
de Lange, T. et al. Structure and variability of human chromosome ends. Mol. Cell. Biol. 10, 518–527 (1990).
Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990).
Lindsey, J., McGill, N. I., Lindsey, L. A., Green, D. K. & Cooke, H. J. In vivo loss of telomeric repeats with age in humans. Mutat. Res. 256, 45–48 (1991).
Harley, C. B. Telomere loss: mitotic clock or genetic time bomb? Mutat. Res. 256, 271–282 (1991).
Greider, C. W. & Blackburn, E. H. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 51, 887–898 (1987).
Greider, C. W. & Blackburn, E. H. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337, 331–337 (1989).
Yu, G. L., Bradley, J. D., Attardi, L. D. & Blackburn, E. H. In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs. Nature 344, 126–132 (1990).
Morin, G. B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521–529 (1989).
Shippen-Lentz, D. & Blackburn, E. H. Telomere terminal transferase activity from Euplotes crassus adds large numbers of TTTTGGGG repeats onto telomeric primers. Mol. Cell. Biol. 9, 2761–2764 (1989).
Zahler, A. M. & Prescott, D. M. Telomere terminal transferase activity in the hypotrichous ciliate Oxytricha nova and a model for replication of the ends of linear DNA molecules. Nucleic Acids Res. 16, 6953–6972 (1988).
Harrington, L. et al. A mammalian telomerase-associated protein. Science 275, 973–977 (1997).
Harrington, L. et al. Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev. 11, 3109–3115 (1997).
Meyerson, M. et al. hEST2, the putative human telomerase catalytic subunit gene, is upregulated in tumor cells and during immortalization. Cell 90, 785–795 (1997).
Kilian, A. et al. Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum. Mol. Genet. 6, 2011–2019 (1997).
Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in human cells leads to elongation of telomeres and extended replicative lifespan. Curr. Biol. 8, 279–282 (1998).
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).
Hiyama, E. et al. Correlating telomerase activity levels with human neuroblastoma outcomes. Nat. Med. 1, 249–257 (1995).
Morales, C. P. et al. Lack of cancer-associated changes in human fibroblasts after immortalization with telomerase. Nat. Genet. 21, 115–118 (1999).
Hiyama, K. et al. Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J. Immunol. 155, 3711–3715 (1995).
Allshire, R. C., Dempster, M. & Hastie, N. D. Human telomeres contain at least three types of G-rich repeat distributed non-randomly. Nucleic Acids Res. 17, 4611–4627 (1989).
Cawthon, R. M. Telomere measurement by quantitative PCR. Nucleic Acids Res. 30, e47 (2002).
Verhulst, S. et al. Commentary: The reliability of telomere length measurements. Int. J. Epidemiol. 44, 1683–1686 (2015).
Eisenberg, D. T. Telomere length measurement validity: the coefficient of variation is invalid and cannot be used to compare quantitative polymerase chain reaction and Southern blot telomere length measurement techniques. Int. J. Epidemiol. 45, 1295–1298 (2016).
Baird, D. M., Rowson, J., Wynford-Thomas, D. & Kipling, D. Extensive allelic variation and ultrashort telomeres in senescent human cells. Nat. Genet. 33, 203–207 (2003).
Baird, D. M. New developments in telomere length analysis. Exp. Gerontol. 40, 363–336 (2005).
Baerlocher, G. M., Vulto, I., de Jong, G. & Lansdorp, P. M. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat. Protoc. 1, 2365–2376 (2006).
Rufer, N., Dragowska, W., Thornbury, G., Roosnek, E. & Lansdorp, P. M. Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat. Biotechnol. 16, 743–747 (1998).
Ludlow, A. T. et al. Quantitative telomerase enzyme activity determination using droplet digital PCR with single cell resolution. Nucleic Acids Res. 42, e104 (2014).
Huang, E. et al. The maintenance of telomere length in CD28+ T cells during lymphocyte stimulation. Sci. Rep. 7, 6785 (2017).
Opresko, P. L. & Shay, J. W. Telomere-associated aging disorders. Ageing Res. Rev. 33, 52–66 (2016).
Shay, J. W. & Wright, W. E. Telomeres in dyskeratosis congenita. Nat. Genet. 36, 437–438 (2004).
Garcia, C. K., Wright, W. E. & Shay, J. W. Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res. 35, 7406–7416 (2007).
Armanios, M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J. Clin. Invest. 123, 996–1002 (2013).
Armanios, M. & Blackburn, E. H. The telomere syndromes. Nat. Rev. Genet. 13, 693–704 (2012).
Chojnowski, A. et al. Progerin reduces LAP2α-telomere association in Hutchinson–Gilford progeria. eLife 4, e07759 (2015).
Cao, K. et al. Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J. Clin. Invest. 121, 2833–2844 (2011).
Gordon, L. B., Rothman, F. G., López-Otín, C. & Misteli, T. Progeria: a paradigm for translational medicine. Cell 156, 400–407 (2014).
Dorado, B. & Andres, V. A-type lamins and cardiovascular disease in premature aging syndromes. Curr. Opin. Cell Biol. 46, 17–25 (2017).
van Steensel, B. & Belmont, A. S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780–791 (2017).
McCord, R. P. et al. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson–Gilford progeria syndrome. Genome Res. 23, 260–269 (2013).
Mitchell, J. R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).
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).
Shay, J. W. & Wright, W. E. Mutant dyskerin ends relationship with telomerase. Science 286, 2284–2285 (1999).
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).
Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001).
Keller, R. B. et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr. Blood Cancer. 59, 311–314 (2012).
Kirwan, M. & Dokal, I. Dyskeratosis congenita: a genetic disorder of many faces. Clin. Genet. 73, 103–112 (2008).
Kirwan, M. et al. Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum. Mutat. 30, 1567–1573 (2009).
Sasa, G. S., Ribes-Zamora, A., Nelson, N. D. & Bertuch, A. A. Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. Clin. Genet. 81, 470–478 (2012).
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).
Gramatges, M. M. & Bertuch, A. A. Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy. Transl Res. 162, 353–363 (2013).
Fogarty, P. F. et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 362, 1628–1630 (2003).
Gadalla, S. M., Cawthon, R., Giri, N., Alter, B. P. & Savage, S. A. Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes. Aging 2, 867–874 (2010).
Goldman, F. R. et al. The effect of TERC haploinsufficiency on the inheritance of telomere length. Proc. Natl Acad. Sci. USA 102, 17119–17124 (2005).
Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011).
Young, N. S. Bone marrow failure and the new telomere diseases: practice and research. Hematology 17 (Suppl. 1), 18–21 (2012).
Polvi, A. T. et al. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am. J. Hum. Genet. 90, 540–549 (2012).
Trahan, C. & Dragon, F. Dyskeratosis congenita mutations in the H/ACA domain of blood of patients with X-linked and autosomal dyskeratosis congenita. Blood Cells Mol. Dis. 27, 353–357 (2009).
Tsakiri, K. D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl Acad. Sci. USA 104, 7552–7557 (2007).
Armanios, M. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).
Armanios, M. Telomerase and idiopathic pulmonary fibrosis. Mutat. Res. 730, 52–58 (2012).
Cronkhite, J. T. et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 729–737 (2008).
Diaz de Leon, A. et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLOS ONE 5, e10680 (2010).
Tsangaris, E. et al. Ataxia and pancytopenia caused by a mutation in TINF2. Hum. Genet. 124, 507–513 (2008).
Vulliamy, T., Marrone, A., Dokal, I. & Mason, P. J. Association between aplastic anaemia and mutations in telomerase RNA. Lancet 359, 2168–2170 (2002).
Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005).
Calado, R. T. et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc. Natl Acad. Sci. USA 106, 1187–1192 (2009).
Touzot, F. et al. Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome. Proc. Natl Acad. Sci. USA 107, 10097–10102 (2010).
Holohan, B. et al. Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency. BMC Genomics 17 (Suppl. 9), 80–87 (2016).
Dekker, J. & Mirny, L. The 3D genome as moderator of chromosomal communication. Cell 164, 1110–1120 (2016).
Chandra, T. & Kirschner, K. Chromosome organization during ageing and senescence. Curr. Opin. Cell Biol. 40, 161–167 (2016).
Rowley, M. J. & Corces, V. G. The three-dimensional genome: principles and roles of long-distance interactions. Curr. Opin. Cell. Biol. 40, 8–14 (2016).
Canela, A. et al. Genome organization drives chromosome fragility. Cell 170, 507–521 (2017).
Gottschling, D. E., Aparicio, O. M., Billinton, B. L. & Zakian, V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63, 751–762 (1990).
Kulkarni, A., Zschenker, O., Reynolds, G., Miller, D. & Murnane, J. P. Effect of telomere proximity on telomere position effect, chromosome healing, and sensitivity to DNA double-strand breaks in a human tumor cell line. Mol. Cell. Biol. 30, 578–589 (2010).
Baur, J. A., Zou, Y., Shay, J. W. & Wright, W. E. Telomere position effect in human cells. Science 292, 2075–2077 (2001).
Bolzan, A. D. Interstitial telomeric sequences in vertebrate chromosomes: Origin, function, instability, and evolution. Mutat. Res. 773, 51–65 (2017).
Burla, R., La Torre, M. & Saggio, I. Mammalian telomeres and their partnership with lamins. Nucleus 7, 187–202 (2016).
Simonet, T. et al. The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats. Cell Res. 21, 1028–1038 (2011).
Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (2001).
Rose, R. & Charlesworth, B. A test of evolutionary theories of senescence. Nature 287, 141–142 (1980).
Partridge, L. Evolutionary theories of ageing applied to long-lived organisms. Exp. Gerontol. 36, 641–650 (2001).
Williams, P. D. & Day, T. Antagonists pleiotropy, mortality source interactions, and the evolutionary theory of senescence. Evolution 57, 1478–1488 (2003).
Shay, J. W. Telomeres and aging. Curr. Opin. Cell Biol. 52, 1–7 (2018).
Luke, B. & Lingner, J. TERRA: telomere repeat-containing RNA. EMBO J. 28, 2503–2510 (2009).
Chen, J.-L., Blasco, M. A. & Greider, C. W. Secondary structure of vertebrate telomerase RNA. Cell 100, 503–514 (2000).
Gillis, A. J., Schuller, A. P. & Skordalakes, E. Structure of the Tribolium castaneum telomerase catalytic subunit. Nature 455, 633–637 (2008).
Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013).
Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013).
Sandin, S. & Rhodes, D. Telomerase structure. Curr. Opin. Struct. Biol. 25, 104–110 (2014).
Nguyen, T. H. D. et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature 557, 190–196 (2018).
Jiang, J. et al. Structure of telomerase with telomeric DNA. Cell 173, 1179–1190 (2018).
Sarek, G., Vannier, J. B., Panier, S., Petrini, J. H. & Boulton, S. J. TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding. Mol. Cell 57, 622–635 (2015).
Walne, A. J., T. Vulliamy, T., Kirwan, M., Plagnol, V. & Dokal, I. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am. J. Hum. Genet. 92, 448–453 (2013).
Vannier, J. B. J. B., Pavicic-Kaltenbrunner, V., Petalcorin, M. I., Ding, H. & Boulton, S. J. RTEL1 dismantles T Loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149, 795–806 (2012).
Ding, H. et al. Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell 117, 873–886 (2004).
Ballew, B. J. et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum. Genet. 132, 473–480 (2013).
Ballew, B. J. et al. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLOS Genet. 9, e1003695 (2013).
Zhong, F. et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25, 11–16 (2011).
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).
Burris, A. M. et al. Hoyeraal-Hreidarsson Syndrome due to PARN mutations: fourteen years of follow-up. Pediatr. Neurol. 56, 62–68 (2015).
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).
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).
Metcalfe, A. et al. Accelerated telomere shortening in ataxia telangiectasia. Nat. Genet. 13, 350–353 (1996).
Smilenov, L. B. et al. Influence of ATM function on telomere metabolism. Oncogene 15, 2659–2665 (1997).
Wood, L. D. et al. Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression. Oncogene 20, 278–288 (2001).
Wong, K. K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003).
Zimmermann, M. M., Kibe, T., Kabir, S. & de Lange, T. TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling. Genes Dev. 28, 2477–2491 (2014).
Du, X. et al. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes. Mol. Cell. Biol. 24, 8437–8446 (2004).
Kellermayer, R. The versatile RECQL4. Genet. Med. 8, 213–216 (2006).
Van Maldergem, L. et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J. Med. Genet. 43, 148–152 (2006).
Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat. Genet. 36, 877–882 (2004).
Crabbe, L. L., Jauch, A., Naeger, C. M., Holtgreve-Grez, H. & Karlseder, J. Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc. Natl Acad. Sci. USA 104, 2205–2210 (2007).
Crabbe, L. L., Verdun, R. E., Haggblom, C. I. & Karlseder, J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306, 1951–1953 (2004).
Opresko, P. L. et al. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol. Cell 14, 763–774 (2004).
Edwards, D. N., Orren, D. K. & Machwe, A. Strand exchange of telomeric DNA catalyzed by the Werner syndrome protein (WRN) is specifically stimulated by TRF2. Nucleic Acids Res. 42, 7748–7761 (2014).
Romero, D. P. & Blackburn, E. H. A conserved secondary structure for telomerase RNA. Cell 67, 343–353 (1991).
This work was supported by the National Institutes of Health (NIH) (AG01228), the Harold Simmons National Cancer Institute Designated Comprehensive Cancer Center support grant (CA142543) and the Southland Financial Corporation Distinguished Chair in Geriatric Research. This work was performed in laboratories constructed with support from the NIH (C06 RR30414). Owing to limited space, the authors apologize for not including all the advances in this field.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jerry W. Shay and Woodring Wright’s homepage: http://www4.utsouthwestern.edu/cellbio/shay-wright/index.html
Telomerase Database: http://telomerase.asu.edu/
- Alternative lengthening of telomeres
(ALT). A telomerase-independent mechanism of maintaining telomere length that involves DNA recombination events.
The thread-like structure in the nucleus that carries genetic information. A normal human cell has 23 pairs of chromosomes (46 total chromosomes). Twenty-two pairs are called somatic or body chromosomes. The remaining two chromosomes are called sex chromosomes and determine whether a person is a male or a female.
- Genetic anticipation
A genetic disorder that is passed on to the next generation with an earlier age of disease and an increase in severity of disease. In the telomere field, this can be due to germline transmission of shorter telomeres in succeeding generations.
- Hayflick limit
The inability of cells to divide (replicate) indefinitely in culture.
The process of cellular ageing generally thought to be irreversible. Senescence can be initiated by short telomeres and by genotoxic stressors (in an occurrence often termed premature senescence).
A six-member protein complex associated with telomeric DNA that protects the telomeres from being recognized as damaged DNA needing repair.
The ribonucleoprotein enzyme complex that adds telomeric sequences to telomeres and has been associated with cellular immortality.
The long natural end sequences of a chromosome composed of repetitive DNA sequences (such as hexameric, TTAGGGn repeats in mammals).
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Shay, J.W., Wright, W.E. Telomeres and telomerase: three decades of progress. Nat Rev Genet 20, 299–309 (2019). https://doi.org/10.1038/s41576-019-0099-1
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