Structural studies of the INO80 chromatin remodeler
File(s)
Author(s)
Ayala Hernandez, Rafael
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2019-11
Date Awarded
2020-04
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Zhang, Xiaodong
Sponsor
Imperial College London
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)