期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
卷 1863, 期 8, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbagrm.2020.194566
关键词
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资金
- Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer Institute Award [P30CA086862]
- National Institutes of Health [GM128705, 1R35GM119647]
- National Science Foundation [CAREER-1452411, ACI-1053575, CAREER-1552862]
- interdisciplinary Institutional Training Grant in Pharmacological Sciences [T32 GM067795]
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.
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