SWI/SNF complex in disorder

Heterozygous germline mutations in components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes were recently identified in patients with non-syndromic intellectual disability, Coffin-Siris syndrome and Nicolaides-Baraitser syndrome. The common denominator of the phenotype of these patients is severe intellectual disability and speech delay. Somatic and germline mutations in SWI/SNF components were previously implicated in tumor development. This raises the question whether patients with intellectual disability caused by SWI/SNF mutations in the germline are exposed to an increased risk of developing cancer. Here we compare the mutational spectrum of SWI/SNF components in intellectual disability syndromes and cancer, and discuss the implications of the results of this comparison for the patients.     

X-ray structures of the Sulfolobus solfataricus SWI2/SNF2 ATPase core and its complex with DNA

SWI2/SNF2 ATPases remodel chromatin or other DNA:protein complexes by a poorly understood mechanism that involves ATP-dependent DNA translocation and generation of superhelical torsion. Crystal structures of a dsDNA-translocating SWI2/SNF2 ATPase core from Sulfolobus solfataricus reveal two helical SWI2/SNF2 specific subdomains, fused to a DExx box helicase-related ATPase core. Fully base paired duplex DNA binds along a central cleft via both minor groove strands, indicating that SWI2/SNF2 ATPases travel along the dsDNA minor groove without strand separation. A structural switch, linking DNA binding and the active site DExx motif, may account for the stimulation of ATPase activity by dsDNA. Our results suggest that torque in remodeling processes is generated by an ATP-driven screw motion of DNA along the active site cleft. The structures also redefine SWI2/SNF2 functional motifs and uncover unexpected structural correlation of mutations in Cockayne and X-linked mental retardation syndromes.     

Advances in the role of SWI/SNF complexes in tumours

Cancer development is a complex process involving both genetic and epigenetic changes. The SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, one of the most studied ATP-dependent complexes, plays an important role in coordinating chromatin structural stability, gene expression and post-translational modifications. The SWI/SNF complex can be classified into BAF, PBAF and GBAF according to their constituent subunits. Cancer genome sequencing studies have shown a high incidence of mutations in genes encoding subunits of the SWI/SNF chromatin remodelling complex, with abnormalities in one or more of these genes present in nearly 25% of all cancers, which indicating that stabilizing normal expression of genes encoding subunits in the SWI/SNF complex may prevent tumorigenesis. In this paper, we will review the relationship between the SWI/SNF complex and some clinical tumours and its mechanism of action. The aim is to provide a theoretical basis to guide the diagnosis and treatment of tumours caused by mutations or inactivation of one or more genes encoding subunits of the SWI/SNF complex in the clinical setting.     

lin-35/Rb cooperates with the SWI/SNF complex to control Caenorhabditis elegans larval development

Null mutations in lin-35, the Caenorhabditis elegans ortholog of the mammalian Rb protein, cause no obvious morphological defects. Using a genetic approach to identify genes that may function redundantly with lin-35, we have isolated a mutation in the C. elegans psa-1 gene. lin-35; psa-1 double mutants display severe developmental defects leading to early larval arrest and adult sterility. The psa-1 gene has previously been shown to encode a C. elegans homolog of yeast SWI3, a critical component of the SWI/SNF complex, and has been shown to regulate asymmetric cell divisions during C. elegans development. We observed strong genetic interactions between psa-1 and lin-35 as well as a subset of the class B synMuv genes that include lin-37 and lin-9. Loss-of-function mutations in lin-35, lin-37, and lin-9 strongly enhanced the defects of asymmetric T cell division associated with a psa-1 mutation. Our results suggest that LIN-35/Rb and a certain class B synMuv proteins collaborate with the SWI/SNF protein complex to regulate the T cell division as well as other events essential for larval growth.     

Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits

Protein complexes of the SWI/SNF family remodel nucleosome structure in an ATP-dependent manner. Each complex contains between 8 and 15 subunits, several of which are highly conserved between yeast, Drosophila, and humans. We have reconstituted an ATP-dependent chromatin remodeling complex using a subset of conserved subunits. Unexpectedly, both BRG1 and hBRM, the ATPase subunits of human SWI/SNF complexes, are capable of remodeling mono-nucleosomes and nucleosomal arrays as purified proteins. The addition of INI1, BAF155, and BAF170 to BRG1 increases remodeling activity to a level comparable to that of the whole hSWI/SNF complex. These data define the functional core of the hSWI/SNF complex.     

SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability

Heterozygous germline mutations in components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes were recently identified in patients with non-syndromic intellectual disability, Coffin-Siris syndrome and Nicolaides-Baraitser syndrome. The common denominator of the phenotype of these patients is severe intellectual disability and speech delay. Somatic and germline mutations in SWI/SNF components were previously implicated in tumor development. This raises the question whether patients with intellectual disability caused by SWI/SNF mutations in the germline are exposed to an increased risk of developing cancer. Here we compare the mutational spectrum of SWI/SNF components in intellectual disability syndromes and cancer, and discuss the implications of the results of this comparison for the patients.     

Direct interaction between Rsc6 and Rsc8/Swh3,two proteins that are conserved in SWI/SNF-related complexes.

The RSC complex of Saccharomyces cerevisiae is closely related to the SWI/SNF complex. Both complexes are involved in remodeling chromatin structure and they share conserved components. The RSC proteins Sth1, Rsc8/Swh3, Sfh1 and Rsc6 are homologs of the SWI/SNF proteins Swi2/Snf2, Swi3, Snf5 and Swp73 respectively. To investigate the RSC complex, we isolated a temperature-sensitive swh3 allele. A screen for multicopy suppressors yielded plasmids carrying the RSC6 and MAK31 loci. RSC6 also suppressed the formamide sensitivity of a strain with a C-terminal truncation of SWH3 . We show that Swh3 and Rsc6 fusion proteins interact in the two-hybrid system and that the swh3-ts mutation impairs this interaction. Finally, bacterially produced Swh3 and Rsc6 fusion proteins interact in vitro , supporting the genetic evidence for direct interaction between Swh3 and Rsc6 in vivo . We have previously shown that Swh3 also interacts with Sth1. These findings, together with the conservation of these proteins in the SWI/SNF complex and in mammalian SWI/SNF-related complexes, strongly suggest that these proteins form a structural core for the complex.     

Stabilization of chromatin structure by PRC1, a Polycomb complex.

The Polycomb group (PcG) genes are required for maintenance of homeotic gene repression during development. Mutations in these genes can be suppressed by mutations in genes of the SWI/SNF family. We have purified a complex, termed PRC1 (Polycomb repressive complex 1), that contains the products of the PcG genes Polycomb, Posterior sex combs, polyhomeotic, Sex combs on midleg, and several other proteins. Preincubation of PRC1 with nucleosomal arrays blocked the ability of these arrays to be remodeled by SWI/SNF. Addition of PRC1 to arrays at the same time as SWI/SNF did not block remodeling. Thus, PRC1 and SWI/SNF might compete with each other for the nucleosomal template. Several different types of repressive complexes, including deacetylases, interact with histone tails. In contrast, PRC1 was active on nucleosomal arrays formed with tailless histones.