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Structural studies of the INO80 chromatin remodeler

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Title: Structural studies of the INO80 chromatin remodeler
Authors: Ayala Hernandez, Rafael
Item Type: Thesis or dissertation
Abstract: The packaging of DNA into chromatin in eukaryotic cells allows large genomes to be contained in the cellular nuclei. Furthermore, it adds a new level of stability and organization of the genome. However, it also creates problems with cellular processes that require access to the DNA, such as transcription, replication and repair of DNA damage, due to the presence of nucleosomes and higher-order chromatin structures. In order to overcome this problem, cells have developed a set of molecular machines able to alter the physical structure of chromatin, known as chromatin remodelers. Chromatin remodelers employ the energy obtained from ATP hydrolysis to perform several activities, such as nucleosome sliding, nucleosome eviction, regular spacing of nucleosomes and histone exchange. They can be composed of one single protein or consist of multi-subunit complexes where several units assemble around a central ATPase of the Snf2-like type of SF2 helicases. Since their initial identification, several remodelers belonging to the four main families (SWI/SNF, CHD1, ISWI and INO80) have been biochemically characterized. Furthermore, over the last five years, structures of several chromatin remodelers of all of the four families bound to a nucleosome substrate have been solved. However, these structures correspond to remodelers with only one or a few subunits, such as Chd1, or comprise only the catalytic ATPase core, such as the nucleosome-bound Snf2 structure. In this work, we present high-resolution cryo-EM structures of the human INO80-nucleosome complex, a chromatin remodeler able to perform nucleosome sliding. These structures provide the first insights about how multi-subunit chromatin remodelers bind nucleosomes. Additionally, by integrating the obtained structural information with previous biochemical data, we have proposed a basic mechanism for the sliding of nucleosomes by INO80.
Content Version: Open Access
Issue Date: Nov-2019
Date Awarded: Apr-2020
URI: http://hdl.handle.net/10044/1/89050
DOI: https://doi.org/10.25560/89050
Copyright Statement: Creative Commons Attribution NonCommercial NoDerivatives Licence
Supervisor: Zhang, Xiaodong
Sponsor/Funder: Imperial College London
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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