Interdisciplinary Graduate Program
Program in Molecular Medicine
First Thesis Advisor
Craig Peterson, PhD
Chromatin, Chromatin Assembly and Disassembly, DNA, Double-Stranded DNA Breaks, DNA Repair, Non-Histone Chromosomal Proteins, Histones
Dissertations, UMMS; Chromatin; Chromatin Assembly and Disassembly; DNA; DNA Breaks, Double-Stranded; DNA Repair; Chromosomal Proteins, Non-Histone; Histones
DNA double-strand break (DSB) repair is essential for maintenance of genome stability. However, the compaction of the eukaryotic genome into chromatin creates an inherent barrier to any DNA-mediated event, such as during DNA repair. This demands that there be mechanisms to modify the chromatin structure and thus access DNA. Recent work has implicated a host of chromatin regulators in the DNA damage response and several functional roles have been defined. Yet the mechanisms that control their recruitment to DNA lesions, and their relationship with concurrent histone modifications, remain unclear. We find that efficient DSB recruitment of many yeast chromatin regulators is cell-cycle dependent. Furthering this, we find recruitment of the INO80, SWR-C, NuA4, SWI/SNF, and RSC enzymes is inhibited by the non-homologous end joining machinery, and that their recruitment is controlled by early steps of homologous recombination. Strikingly, we find no significant role for H2A.X phosphorylation (γH2AX) in the recruitment of chromatin regulators, but rather that their recruitment coincides with reduced levels of γH2AX. We go on to determine the chromatin remodeling enzyme Fun30 functions in histone dynamics surround a DSB, but does not significantly affect γH2AX dynamics. Additionally, we describe a conserved functional interaction among the chromatin remodeling enzyme, SWI/SNF, the NuA4 and Gcn5 histone acetyltransferases, and phosphorylation of histone H2A.X. Specifically, we find that the NuA4 and Gcn5 enzymes are both required for the robust recruitment of SWI/SNF to a DSB, which in turn promotes the phosphorylation of H2A.X.
Bennett, GM. Chromatin Regulators and DNA Repair: A Dissertation. (2014). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 742. DOI: 10.13028/M2PS3D. https://escholarship.umassmed.edu/gsbs_diss/742
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