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The Role of RAD51 Paralog and the Replicative Helicase in Mediating DNA Lesion Bypass
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The Role of RAD51 Paralog and the Replicative Helicase in Mediating DNA Lesion Bypass
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Dissertation
The Role of RAD51 Paralog and the Replicative Helicase in Mediating DNA Lesion Bypass
2024
Overview
Preserving genomic integrity hinges upon the meticulous accuracy of DNA replication, which is crucial for preventing cancer. Homologous recombination, particularly mediated by the yeast Shu complex, emerges as a linchpin in ensuring high-fidelity DNA damage tolerance during replication, notably against potent agents like methyl methanesulfonate (MMS). Our investigation into the mechanism underlying the Shu complex’s function in bypassing MMS-induced DNA damage led us to explore its DNA binding preferences, focusing on the Csm2 subunit. Through unbiased genome-wide chromatin immunoprecipitation sequencing, we discovered a significant enrichment of Csm2 at autonomous replicating sequences (ARS). Delving deeper into evolutionary history, we uncovered a co-evolution between yeast and human Shu complexes and specific replication initiation factors. This suggests a symbiotic relationship wherein the Shu complex interfaces intricately with replication initiation machinery, particularly the origin recognition complex (ORC) and the minichromosome maintenance (MCM) complex in G1 and S phases of the cell cycle. Through meticulous experimental endeavors, including yeast two-hybrid assays, ChIP sequencing (chromatin immunoprecipitation followed by DNA sequencing), mutational assay, direct repeat recombination assay, and co-immunoprecipitation experiments, we unveiled a nexus where multiple Shu complex constituents engage in an intricate interplay with replication initiation complexes. Based on our findings, we propose an elegant model wherein the Shu complex, through the conserved N-terminal of Psy3, safeguards DNA replication integrity by facilitating error-free bypass of DNA damage alongside the replication machinery. Overall, our results suggest that these interactions are independent of broader homologous recombination machinery, emphasizing the Shu complex’s unique role in maintaining genetic fidelity via the DNA damage tolerance (DDT) pathway.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9798302182654
