Structure of SWI/SNF chromatin remodeller RSC bound to a nucleosome and implications for chromatin remodelling

Eukaryotic cells condense their DNA into chromatin, which hampers the accessibility of genetic information. Nucleosomes are the smallest building blocks of chromatin and are comprised of an octameric core of histone proteins, around which 145 – 147 base pairs of DNA are tightly wrapped. Fundamental cellular processes such as transcription require free DNA devoid of nucleosomes. To that end, chromatin remodellers are employed to manoeuvre nucleosomes, providing the cell with means to regulate gene expression through DNA accessibility. These large molecular machines are grouped into four families, each dedicated to specific functions. While these families share a similar enzymatic subunit, they differ in auxiliary subunits, which account for most of their mass. Although recent structural and biochemical work has advanced our knowledge on the general mechanism of remodelling, the role of non-enzymatic subunits is still poorly understood. Moreover, the principles underlying their functional diversity despite utilising the structurally and functionally highly similar active subunit remain ambiguous. The multi-subunit chromatin remodelling complexes of the SWI/SNF family are responsible for the formation of nucleosome-depleted regions and transcriptionally active promoters in the eukaryotic genome. Here, we solved the structure of a Saccharomyces cerevisiae SWI/SNF family member, the 16-subunit remodeller RSC, in complex with a nucleosome substrate. The structure reveals a modular architecture and suggests key features of the remodelling mechanism. RSC forms an intricate structure composed of the five intertwined modules: the body, arm, ARP, ATPase and DNA- interaction modules. The body provides a scaffolding base connecting the other modules. The DNA-interacting module grasps extra-nucleosomal DNA and helps recruit RSC to promoters. The ATPase and arm modules sandwich the nucleosome disc with their ‘SnAC’ and ‘finger’ elements, respectively. The dynamic ARP module bridges between the body and the ATPase modules suggesting a regulation mechanism for the remodeller. The translocase motor engages with the edge of the nucleosome at superhelical location +2 to pump DNA along the nucleosome, resulting in a sliding of the histone octamer along DNA. The results presented here elucidate the important roles of the non-enzymatic subunits for chromatin remodelling by large, multi-subunit complexes, and shed light on the formation of nucleosome-depleted regions. Furthermore, the structure of RSC from yeast provides a basis for understanding human chromatin remodellers of the SWI/SNF family and the consequences of many cancer mutations that frequently occur in these complexes