Role of NuA4 histone acetyltransferase complex in DNA damage response pathways
|Abstract:||The organization of the eukaryotic cell genome into chromatin structure is intricately linked to the regulation of many cellular processes. DNA damage response (DDR) takes place in the context of chromatin and the latter plays a central role in the regulation of cellular DDR pathways. The NuA4 histone acetyltransferase (HAT) is a highly conserved multi-subunit complex responsible for acetylation of nucleosomal histone H4 and H2A. It is important for gene expression but also the efficient repair of DNA double-strand breaks (DSBs). Although it was shown that NuA4 is rapidly recruited to chromatin surrounding a DSB, the specific mechanism of this recruitment and NuA4 function after its recruitment remains unknown. My PhD project focuses on investigating NuA4 recruitment mechanism and the functional consequences of this recruitment. Taking advantage of in vitro and in vivo approaches, we found that NuA4 is recruited by the MRX complex to a DSB site and spreads along with DNA resection. After recruitment and spreading, NuA4 participates in DDR through acetylation of nucleosomes to assist their removal. In addition, NuA4 also acetylates key DDR factors, such as RPA and Sae2, to regulate their dynamics and functions. By dissecting NuA4 involvement in specific DDR steps, we found that the complex is involved in different stages of homologous recombination (HR) repair, including resection and D-loop formation, during which it cooperates with another HAT, Gcn5/SAGA. Altogether, the data presented in this thesis delineate the intricate functions of NuA4 in DDR pathways and extend our understanding on how chromatin and its regulation orchestrate chromatin-based cellular processes during DNA repair|
|Document Type:||Thèse de doctorat|
|Open Access Date:||23 May 2019|
|Collection:||Thèses et mémoires|
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