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Molecular characterization of inter-telomere and intra-telomere mutations in human ALT cells

Nature Genetics volume 30, pages 301305 (2002) | Download Citation

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Abstract

Telomeres in most immortal cells1,2,3 are maintained by the enzyme telomerase4, allowing cells to divide indefinitely. Some telomerase-negative tumors and immortal cell lines maintain long heterogeneous telomeres by the ALT (alternative lengthening of telomeres) mechanism5,6; such tumors are expected to be resistant to anti-telomerase drug therapies. Occasionally telomerase-negative Saccharomyces cerevisiae mutants survive, and 10% of them (type II survivors) have unstable telomeres7,8. As in human ALT+ cells9, short telomeres in yeast type II survivors lengthen abruptly; in yeast, this is dependent on the recombination proteins Rad52p and Rad50p10. In human cells, ALT involves copying of sequence from a donor to a recipient telomere11. We have characterized for the first time a class of complex telomere mutations seen only in ALT+ cells. The mutant telomeres are defined by the replacement of the progenitor telomere at a discrete point (fusion point) with a different telomere repeat array. Among 19 characterized fusion points, one occurred within the first six repeats of the telomere, indicating that these recombination-like events can occur anywhere within the telomere. One mutant telomere may have been involved in a secondary recombination-like mutation event, suggesting that these mutations are sporadic but ongoing in ALT+ cells. We also identified simple intra-allelic mutations at high frequency, which evidently contribute to telomere instability in ALT+ cells.

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Acknowledgements

We thank A.J. Jeffreys and C. May for their valuable comments on the manuscript. The work was funded by a UK Medical Research Council component group grant (to N.J.R.) and funding (to R.R.) from the Carcinogenesis Fellowship of the New South Wales Cancer Council. H.A.P. was supported by a UK-MRC studentship.

Author information

Affiliations

  1. Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH, UK.

    • Helen Varley
    • , Hilda A. Pickett
    • , Jennifer L. Foxon
    •  & Nicola J. Royle
  2. Cancer Research Unit, Children's Medical Research Institute, Westmead, Sydney, Australia.

    • Roger R. Reddel

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Correspondence to Nicola J. Royle.

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https://doi.org/10.1038/ng834

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