@article{3713,
  keywords = {Humans, Transcription Factors, Mutant Proteins, Protein Binding, Mutation, Models, Molecular, HeLa Cells, Amino Acid Sequence, Female, Male, HEK293 Cells, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Nucleosomes, Genome, Human, Chromatin Assembly and Disassembly, Heterozygote, Protein Domains, SMARCB1 Protein},
  author = {Alfredo Valencia and Clayton Collings and Hai Dao and Roodolph St Pierre and Yung-Chih Cheng and Junwei Huang and Zhen-Yu Sun and Hyuk-Soo Seo and Nazar Mashtalir and Dawn Comstock and Olubusayo Bolonduro and Nicholas Vangos and Zoe Yeoh and Mary Dornon and Crystal Hermawan and Lee Barrett and Sirano Dhe-Paganon and Clifford Woolf and Tom Muir and Cigall Kadoch},
  title = {Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling.},
  abstract = { <p>Mammalian switch/sucrose non-fermentable (mSWI/SNF) complexes are multi-component machines that remodel chromatin architecture. Dissection of the subunit- and domain-specific contributions to complex activities is needed to advance mechanistic understanding. Here, we examine the molecular, structural, and genome-wide regulatory consequences of recurrent, single-residue mutations in the putative coiled-coil C-terminal domain (CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual disability disorder Coffin-Siris syndrome (CSS), and are recurrently found in cancers. We find that the SMARCB1 CTD contains a basic α helix that binds directly to the nucleosome acidic patch and that all CSS-associated mutations disrupt this binding. Furthermore, these mutations abrogate mSWI/SNF-mediated nucleosome remodeling activity and enhancer DNA accessibility without changes in genome-wide complex localization. Finally, heterozygous CSS-associated SMARCB1 mutations result in dominant gene regulatory and morphologic changes during iPSC-neuronal differentiation. These studies unmask an evolutionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.</p> },
  year = {2019},
  journal = {Cell},
  volume = {179},
  pages = {1342-1356.e23},
  month = {2019 Nov 27},
  issn = {1097-4172},
  doi = {10.1016/j.cell.2019.10.044},
  language = {eng},
}