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Cac1p and Rrm3p alter the frequency of epigenetic conversions at the telomeres in S.cerevisiae

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Title: Cac1p and Rrm3p alter the frequency of epigenetic conversions at the telomeres in S.cerevisiae
Author: Oshidari, Roxanne
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Yankulov, Krassimir
Abstract: An epigenetic conversion is any inheritable change in gene expression due to change in chromatin structure and not to DNA sequence. These conversions are integral for functional and developmental differentiation in humans, as well as for the immune-evasiveness of certain pathogens. On the other hand, untimely epigenetic switches can cause certain psychiatric disorders and cancer. Despite their significance, the underlying mechanisms involved in epigenetic conversions are yet to be elucidated. The subtelomeric regions of Saccharomyces cerevisiae undergo relatively frequent epigenetic shifts, and as a result, display variegated expression phenotypes. This makes the subtelomeric regions an ideal model system for studying epigenetic conversions. Preliminary findings suggest that pausing of the replication fork may be involved in epigenetic switching. As such, I have hypothesized that the pausing of replication forks stimulates epigenetic shifts and the deletion of genes involved in the regulation of paused forks will affect frequency of variegation. I further hypothesized that pausing of RNA polymerase II during transcription could similarly affect the frequency of variegation. In this thesis I have used a newly developed variegation assay to determine the frequency of epigenetic shifts at the telomeres of several S.cerevisiae strains. These strains harbor mutations in genes involved in replication fork and transcription pausing. I show that there was no impact on the frequency of epigenetic conversions in the transcriptional pausing (Δspt4 and Δdst1) and the fork stabilizing (Δtof1) mutants. However, deletion of the paused replication fork resolving helicase RRM3 (Δrrm3) caused a loss of variegation phenotype, similar to the phenotype observed in Δcac1 cells. These findings suggest that there may be a relationship between replication fork pausing and epigenetic conversions, and furthermore allude to a possible shared mechanism between Rrm3p and Cac1p at a paused fork.
Date: 2014-12

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