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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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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