Jain, D.; (2010) HAATI: heterochromatin amplification dependent and telomerase independent survival. Doctoral thesis , UCL (University College London).

Abstract

While telomerase-mediated DNA extension is the most commonly used mode of eukaryotic chromosome end maintenance, the requirement of stable chromosome ends for genomic stability has selected for the evolution of alternative strategies. Telomerase deletion leads to progressive loss of telomeric DNA and loss of viability for the majority of cells. However, populations of survivors arise. In fission yeast, these survivors either maintain their telomeres via recombination or survive complete telomere loss by undergoing intra-chromosomal fusion (circularisation) of their chromosomes. Previous work in the lab led to the identification of a novel class of survivors that appear to lack telomeric DNA, but do not circularise their chromosomes. Intriguingly, these novel survivors have amplified either of two classes of repetitive sequences at their chromosome ends, the rDNA or the subtelomeric elements; in the latter case, these elements have also spread throughout the genome. This thesis involves the characterisation of these survivors, named HAATI survivors. The amplified repetitive sequences in HAATI are associated with heterochromatin and we find that the heterochromatin machinery is crucial for HAATI survival. Furthermore, chromosome linearity in HAATI relies on Pot1, a canonical chromosome end protection factor whose recruitment to chromosome ends had been thought to rely on telomere sequences. Our data suggest that Pot1 localises to HAATI chromosome ends via interactions with the heterochromatin machinery and non-telomeric single strand overhangs at the chromosome termini. This discovery not only reveals a previously unrecognised mode by which cancer cells could escape the requirement for telomerase activation, but also provides a tool for studying genomes that sustain unusually high levels of heterochromatinization.

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