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Cancer-Associated Gain-of-Function Mutations Activate a SWI/SNF-Family Regulatory Hub

Cedric R Clapier1, Naveen Verma1, Timothy J Parnell2

  • 1Department of Oncological Sciences and Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.

Molecular Cell
|October 15, 2020
PubMed

Insights

Cancer-associated mutations in BRG1 can either disable or enhance SWI/SNF chromatin remodelers. Gain-of-function mutations increase DNA translocation and chromatin accessibility, revealing a structural hub mechanism for cancer hyperactivity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • SWI/SNF-family remodelers (BAF/PBAF) are crucial chromatin regulators.
  • Mutations in these components are linked to approximately 20% of human cancers.
  • Previous studies identified cancer-associated BRG1 mutations as loss-of-function.

Purpose of the Study:

  • To investigate the functional consequences of cancer-associated BRG1 mutations in the yeast RSC remodeler.
  • To elucidate the structural and mechanistic basis of SWI/SNF ATPase activity regulation.
  • To understand how specific mutations lead to altered DNA translocation and chromatin remodeling.

Main Methods:

  • Site-directed mutagenesis of the Sth1 ATPase (yeast ortholog of BRG1).
  • In vitro biochemical assays to measure ATPase activity and nucleosome remodeling.
  • Structural analysis of a key regulatory hub within the Sth1 remodeler.
  • In vivo assessment of chromatin accessibility in yeast models.

Main Results:

  • Cancer-associated BRG1 mutations segregated into loss-of-function and gain-of-function categories in the Sth1 remodeler.
  • Gain-of-function mutations significantly enhanced DNA translocation efficiency and nucleosome remodeling in vitro.
  • A structural hub involving multiple Sth1 domains was identified as critical for regulating ATPase activity and DNA translocation.
  • Gain-of-function mutations localized to regions regulating DNA translocation, while loss-of-function mutations affected its implementation.
  • Only gain-of-function mutations led to increased chromatin accessibility in vivo.

Conclusions:

  • Cancer-associated BRG1 mutations can confer gain-of-function activity to SWI/SNF remodelers.
  • A specific structural hub in the ATPase regulates DNA translocation and remodeling efficiency.
  • Gain-of-function mutations promote hyperactivity by enhancing DNA translocation, leading to precocious chromatin accessibility.
  • This study provides a mechanistic link between specific mutations, altered enzyme function, and cancer-associated chromatin changes.
Keywords:
BAFBRG1DNA accessibilityRSCSTH1SWI/SNFcancerchromatin remodelingnucleosome

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