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HAATI survivors replace canonical telomeres with blocks of generic heterochromatin

Nature volume 467, pages 223–227 (2010)Cite this article

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Abstract

The notion that telomeres are essential for chromosome linearity stems from the existence of two chief dangers: inappropriate DNA damage response (DDR) reactions that mistake natural chromosome ends for double-strand DNA breaks (DSBs), and the progressive loss of DNA from chromosomal termini due to the end replication problem. Telomeres avert the former peril by binding sequence-specific end-protection factors that control the access of DDR activities1,2. The latter threat is tackled by recruiting telomerase, a reverse transcriptase that uses an integral RNA subunit to template the addition of telomere repeats to chromosome ends3. Here we describe an alternative mode of linear chromosome maintenance in which canonical telomeres are superseded by blocks of heterochromatin. We show that in the absence of telomerase, Schizosaccharomyces pombe cells can survive telomere sequence loss by continually amplifying and rearranging heterochromatic sequences. Because the heterochromatin assembly machinery is required for this survival mode, we have termed it ‘HAATI’ (heterochromatin amplification-mediated and telomerase-independent). HAATI uses the canonical end-protection protein Pot1 (ref. 4) and its interacting partner Ccq1 (ref. 5) to preserve chromosome linearity. The data suggest a model in which Ccq1 is recruited by the amplified heterochromatin and provides an anchor for Pot1, which accomplishes its end-protection function in the absence of its cognate DNA-binding sequence. HAATI resembles the chromosome end-maintenance strategy found in Drosophila melanogaster, which lacks specific telomere sequences but nonetheless assembles terminal heterochromatin structures that recruit end-protection factors. These findings reveal a previously unrecognized mode by which cancer cells might escape the requirement for telomerase activation, and offer a tool for studying genomes that sustain unusually high levels of heterochromatinization.

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Figure 1: Characterization of HAATI strains.
Figure 2: Trt1 addition reveals extensive genomic rearrangements in HAATI cells.
Figure 3: HAATI survival requires Clr4 and Rhp51.
Figure 4: HAATI strains lack terminal telomere sequences but require Pot1 for end-protection.

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Acknowledgements

We thank T. Cech for discussions and gratefully acknowledge that initial work by T.M.N. on reintroducing Trt1 to circular strains was performed in the Cech laboratory. We thank our current and former laboratory members for discussions and advice. This work was supported by Cancer Research UK.

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Authors and Affiliations

  1. Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK ,

    Devanshi Jain & Julia Promisel Cooper

  2. Imperial College London Ovarian Cancer Action Group, London W12 0NN, UK ,

    Anna K. Hebden

  3. Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, 60607, Illinois, USA

    Toru M. Nakamura

  4. Gurdon Institute, Cambridge CB2 1QN, UK ,

    Kyle M. Miller

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  1. Devanshi Jain
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Contributions

D.J. performed the experiments in Figs 3 and 4, Supplementary Figs 6 and 9–17 and Supplementary Tables 1 and 2, and reproduced Figs 1a, b, 2a, d and Supplementary Figs 2 and 8a. A.K.H. first isolated HAATI survivors and performed the experiments in Figs 1 and 2b–d, and Supplementary Figs 2, 4, 5 and 8. T.M.N. performed the experiments in Fig. 2a. K.M.M. first showed that circular strains are hypersensitive to DSB-inducing agents. J.P.C. designed and supervised the study. J.P.C. and D.J. generated the figures and wrote the paper.

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Correspondence to Julia Promisel Cooper.

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The authors declare no competing financial interests.

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The file contains Supplementary Figures 1-17 with legends, Supplementary Tables 1-2 and a Strain Table. (PDF 913 kb)

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Jain, D., Hebden, A., Nakamura, T. et al. HAATI survivors replace canonical telomeres with blocks of generic heterochromatin. Nature 467, 223–227 (2010). https://doi.org/10.1038/nature09374

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