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The molecular basis of selective DNA binding by the BRG1 AT-hook and bromodomain.

Abstract
The ATP-dependent BAF chromatin remodeling complex plays a critical role in gene regulation by modulating chromatin architecture, and is frequently mutated in cancer. Indeed, subunits of the BAF complex are found to be mutated in >20% of human tumors. The mechanism by which BAF properly navigates chromatin is not fully understood, but is thought to involve a multivalent network of histone and DNA contacts. We previously identified a composite domain in the BRG1 ATPase subunit that is capable of associating with both histones and DNA in a multivalent manner. Mapping the DNA binding pocket revealed that it contains several cancer mutations. Here, we utilize SELEX-seq to investigate the DNA specificity of this composite domain and NMR spectroscopy and molecular modelling to determine the structural basis of DNA binding. Finally, we demonstrate that cancer mutations in this domain alter the mode of DNA association.
AuthorsJulio C Sanchez, Liyang Zhang, Stefania Evoli, Nicholas J Schnicker, Maria Nunez-Hernandez, Liping Yu, Jeff Wereszczynski, Miles A Pufall, Catherine A Musselman
JournalBiochimica et biophysica acta. Gene regulatory mechanisms (Biochim Biophys Acta Gene Regul Mech) Vol. 1863 Issue 8 Pg. 194566 (08 2020) ISSN: 1876-4320 [Electronic] Netherlands
PMID32376391 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Chromatin
  • Histones
  • Nuclear Proteins
  • Transcription Factors
  • DNA
  • SMARCA4 protein, human
  • DNA Helicases
Topics
  • Base Pairing
  • Chromatin
  • Chromatin Assembly and Disassembly
  • DNA (metabolism)
  • DNA Helicases (chemistry, genetics, metabolism)
  • Gene Expression Regulation
  • Histones (metabolism)
  • Humans
  • Molecular Dynamics Simulation
  • Mutation
  • Neoplasms (genetics)
  • Nuclear Proteins (chemistry, genetics, metabolism)
  • Protein Conformation
  • Protein Domains
  • Transcription Factors (chemistry, genetics, metabolism)

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