Review
Structure and function of SWI/SNF chromatin remodeling complexes and mechanistic implications for transcription

https://doi.org/10.1016/j.pbiomolbio.2010.05.001Get rights and content

Abstract

ATP-dependent chromatin remodeling complexes are specialized protein machinery able to restructure the nucleosome to make its DNA accessible during transcription, replication and DNA repair. During the past few years structural biologists have defined the architecture and dynamics of some of these complexes using electron microscopy, shedding light on the mechanisms of action of these important assemblies. In this paper we review the existing structural information on the SWI/SNF family of the ATP-dependent chromatin remodeling complexes, and discuss their mechanistic implications.

Introduction

Cells have developed several mechanisms to manipulate DNA and tightly package it into chromatin. The building block of chromatin is the nucleosome, which comprises 147 base pairs of DNA wrapped around an octamer of core histones H2A, H2B, H3 and H4 (Luger et al., 1997, Kornberg, 1974). DNA-wrapped nucleosomes assume a spacing of approximately 10–90 bp along the DNA strand. Under physiological conditions, nucleosomal arrays condense into a more compacted and higher-ordered structure known as heterochromatin (Thoma et al., 1979, Widom and Klug, 1985).

Although cells utilize this compaction as a convenient way to store large amounts of DNA, at any given time thousands of genes need to be activated or repressed in a coordinated process, and the chromatin must be remodeled to permit these events. Histone modifying enzymes (reviewed in Wang et al., 2004) and ATP-dependent chromatin remodeling complexes (reviewed in Saha et al., 2006, Clapier and Cairns, 2009) work in concert to regulate this process. Histone-modifying enzymes recognize and covalently mark (by acetylation, methylation, phosphorylation, ribosylation and ubiquitination) specific residues of the histone tails (Strahl and Allis, 2000). ATP-dependent chromatin remodeling complexes specifically recognize these histones marks, and through ATP hydrolysis unwrap, mobilize, exchange or eject the nucleosome, subsequently recruiting the transcriptional apparatus to nucleosomal DNA (Fig. 1; Owen-Hughes, 2003, Levine and Tjian, 2003, Cosma, 2002). In this manner, chromatin structure simultaneously provides a packaging solution and a sophisticated apparatus for regulating gene expression.

ATP-dependent chromatin remodeling complexes are large (>1 MDa) multi-component complexes (consisting of between 4 and 17 subunits) that are highly conserved within eukaryotes. They are characterized by the presence of an ATPase subunit belonging to the superfamily II helicase-related proteins (Singleton and Wigley, 2002). Proteins belonging to this class contain an ATPase domain that is itself comprised of two parts, the DExx and HELICc regions, which are separated by a linker. This class can be further classified into at least 4 different families (SWI/SNF, ISWI, NURD/Mi-2/CHD and INO80) based on the additional presence of unique domains within or adjacent to the ATPase domain (Fig. 2). In this review we will explore the function, the architecture, and the structural implication of the nucleosome remodeling activity of the SWI/SNF family of the ATP-dependent chromatin remodeling complexes.

Section snippets

The SWI/SNF family

The SWI/SNF family of chromatin remodeling complexes was initially discovered in yeast by two independent screenings aimed at identifying mutations in genes that affect the mating-type switching (SWI) and sucrose fermentation (Sucrose Non Fermenting-SNF) pathways (Workman and Kingston, 1998, Sudarsanam and Winston, 2000). A genetic screening for suppressive mutations of the SWI/SNF phenotypes identified different histones and chromatin components, suggesting that these proteins were possibly

Domain organization of the SWI/SNF remodeling complexes

SWI/SNF and RSC complexes contain within their components different protein–protein or protein–DNA interaction modules, which cooperate to achieve the nucleosome remodeling activity. Given the homology between different species, here we focus on the domain composition and organization of the human BAF and PBAF complexes (Fig. 3). The central core, as reported previously, is the ATPase catalytic subunit BRG1/hBRM. This subunit, apart from the HELICc and DExx catalytic domains, also contains four

SWI/SNF dependent nucleosome remodeling mechanism

Chromatin remodeling complexes use the energy of ATP hydrolysis to slide the DNA around the nucleosome (Fig. 4). The first step consists in the binding between the remodeler and the nucleosome. This binding occurs with nanomolar affinity (Lorch et al., 1998) and reduces the digestion of nucleosomal DNA by nucleases (Saha et al., 2005).

Based on single molecule experiments (Zhang et al., 2006), the translocase domain, which has been proposed to be composed of a torsion sub-domain and a tracking

Structures of the SWI/SNF chromatin remodeling complexes

Understanding the structural details by which the SWI/SNF and RSC complexes engage and remodel the nucleosome is one of the open questions in the field of gene regulation. Because of the dimensions, flexibility and the difficulties in obtaining a large amount of sample, electron microscopy and 3D reconstruction have been the structural technique of choice. During the last few years, different structures of the SWI/SNF and RSC complexes have been proposed from different labs.

The first structure

Concluding remarks

Despite the huge amount of genetic, biochemical and structural biology data published during the last several decades, the mechanism by which ATP-dependent remodeling complexes recognize, bind and remodel the nucleosome is still far from being completely understood. High-resolution structure determination will certainly be invaluable for understanding this process in mechanistic detail. Given the dimensions, the complexity and the flexibility of these complexes, high-resolution cryo-EM would be

Acknowledgments

We thank Gabriel C. Lander for critical reading of the manuscript. This work was supported by a Li Ka Shing grant (L.T. and E.N.), and funding from the National Cancer Institute (E.N.) C.C. is a recipient of the American Italian Cancer Foundation. E.N. is a Howard Hughes Medical Institute Investigator.

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