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Research Watch

An ATPase Module Guides Mammalian SWI/SNF Complex Specificity

DOI: 10.1158/2159-8290.CD-RW2019-040 Published May 2019
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  • Major Finding: SMARCA4/2 are required for specifying SWI/SNF subcomplex formation and chromatin remodeling activity.

  • Concept: The ATPase subunits of mammalian SWI/SNF complexes dictate subcomplex formation and functionality.

  • Impact: Altered SWI/SNF targeting underlies selection for dual SWI/SNF ATPase subunit loss in some cancers.

The mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes are responsible for regulating gene expression due to their nucleosome remodeling capacity, and inactivating mutations in the genes encoding either of the mutually exclusive ATPase subunits, SMARCA4 and SMARCA2, occur in a variety of tumor types. Surprisingly, perturbations to both SMARCA4 and SMARCA2 are found in several cancer types, but the consequences of dual SWI/SNF ATPase subunit loss are unknown. Pan and colleagues used a cell line model of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), distinguished by dual SMARCA4/2 loss, to explore how the ATPase subunits regulate mSWI/SNF subcomplex composition and functionality. Extensive biochemical characterization of BAF and PBAF subunits in SMARCA4/2-deficient cell lines identified a residual mSWI/SNF complex that retained DNA-binding ability. However, this residual complex lost the biochemical size profiles that are characteristic of the BAF and PBAF subcomplexes, despite the presence of subcomplex-specific subunits. Chromatin immunoprecipitation–sequencing profiling of the residual complex revealed that even through ATPase-deficient complexes retained DNA-binding ability, their subcomplex-specific genomic targeting patterns were lost. This suggests that mSWI/SNF subcomplexes exhibit a modular organization pattern, wherein the ATPase module determines subcomplex identity and functional specificity. Rescue of the ATPase subunit with catalytically active, dead, or deficient SMARCA4 variants revealed that although rescue of the ATPase subunit restored biochemical subcomplex composition and genomic targeting to enhancer regions, wild-type ATPase activity was required for remodeling activity and subsequent enhancer activation. Catalytically active mSWI/SNF BAF and PBAF subcomplexes also collaborated to rewire transcriptional states, and RNA sequencing revealed that dual SWI/SNF ATPase subunit loss in SCCOHT halts normal ovarian differentiation programs and that a majority of mSWI/SNF-driven gene expression changes, including in tumor-suppressive gene programs, required ATPase activity. These findings identify principles underlying mSWI/SNF complex assembly and function and provide mechanistic insight into the consequences of SMARCA4/2 loss on chromatin state and transcriptional state in SMARCA4/2-deficient cancers.

Pan J, McKenzie ZM, D'Avino AR, Mashtalir N, Lareau CA, St. Pierre R, et al. The ATPase module of mammalian SWI/SNF family complexes mediates subcomplex identity and catalytic activity–independent genomic targeting. Nat Genet 2019 Mar 11 [Epub ahead of print].

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (5)
May 2019
Volume 9, Issue 5
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An ATPase Module Guides Mammalian SWI/SNF Complex Specificity
Cancer Discov May 1 2019 (9) (5) OF6; DOI: 10.1158/2159-8290.CD-RW2019-040

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An ATPase Module Guides Mammalian SWI/SNF Complex Specificity
Cancer Discov May 1 2019 (9) (5) OF6; DOI: 10.1158/2159-8290.CD-RW2019-040
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