Hebden, A.K.; (2006) The role of telomeres and chromosome linearity in the survival of DNA damage. Doctoral thesis , University of London.

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Abstract

The DNA at the ends of most eukaryotic chromosomes is comprised of repetitive sequences packaged with proteins into structures called telomeres. These complexes differentiate natural chromosome ends from those of DNA breaks and therefore play an important role in maintaining genome integrity. Telomerase maintains telomeres by the addition of DNA repeats to chromosome ends. Disruption of this enzyme leads to loss of telomeric DNA with successive rounds of DNA replication, and in most cases, senescence. Following loss of Trt1, the catalytic subunit of telomerase in fission yeast, a population of cells survive having lost all telomeric DNA. These cells survive by maintaining each of the three chromosomes as individual circles. Reminiscent of strains lacking the telomere binding protein Taz1, circular strains are hypersensitive to agents that induce DNA double strand breaks. Here we present our data into the further understanding of the role telomeres play in survival following damage. A partial suppression of sensitivity is observed upon linearisation of a single chromosome. To further distinguish between the topological issue of chromosome circularity and the presence or absence of telomere sequence, we created strains containing telomere repeats lacking ends, either plasmid based (to allow high copy number) or integrated within the genome. In most cases the presence of telomere repeats did not affect the drug sensitivity. Intriguingly, however, we observed rare survivors with greatly suppressed drug sensitivity upon disruption of telomerase. Analysis shows these strains have survived by a novel mechanism. While they appear to lack the majority of telomeric DNA, they show behaviours distinct from those of typical circular chromosome-containing survivors. Our data suggest that one of these strains survives by amplifying subtelomeric repeat sequences, and the other by amplifying rDNA sequences. These strains have aided us in our understanding of the role telomeres play in survival following genotoxic insult.

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