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Title

Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin

Authors
Stanton, Benjamin Z
Hodges, Courtney
Calarco, Joseph P
Ku, Wai Lim
Kadoch, Cigall
Zhao, Keji
Crabtree, Gerald R
Published in Nature genetics. 2017, vol. 49, no. 2, p. 282-288
Abstract Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs). This opposition underlies the tumor-suppressive role of BAF subunits and is expected to contribute to neurodevelopmental disorders. However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity. We show that point mutations in SMARCA4 (also known as BRG1) mapping to the ATPase domain cause loss of direct binding between BAF and PRC1 that occurs independently of chromatin. Release of this direct interaction is ATP dependent, consistent with a transient eviction mechanism. Using a new chemical-induced proximity assay, we find that BAF directly evicts Polycomb factors within minutes of its occupancy, thereby establishing a new mechanism for the widespread BAF-PRC opposition underlying development and disease.
Keywords Adenosine Triphosphatases/geneticsAdenosine Triphosphate/geneticsAnimalsCell Cycle Proteins/geneticsChromatin/geneticsChromatin Assembly and Disassembly/geneticsDNA Helicases/geneticsDNA-Binding Proteins/geneticsMiceNeurodevelopmental Disorders/geneticsNuclear Proteins/geneticsPoint Mutation/geneticsPolycomb-Group Proteins/geneticsTranscription Factors/genetics
Identifiers
PMID: 27941795
Full text
Research group Régulation de la chromatine dans le développement du cerveau (1031)
Citation
(ISO format)
STANTON, Benjamin Z et al. Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. In: Nature Genetics, 2017, vol. 49, n° 2, p. 282-288. doi: 10.1038/ng.3735 https://archive-ouverte.unige.ch/unige:154532

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Deposited on : 2021-09-08

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