Telomeres and telomerase: three decades of progress
Abstract
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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Telomeres are repetitive DNA structures found in terminal loops at chromosomal ends and stabilized by the Shelterin protein complex.
“Telomeres are repetitive DNA structures found in terminal loops at chromosomal ends and stabilized by the Shelterin protein complex.”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Shay and Wright, 2019
Telomerase activity reconstitution in normal cells leads to telomere elongation, extending their replicative lifespan in culture.
“over, telomerase activity reconstitution in normal cells leads to telomere elongation, extending their replicative lifespan in culture (Bodnar et al., 1998; Shay and Wright, 2019).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Shay and Wright, 2019
Another form of DNA damage, termed telomere-associated foci (TAFs), can exist at telomeres due to oxidative DNA damage at telomeric G-reach repeats, irrespective of telomere length or shelterin loss.
“Another form of DNAdamage, termed telomere-associated foci (TAFs), can exist at telomeres due to oxidative DNA damage at telomeric G-reach repeats, irrespective of telomere length or shelterin loss (de Lange, 2018; Shay and Wright, 2019).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Shay and Wright, 2019
Telomere shortening is the first molecular feature associated with senescence, a result of the DNA end-replication problem during serial passages.
“DNA Damage . The first molecular feature associated with senescence was telomere shortening, a result of the DNA end-replication problem , during serial passages (Shay and Wright, 2019).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Shay and Wright, 2019
This organization renders telomeres unrecognizable by the DNA damage response (DDR) and double-strand DNA break (DSB) repair pathways.
“This organization renders telomeres unrecognizable by the DNA damage response (DDR) and doublestrand DNA break (DSB) repair pathways (de Lange, 2018; Shay and Wright, 2019).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Shay and Wright, 2019
Human somatic cells lack the catalytic subunit of telomerase at a level sufficient to maintain telomeres after repeated cell division, which results in shortening of telomeres due to the end replication problem.
“Human somatic cells lack the catalytic subunit of telomerase at a level sufficient to maintain telomeres after repeated cell division which results in shortening of telomeres due to the end replication problem (Shay and Wright, 2019).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Shay and Wright, 2019
Cites
Specific Association of Human Telomerase Activity with Immortal Cells and Cancer
Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C. B., West, M. D., Ho, P. L. C., Coviello, G. M., Wright, W. E., Weinrich, S. L., & Shay, J. W. (1994) · Science · doi:10.1126/science.7605428 · Cited by 7,091 · see citing works
Self-citationTelomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750 · see citing works
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., & Wright, W. E. (1998) · Science · doi:10.1126/science.279.5349.349 · Cited by 4,975 · see citing works
Self-citationShelterin: the protein complex that shapes and safeguards human telomeres
de Lange, T. (2005) · Genes & Development · doi:10.1101/gad.1346005 · Cited by 3,056 · see citing works
A survey of telomerase activity in human cancer
Shay, J. W., & Bacchetti, S. (1997) · European Journal of Cancer · doi:10.1016/s0959-8049(97)00062-2 · Cited by 2,794 · see citing works
Self-citationTRF2 Protects Human Telomeres from End-to-End Fusions
van Steensel, B., Smogorzewska, A., & de Lange, T. (1998) · Cell · doi:10.1016/s0092-8674(00)80932-0 · Cited by 1,709 · see citing works
A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis
Greider, C. W., & Blackburn, E. H. (1989) · Nature · doi:10.1038/337331a0 · Cited by 1,643 · see citing works
Morin, G. B. (1989) · Cell · doi:10.1016/0092-8674(89)90035-4 · Cited by 1,495 · see citing works
Hemann, M. T., Strong, M. A., Hao, L.-Y., & Greider, C. W. (2001) · Cell · doi:10.1016/s0092-8674(01)00504-9 · Cited by 1,219 · see citing works
Greider, C. W., & Blackburn, E. H. (1987) · Cell · doi:10.1016/0092-8674(87)90576-9 · Cited by 1,150 · see citing works
Vaziri, H., & Benchimol, S. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70109-5 · Cited by 1,003 · see citing works
Armanios, M., & Blackburn, E. H. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3246 · Cited by 982 · see citing works
The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita
Vulliamy, T., Marrone, A., Goldman, F., Dearlove, A., Bessler, M., Mason, P. J., & Dokal, I. (2001) · Nature · doi:10.1038/35096585 · Cited by 960 · see citing works
Adult-onset pulmonary fibrosis caused by mutations in telomerase
Tsakiri, K. D., Cronkhite, J. T., Kuan, P. J., Xing, C., Raghu, G., Weissler, J. C., Rosenblatt, R. L., Shay, J. W., & Garcia, C. K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701009104 · Cited by 894 · see citing works
Self-citationActivation of telomerase in human lymphocytes and hematopoietic progenitor cells
Hiyama, K., Hirai, Y., Kyoizumi, S., Akiyama, M., Hiyama, E., Piatyszek, M. A., Shay, J. W., Ishioka, S., & Yamakido, M. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.8.3711 · Cited by 853 · see citing works
Self-citationControl of Human Telomere Length by TRF1 and TRF2
Smogorzewska, A., van Steensel, B., Bianchi, A., Oelmann, S., Schaefer, M. R., Schnapp, G., & de Lange, T. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.5.1659-1668.2000 · Cited by 768 · see citing works
Mutations in <i>TERT,</i> the Gene for Telomerase Reverse Transcriptase, in Aplastic Anemia
Yamaguchi, H., Calado, R. T., Ly, H., Kajigaya, S., Baerlocher, G. M., Chanock, S. J., Lansdorp, P. M., & Young, N. S. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa042980 · Cited by 723 · see citing works
Correlating telomerase activity levels with human neuroblastoma outcomes
Hiyama, E., Hiyama, K., Yokoyama, T., Matsuura, Y., Piatyszek, M. A., & Shay, J. W. (1995) · Nature Medicine · doi:10.1038/nm0395-249 · Cited by 611 · see citing works
Self-citationDNA sequences of telomeres maintained in yeast
Shampay, J., Szostak, J. W., & Blackburn, E. H. (1984) · Nature · doi:10.1038/310154a0 · Cited by 551 · see citing works
Herbert, B.-S., Pitts, A. E., Baker, S. I., Hamilton, S. E., Wright, W. E., Shay, J. W., & Corey, D. R. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.25.14276 · Cited by 539 · see citing works
Self-citationGomes, N. M. V., Ryder, O. A., Houck, M. L., Charter, S. J., Walker, W., Forsyth, N. R., Austad, S. N., Venditti, C., Pagel, M., Shay, J. W., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00718.x · Cited by 464 · see citing works
Self-citationIn vivo loss of telomeric repeats with age in humans
Lindsey, J., McGill, N. I., Lindsey, L. A., Green, D. K., & Cooke, H. J. (1991) · Mutation Research/DNAging · doi:10.1016/0921-8734(91)90032-7 · Cited by 463 · see citing works
Essential role of limiting telomeres in the pathogenesis of Werner syndrome
Chang, S., Multani, A. S., Cabrera, N. G., Naylor, M. L., Laud, P., Lombard, D., Pathak, S., Guarente, L., & DePinho, R. A. (2004) · Nature Genetics · doi:10.1038/ng1389 · Cited by 462 · see citing works
Armanios, M., Chen, J.-L., Chang, Y.-P. C., Brodsky, R. A., Hawkins, A., Griffin, C. A., Eshleman, J. R., Cohen, A. R., Chakravarti, A., Hamosh, A., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508124102 · Cited by 452 · see citing works
Flow cytometry and FISH to measure the average length of telomeres (flow FISH)
Baerlocher, G. M., Vulto, I., de Jong, G., & Lansdorp, P. M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.263 · Cited by 449 · see citing works
Savage, S. A., Giri, N., Baerlocher, G. M., Orr, N., Lansdorp, P. M., & Alter, B. P. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.10.004 · Cited by 414 · see citing works
Genome Organization Drives Chromosome Fragility
Canela, A., Maman, Y., Jung, S., Wong, N., Callen, E., Day, A., Kieffer-Kwon, K.-R., Pekowska, A., Zhang, H., Rao, S. S. P., et al. (2017) · Cell · doi:10.1016/j.cell.2017.06.034 · Cited by 383 · see citing works
Telomere Lengths, Pulmonary Fibrosis and Telomerase (TERT) Mutations
Diaz de Leon, A., Cronkhite, J. T., Katzenstein, A.-L. A., Godwin, J. D., Raghu, G., Glazer, C. S., Rosenblatt, R. L., Girod, C. E., Garrity, E. R., Xing, C., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010680 · Cited by 377 · see citing works
Aubert, G., Hills, M., & Lansdorp, P. M. (2012) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2011.04.003 · Cited by 342 · see citing works
Vulliamy, T., Beswick, R., Kirwan, M., Marrone, A., Digweed, M., Walne, A., & Dokal, I. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800042105 · Cited by 334 · see citing works
Walne, A. J., Vulliamy, T., Marrone, A., Beswick, R., Kirwan, M., Masunari, Y., Al-Qurashi, F.-H., Aljurf, M., & Dokal, I. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm111 · Cited by 316 · see citing works
Fogarty, P. F., Yamaguchi, H., Wiestner, A., Baerlocher, G. M., Sloand, E., Zeng, W. S., Read, E. J., Lansdorp, P. M., & Young, N. S. (2003) · The Lancet · doi:10.1016/s0140-6736(03)14797-6 · Cited by 277 · see citing works
Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita
Zhong, F., Savage, S. A., Shkreli, M., Giri, N., Jessop, L., Myers, T., Chen, R., Alter, B. P., & Artandi, S. E. (2011) · Genes & Development · doi:10.1101/gad.2006411 · Cited by 262 · see citing works
Telomerase and idiopathic pulmonary fibrosis
Armanios, M. (2012) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2011.10.013 · Cited by 245 · see citing works
Variability at the Telomeres of the Human X/Y Pseudoautosomal Region
Cooke, H. J., & Smith, B. A. (1986) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1986.051.01.026 · Cited by 233 · see citing works
Parry, E. M., Alder, J. K., Qi, X., Chen, J. J.-L., & Armanios, M. (2011) · Blood · doi:10.1182/blood-2010-11-322149 · Cited by 194 · see citing works
Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia
Calado, R. T., Regal, J. A., Hills, M., Yewdell, W. T., Dalmazzo, L. F., Zago, M. A., Lansdorp, P. M., Hogge, D., Chanock, S. J., Estey, E. H., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807057106 · Cited by 184 · see citing works
Shay, J. W. (2018) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.12.001 · Cited by 174 · see citing works
Kirwan, M., Vulliamy, T., Marrone, A., Walne, A. J., Beswick, R., Hillmen, P., Kelly, R., Stewart, A., Bowen, D., Schonland, S. O., et al. (2009) · Human Mutation · doi:10.1002/humu.21115 · Cited by 109 · see citing works
Wood, L. D., Halvorsen, T. L., Dhar, S., Baur, J. A., Pandita, R. K., Wright, W. E., Hande, M. P., Calaf, G., Hei, T. K., Levine, F., et al. (2001) · Oncogene · doi:10.1038/sj.onc.1204072 · Cited by 91 · see citing works
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Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · see citing works
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
Determinants of telomere length across human tissues
Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., Zhang, C., Shinkle, J., Sabarinathan, M., Lin, H., et al. (2020) · Science · doi:10.1126/science.aaz6876 · Cited by 515 · see citing works
Yuan, X., Larsson, C., & Xu, D. (2019) · Oncogene · doi:10.1038/s41388-019-0872-9 · Cited by 450 · see citing works
Vaiserman, A., & Krasnienkov, D. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2020.630186 · Cited by 454 · see citing works
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Moskalev, A., Guvatova, Z., Lopes, I. D. A., Beckett, C. W., Kennedy, B. K., De Magalhaes, J. P., & Makarov, A. A. (2022) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2022.01.007 · Cited by 164 · see citing works
Telomeres as Therapeutic Targets in Heart Disease
Yeh, J.-K., Lin, M.-H., & Wang, C.-Y. (2019) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2019.05.009 · Cited by 49 · see citing works
Deuterium metabolic imaging reports on tert expression and early response to therapy in cancer
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Exploring the anti-aging effects of fisetin in telomerase-deficient progeria mouse model
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“Telomerase, comprising the RNA component (Terc) and reverse transcriptase (Tert), is responsible for preserving telomere length ( Shay & Wright, 2019 ; Wu et al., 2017 ).”
Background
- Authors
- Shay, J. W., & Wright, W. E.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Shay, Jerry W.
- Venue
- Nature Reviews Genetics
- Published
- 2019-02-13
- Volume
- 20
- Issue
- 5
- Pages
- 299-309
- ISSN
- 1471-0056 (ISSN-L)
- 1471-0064
- OpenAlex
- W2914968800
- Cited by
- 924
- References
- 40
- Citations by year
- 2026: 90 · 2025: 118 · 2024: 144 · 2023: 173 · 2022: 134 · 2021: 130 · 2020: 98 · 2019: 35 · 2018: 1
- FWCI
- 11.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- telomeres, telomerase, telomere shortening, cellular senescence, aging, telomerase inhibition, telomere length regulation, gene expression regulation, chromosome ends
- MeSH terms
- Abnormalities, Multiple, Shelterin Complex, Aging, Animals, DNA, Gene Expression Regulation, Humans, Neoplasms, Nuclear Proteins, Progeria, Telomere, Ribonucleoproteins, Small Nuclear, Cell Cycle Proteins, Molecular Chaperones, Telomerase, Ribonucleoproteins, Small Nucleolar, Genomics, Telomere-Binding Proteins, History, 20th Century, History, 21st Century, Telomere Homeostasis
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