Systematic Characterization of BAF Mutations Provides Insights Into Intracomplex Synthetic Lethalities in Human Cancers

Nat Genet. 2019 Sep;51(9):1399-1410. doi: 10.1038/s41588-019-0477-9. Epub 2019 Aug 19.

Abstract

Aberrations in genes coding for subunits of the BRG1/BRM associated factor (BAF) chromatin remodeling complexes are highly abundant in human cancers. Currently, it is not understood how these mostly loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer-type-specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knockout cell lines deficient for 22 BAF subunits. We observe strong, specific and sometimes discordant alterations dependent on the targeted subunit and show that these explain intracomplex codependencies, including the synthetic lethal interactions SMARCA4-ARID2, SMARCA4-ACTB and SMARCC1-SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest approaches to therapeutically target BAF-mutant cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin Assembly and Disassembly / genetics*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Mutation*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome

Substances

  • ARID2 protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • SMARCC1 protein, human
  • SMARCC2 protein, human
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases