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Role of Chromatin and Transcriptional Regulation in the DNA Damage Response

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Abstract

DNA is the repository of genetic information and thus, it is important to maintain its integrity over time and generations. However, DNA can be damaged by a multitude of endogenous and exogenous damaging agents leading to genome instability. In order to maintain genomic integrity and organismal fitness, organisms have evolved highly conserved mechanisms – collectively termed the DNA damage response (DDR) – that coordinate key biological processes needed to repair damaged DNA, including cell cycle arrest, gene regulation, DNA repair and programmed cell death. As a first step, the DDR includes the recognition of the DNA lesion in the context of the local chromatin landscape followed by activation of signaling cascades and transcriptional programs, depending on the type of DNA damage. Two critical, but as yet poorly understood aspects of the DDR in the plant model, Arabidopsis thaliana, are: (1) the kinetics and regulatory networks controlling the expression of genes orchestrating key biological processes during the DDR and (2) the roles of specific chromatin modifications and chromatin modifying complexes in regulating the process of DNA repair. In the studies comprising my thesis, we worked to shed light on both these knowledge gaps using a combination of genetic, genomic, and biochemical approaches. Chapter one introduces what is currently known about the transcriptional and chromatin-mediated aspects of the DNA damage response, specially focusing on plants. Chapter two presents the development of a temporal model of the Arabidopsis transcriptional response to DNA damage as well as the identification and characterization of key factors that regulate this transcriptional network. Chapter three outlines the setup of a reverse genetic screen to identify candidate chromatin-associated factors required for DNA repair. It also includes the characterization of a candidate chromatin reader, YAF9B, and its homolog YAF9A, in DNA repair. Chapter four concludes by synthesizing the core achievements of the dissertation and suggesting future directions. Together, these chapters have helped understand the multifaceted roles of chromatin in orchestrating DNA repair by revealing the (1) dynamics of transcriptional regulation during the DNA damage response and (2) demonstrating roles for two histone reader proteins, YAF9B and YAF9A, in double strand break repair via homologous recombination-like mechanisms.

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This item is under embargo until September 17, 2023.