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Telomeres and human disease: ageing, cancer and beyond
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Journal Article
Telomeres and human disease: ageing, cancer and beyond
2005
Overview
Key Points
Telomeres are specialized chromatin structures at the ends of chromosomes, which consist of tandem DNA repeats (of TTAGGG) and associated proteins. Telomeres are also bound by nucleosome arrays, which contain epigenetic modifications that are characteristic of constitutive heterochromatin.
Telomeres protect chromosome ends from repair and degradation activities. This function is impaired by both the shortening of TTAGGG repeats to below a critical length, and the loss of telomere-binding proteins.
Dysfunctional telomeres trigger a DNA damage response, which results in cell-cycle arrest or apoptosis. Telomere dysfunction can also lead to end-to-end chromosome fusions, and can interfere with the repair of DNA lesions in non-telomeric regions, resulting in hypersensitivity to various genotoxic agents.
Telomerase is a cellular reverse transcriptase that synthesizes
de novo
telomeric repeats at chromosome ends. Most somatic tissues lack telomerase activity and show progressive telomere shortening coupled to cell division.
Various diseases associated with ageing, including cancer, as well as a number of premature ageing syndromes, are characterized by critically short telomeres. Telomere shortening and the absence of telomerase in normal tissues is a tumour-suppression mechanism. By contrast, tumours aberrantly upregulate telomerase, which elongates short telomeres and allows continuous growth.
Mice that lack telomerase activity age prematurely and are more resistant to cancer. Human premature ageing syndromes that are characterized by short telomeres are recapitulated in the mouse only when in the context of telomerase-deficiency and short telomeres.
The telomerase core components telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), as well as telomerase-interacting protein dyskeratosis congenita 1, dyskerin (DKC1), are mutated in the premature ageing human diseases dyskeratosis congenita and aplastic anaemia.
Several telomere-binding proteins are altered in human cancer and premature ageing syndromes that are characterized by chromosomal instability.
Telomerase and telomere-binding proteins are new potential targets for anti-cancer and anti-ageing therapies.
Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.
Publisher
Nature Publishing Group UK,Nature Publishing Group
