Rog, O.; (2008) Characterization and consequences of Telomere replication gone awry. Doctoral thesis , UCL (University College London).

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Abstract

Telomeres, the ends of linear eukaryotic chromosomes, pose several unique challenges to genome stability. My thesis work is concerned with the difficulties the replication machinery encounters when attempting to replicate telomeres, and with possible consequences of defects in telomere replication. The relevance of the DNA replication machinery precipitated while characterizing fission yeast cells lacking the telomeric binding protein Taz1 (a homologue of mammalian TRF1 & 2). In the absence of Taz1, replication forks stall when encountering telomeric sequences, leading to telomere breakage and loss. This unanticipated function of the telomeric complex suggests that telomeric sequences pose an obstacle to the replication machinery. Indeed, further experiments suggested that any repeated sequence has a propensity to cause replication fork stalling, suggesting that our findings may also be applicable to other parts of the genome. Challenges to semi-conservative replication in cells lacking Taz1 are likely to be the underlying cause of another taz1Δ-specific phenomenon: telomere entanglement and loss of viability occurring specifically at cold temperatures. Screening for suppressors of this phenotype led to the identification of two additional factors involved in the etiology of dysfunctional telomeres: the post- translational modification SUMO, and the fission yeast member of the conserved RecQ helicase family, Rqh1. A novel sumoylation deficient allele of Rqh1 was able to suppress several taz1Δ-specific phenomena without dramatically affecting other genome-wide functions of Rqh1. Interestingly, genetic analysis revealed that this allele acts in a loss-of-function manner, suggesting that Rqh1 activity is detrimental for taz1Δ telomeres. Our findings underscore the significance of telomere-specific regulation, as Rqh1, and many other factors participating in telomere metabolism, are not exclusive to telomeres.

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