Abstract
SWI/SNF component SMARCB1's C-terminal domain binds nucleosomes and mediates chromatin remodeling.
Major Finding: SWI/SNF component SMARCB1's C-terminal domain binds nucleosomes and mediates chromatin remodeling.
Concept: Disease-associated mutations map to parts of the C-terminal domain involved in nucleosome binding.
Impact: This study identifies a mechanistic role for SMARCB1's C-terminal domain, which may be targetable.
Mutations affecting components of mammalian switch/sucrose nonfermentable (mSWI/SNF) chromatin-remodeling complexes are associated with several diseases, with mutations in the C-terminal domain (CTD) of the SMARCB1 (also known as BAF47) subunit causing the intellectual disorder Coffin-Siris syndrome (CSS) and being associated with several cancers. Valencia and colleagues found that recurrent mutations affecting single amino-acid residues of the SMARCB1 CTD did not prevent SMARCB1 from stably incorporating into mSWI/SNF complexes in vitro. However, the same mutations led to reduced mSWI/SNF-mediated nucleosome remodeling and ATPase activity when bound to nucleosome substrates, but not to free DNA. Structural studies implied that the SMARCB1 CTD contains a single alpha helix flanked on each side by a dynamic random coil, and this alpha helix possessed a cluster of basic amino-acid residues known to be affected by missense mutations in many patients with CSS; further analyses demonstrated the SMARCB1 CTD's direct role in binding a nucleosomal acidic patch. Unexpectedly, experiments in human cell lines showed that CSS-associated SMARCB1 mutations did not affect genome-wide targeting or alter histone H3 lysine 27 acetylation; however, further investigation revealed that SMARCB1 with CSS-associated mutations was not as capable as wild-type SMARCB1 at increasing chromatin accessibility at its binding sites. In induced pluripotent human stem cells, SMARCB1 mutations associated with CSS inhibited neuronal differentiation, consistent with the intellectual disability characteristic of CSS. Together, these in vitro and cell-based studies support a crucial role for SMARCB1's CTD and identify the CTD–nucleosome interface as a site that might be targetable with small molecules to alter mSWI/SNF-mediated chromatin remodeling.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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