Faithin Omaha eBook Collection

Download or read book Investigating the Cellular Response to DNA Damaging Agents Through High-Resolution Phenotyping in Saccharomyces Cerevisiae written by Nikko Paulo Torres and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Genome maintenance is paramount for cell viability. Cells have at their disposal an intricate and versatile set of pathways that repair DNA damage and maintain genome integrity during DNA replication stress. In this thesis I challenge the robustness of these stress response and repair pathways using pairwise drug combinations. I found that synergy is rare and that cells are able to respond to DNA damaging agents with different modes of action. Moreover, synergy was generally reduced when drugs were applied sequentially, supporting the notion that an initial dose of DNA damage primes cells for another. I then investigated the robustness of genome maintenance pathways from the perspective of the proteins that carry out repair and stress response functions. By determining the kinetics of replication stress-induced protein relocalizations previously observed (Tkach et al., 2012), I found that proteins of similar function moved with similar timing, and that relocalization timing is unique for distinct forms of replication stress. A subset of protein relocalizations is regulated by the canonical replication stress signaling cascade. Together, these findings support the notion that robustness of genome maintenance pathways stem from their multifaceted regulation. Finally, I highlight a novel function of the replication stress effector kinase Rad53 in controlling a transcriptional program by regulating Rpn4 localization.