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Nat Genet. 2019 Apr;51(4):618-626. doi: 10.1038/s41588-019-0363-5. Epub 2019 Mar 11.

The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity-independent genomic targeting.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
3
Biological and Biomedical Science, Harvard Medical School, Boston, MA, USA.
4
Harvard Medical School, Boston, MA, USA.
5
Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA, USA.
6
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
7
Chemical Biology Program, Harvard Medical School, Boston, MA, USA.
8
Department of Biochemistry and Molecular Genetics, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
9
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Cigall_kadoch@dfci.harvard.edu.
10
Broad Institute of Harvard and MIT, Cambridge, MA, USA. Cigall_kadoch@dfci.harvard.edu.
11
Harvard Medical School, Boston, MA, USA. Cigall_kadoch@dfci.harvard.edu.

Abstract

Perturbations to mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events in cancer1. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)2-5, SMARCA4-deficient thoracic sarcomas6 and dedifferentiated endometrial carcinomas7. However, the consequences of dual ATPase subunit loss on mSWI/SNF complex subunit composition, chromatin targeting, DNA accessibility and gene expression remain unknown. Here we identify an ATPase module of subunits that is required for functional specification of the Brahma-related gene-associated factor (BAF) and polybromo-associated BAF (PBAF) mSWI/SNF family subcomplexes. Using SMARCA4/2 ATPase mutant variants, we define the catalytic activity-dependent and catalytic activity-independent contributions of the ATPase module to the targeting of BAF and PBAF complexes on chromatin genome-wide. Finally, by linking distinct mSWI/SNF complex target sites to tumor-suppressive gene expression programs, we clarify the transcriptional consequences of SMARCA4/2 dual loss in SCCOHT.

PMID:
30858614
DOI:
10.1038/s41588-019-0363-5
[Indexed for MEDLINE]

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