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Role of the fission yeast Taz1p in promoting genomic stability

Miller, Kyle Malcolm; (2004) Role of the fission yeast Taz1p in promoting genomic stability. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Telomeres define the ends of eukaryotic chromosomes and comprise multiprotein complexes bound to terminal DNA sequence repeats. An intrinsic role of telomeres is to protect chromosomal termini from being processed as damaged-induced DNA breaks; this role is critical for maintaining genomic integrity. The fission yeast Taz1 protein regulates telomere functions throughout the mitotic and meiotic cell cycles. In this study, we employed biochemical, molecular and genetic analysis to dissect the regulation and role that taz1+ and other telomere proteins play in promoting genomic stability. We find during growth at low temperatures, loss of taz1+ results in decreased viability, chromosome missegregation and DNA damage checkpoint activation. Strikingly, these cells exhibit entangled chromosomes and a pronounced de novo accumulation of DNA double strand breaks (DSBs). These defects are suppressed by altered topoisomerase II function, implicating unprotected telomeres as substrates for Top2p. Furthermore, taz1δ cells are sensitive to treatments that induce DSBs suggesting a role for Taz1p in general DSB repair. Recent data obtained from 2-D DNA gel electrophoresis suggests that Taz1 is specifically required for telomere replication and that loss of Taz1 results in perturbed fork progression through both telomere and telomere associated sequences. These data suggest a model whereby aberrant replication in taz1δ cells results in entangled chromosomes, leading to a requirement for altered Top2 activity and homologous recombination. These phenotypes are specific to taz1δ cells and not other telomere mutants suggesting that Taz1 plays a central role in promoting genomic stability that is separable from its interacting partners.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Role of the fission yeast Taz1p in promoting genomic stability
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Pure sciences; Telomeres
URI: https://discovery.ucl.ac.uk/id/eprint/10097658
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