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Nature. 2010 Sep 9;467(7312):223-7. doi: 10.1038/nature09374.

HAATI survivors replace canonical telomeres with blocks of generic heterochromatin.

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


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 activities. 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 ends. Here we describe an alternative mode of linear chromosome maintenance in which canonical telomeres are superseded by blocks of heterochromatin.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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