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Telomerase

Cancer and the knockout mouse

Nature volume 389, pages 551–552 (1997)Cite this article

Telomeres are specialized structures at the ends of linear chromosomes. They usually consist of tandem arrays of a short DNA sequence (TTAGGG in vertebrates) and associated proteins, and they are thought to have at least two essential functions1. First, they stop natural chromosome ends behaving as random breaks, which might otherwise generate interchromosomal fusions and activate DNA-damage-induced cell-cycle arrest. Second, they provide the structural basis for solving the end-replication problem2 — the inability of DNA polymerases to completely replicate the end of a DNA duplex (see box).

Telomerase contains an essential RNA component that provides the template for the specific synthesis of TTAGGG repeats. Blasco et al. used transgenic technology to create a germline deletion of the mTR gene, which encodes the RNA component of mouse telomerase. The authors bred homozygous, null mTR −/− mice which turned out to be both viable and fertile, despite having no detectable telomerase activity. Moreover, the mice have now been maintained for six generations (G1-6). The absence of any initial phenotype is striking. So is the fact that the next few generations have also shown no symptoms, suggesting that the telomerase inhibitors that have been envisaged for cancer therapy will not have any acute toxicity. But telomere shortening is occurring: by the latest generation studied (G6), there is clear evidence of telomere erosion, with around five per cent of chromosomes in embryonic fibroblasts lacking detectable TTAGGG, accompanied by increasingly frequent chromosome fusions.

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Figure 1: Synthesis of telomeric DNA by telomerase.

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Authors and Affiliations

  1. the Department of Pathology, University of Wales College of Medicine, Heath Park, CF4 4XN, Cardiff, UK

    David Wynford-Thomas & David Kipling

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  1. David Wynford-Thomas
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  2. David Kipling
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Wynford-Thomas, D., Kipling, D. Cancer and the knockout mouse. Nature 389, 551–552 (1997). https://doi.org/10.1038/39207

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