dc.contributor.advisor | Friedman, Katherine | |
dc.creator | Hoerr, Remington | |
dc.date.accessioned | 2024-05-15T17:19:37Z | |
dc.date.created | 2024-05 | |
dc.date.issued | 2024-03-12 | |
dc.date.submitted | May 2024 | |
dc.identifier.uri | http://hdl.handle.net/1803/18952 | |
dc.description.abstract | The ends of most linear chromosomes are protected by protein-bound repetitive sequences termed telomeres. Telomerase is the reverse transcriptase that extends the TG-rich 3’ overhang of telomeres. Rarely, telomerase acts at internal sequences to form a new or de novo telomere addition. De novo telomere addition results in loss of sequence terminal to the site of telomerase action, but if this occurs in a nonessential region, the new telomere may allow a cell to survive a persistent or irreparable break. In Saccharomyces cerevisiae, telomerase recruitment primarily depends on the single-stranded binding protein Cdc13. Sites of Repair-associated Telomere Addition (SiRTA) are sequences within the S. cerevisiae genome that stimulate de novo telomere addition at unusually high frequencies. In Chapter 2, I describe the identification of a SiRTA that stabilizes acentric linear fragments conferring a selective growth advantage in sulfate-limiting conditions. Characterization of this SiRTA reveals key sequence requirements associated with Cdc13 binding to stimulate de novo telomere addition. Previous reports describe Mec1-dependent inhibition of Cdc13 that prevents de novo telomere addition, only at short TG-tracts adjacent to a double-strand break. In Chapter 3, I describe the characterization of this inhibitory pathway on SiRTA function and show that Mec1-dependent phosphorylation of Cdc13 inhibits de novo telomere addition at a high efficiency SiRTA indicating that this pathway of negative inhibition does not distinguish between short and long TG-tracts in this context. Mec1-dependent inhibition of Cdc13 is opposed by the phosphatase Pph3 and its activator Rrd1. I propose a secondary function of Rrd1 in promoting de novo telomere addition, likely through attenuation of the checkpoint response. This work expands the understanding of inhibition of de novo telomere addition at naturally occurring hotspots of telomere addition. | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dc.subject | telomere addition, DNA repair | |
dc.title | When the Ends Justify the Means: Understanding Mechanisms That Promote De Novo Telomere Addition in Saccharomyces cerevisiae | |
dc.type | Thesis | |
dc.date.updated | 2024-05-15T17:19:37Z | |
dc.type.material | text | |
thesis.degree.name | PhD | |
thesis.degree.level | Doctoral | |
thesis.degree.discipline | Biological Sciences | |
thesis.degree.grantor | Vanderbilt University Graduate School | |
local.embargo.terms | 2026-05-01 | |
local.embargo.lift | 2026-05-01 | |
dc.creator.orcid | 0000-0003-0102-9799 | |
dc.contributor.committeeChair | Graham, Todd | |