Title | The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity-independent genomic targeting. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Pan J, McKenzie ZM, D'Avino AR, Mashtalir N, Lareau CA, St Pierre R, Wang L, Shilatifard A, Kadoch C |
Journal | Nat Genet |
Volume | 51 |
Issue | 4 |
Pagination | 618-626 |
Date Published | 2019 04 |
ISSN | 1546-1718 |
Keywords | Adenosine Triphosphatases, Animals, Catalysis, Chromatin, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, Genomics, Mammals, Transcription Factors |
Abstract | Perturbations to mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events in cancer. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), SMARCA4-deficient thoracic sarcomas and dedifferentiated endometrial carcinomas. 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. |
DOI | 10.1038/s41588-019-0363-5 |
Alternate Journal | Nat. Genet. |
PubMed ID | 30858614 |
PubMed Central ID | PMC6755913 |
Grant List | DP2 CA195762 / CA / NCI NIH HHS / United States T32 GM096911 / GM / NIGMS NIH HHS / United States |
Submitted by api_import on December 23, 2019 - 10:21am